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How are mitochondrial diseases like MERRF inherited?

How are mitochondrial diseases like MERRF inherited?


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I am doing a project on the disorder MERRF in Mitochondrial DNA. I have to make a pedigree and explain how it is transferred on from generation to generation. I know that it is inherited maternally, but I am confused about how it is inherited. Would it be inherited inherited like autosomal DNA in a Mendelian fashion? If so, would this gene be dominant or recessive? Or would the children just automatically inherit whatever gene their mothers have? Also, how would the genotypes for Mitochondrial DNA be displayed? Any other useful information on Mitochondrial DNA or MERRF would also greatly appreciated. Thanks.


Mitochondria are primarily thought to be inherited from the mother but there is evidence now that the father can also contribute mitochondria (Schwartz and Vissing, 2002; Luo et al., 2018).

Even if the mitochondria were purely maternally inherited, a cell (including oocyte) typically contains many mitochondria and not all of the mitochondria may have the (deleterious) mutation. This phenomenon is called heteroplasmy.

MERRF is associated with a loss of function mutation in mitochondrial tRNAs (See NIH, Genetics Home Reference). The extent to which a cell will be affected would depend on number of mutated mitochondria it contains. Therefore different cells would be affected differently.

The trait inheritance would therefore not be in the typical Mendelian fashion.


Rare Disease Database

NORD gratefully acknowledges Kathryn Elliott, MS, NORD Editorial Intern from the Stanford University MS Program in Human Genetics and Genetic Counseling, and Hannah Wand, MS, Clinical Instructor (Affiliated), Dept of Pediatrics, Division of Medical Genetics, Stanford University, for assistance in the preparation of this report.

Synonyms of MERRF Syndrome

  • myoclonic epilepsy associated with ragged red fibers
  • MERRF
  • Fukuhara syndrome
  • myoclonus epilepsy associated with ragged red fibers
  • myoencephalopathy ragged-red fiber disease

General Discussion

MERRF (myoclonus epilepsy with ragged-red fibers) syndrome is an extremely rare disorder that appears in childhood, adolescence or adulthood after normal development early in life. MERRF syndrome affects the nervous system, skeletal muscles and other body systems. The distinguishing feature in MERRF is muscle jerks (myoclonus), consisting of sudden, brief spasms that can affect the arms, legs or entire body. Individuals with MERRF syndrome may also have seizures (generalized epilepsy), impaired ability to coordinate movements (ataxia), muscle weakness (myopathy), exercise intolerance and a slow decline of intellectual function (dementia). Decreased body height (short stature), vision problems (optic atrophy), hearing loss, heart disease of the heart muscles (cardiomyopathy) and abnormal sensation from nerve damage (peripheral neuropathy) are other common symptoms. Individuals with MERRF syndrome will also have abnormal muscle cells that appear as ragged red fibers (RRF) when stained and viewed microscopically.

MERRF syndrome is a mitochondrial disorder. Mitochondria are structures found in the cell that produce energy. Mitochondrial disorders can occur when the mitochondrial genetic material (mtDNA) has a genetic change (mutation) that prevents the mitochondria from carrying out their function. As a result, parts of the body like the brain and muscles may not work properly due to lack of energy. MERRF syndrome is caused by mutations in mtDNA and is inherited from the mother.

Introduction

MERRF syndrome was first reported in 1973 when a family was described with muscle jerks (myoclonus), seizures and abnormal muscle cells showing characteristic ragged red fibers (RRF). By 1988, 25 people had been identified with a similar collection of features. That same year it was determined that MERRF syndrome is caused by mutations in mitochondrial DNA, and two years later, in 1990, the first causal genetic mutation was discovered.

Today MERRF syndrome is typically diagnosed by a combination of clinical features (myoclonus, seizures, and ataxia) and RRF seen on muscle biopsy. However, not all individuals diagnosed with MERRF syndrome will have, or develop, the same symptoms. A molecular diagnosis of MERRF is made when a genetic mutation is identified in a mitochondrial gene that is known to be associated with the condition. A diagnosis of MERRF syndrome can help guide surveillance, treatment of symptoms and possibly aid in prevention of disease progression. A genetic diagnosis can also clarify risk to siblings, parents, extended family members and biological offspring, and can help in family planning.

Signs & Symptoms

Symptoms of MERRF syndrome can begin in childhood, adolescence or early adulthood after a period of normal early development. Signs, symptoms and physical findings associated with MERRF syndrome may vary greatly between affected individuals in the same family and between different families. The age of onset and how quickly the condition progresses can differ between individuals.

Brief, sudden, jerking muscle spasms (myoclonus) is usually the first symptom of MERRF syndrome followed by seizures (generalized epilepsy), impaired ability to coordinate movements (ataxia), muscle weakness (myopathy) and exercise intolerance. Decreased body height (short stature), hearing loss, decline of intellectual function (dementia) and altered sensation (pins-and-needles or pain) from nerve damage (peripheral neuropathy) are also common symptoms. Some individuals may have vision problems or vision loss, most commonly caused by degeneration of the optic nerve (optic atrophy). Vision impairment may also result from drooping upper eyelids (ptosis), progressive damage to the receptors that respond to light in the retina of the eye (pigmentary retinopathy) or weakness of the eye muscles (ophthalmoplegia). Heart problems may also arise, including heart disease of the heart muscle (cardiomyopathy) and problems of the heart rhythm (arrhythmia) such as Wolff-Parkinson-White syndrome. Occasionally, people with MERRF syndrome have benign fat cell tumors (lipomas) especially around the neck, too much sugar in the blood (diabetes mellitus) and involuntary muscle stiffness (spasticity) along with other differences in reflexes and movement (pyramidal signs). People with MERRF syndrome frequently have an accumulation of lactic acid in the blood (lactic acidosis) which can cause vomiting, abdominal pain, decreased appetite, unusual sleepiness or fatigue, muscle pain or weakness and difficulty breathing.

Causes

MERRF syndrome is caused by genetic changes (mutations) in mitochondrial DNA (mtDNA). Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. MtDNA encodes specific genes that are the instructions for making some of the essential parts of the mitochondria.

MERRF syndrome is caused by mutations in the mtDNA. The genes associated with MERRF syndrome are the instructions for specific molecules called transfer RNAs. Transfer RNAs (tRNAs) help assemble proteins, which then carry out the mitochondrial function of producing energy. Mutations in the mtDNA genes associated with MERRF lead to abnormal tRNAs, and consequently reduce the ability of the mitochondria to build proteins and produce energy for the body. Parts of the body that require a lot of energy, like the muscles and brain, will be the most affected by these mutations.

More than 90% of cases of MERRF syndrome are caused by mutations in one mtDNA gene, MT-TK. One specific MT-TK mutation, called m.8344A>G, accounts for 80% of cases. Mutations in MT-TF, MT-TH, MT-TI, MT-TL1, MT-TP, MT-TS1, and MT-TS2 have also been associated with MERRF syndrome.

Genes for mitochondria (mtDNA) are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization. As a result, all human mtDNA comes from the mother. A mother with a non-working gene in mtDNA will pass on the non-working gene to all her children, but only her daughters will pass on the non-working gene to their children.

As cells divide, the number of normal mtDNA and non-working (mutated) mtDNA are distributed in an unpredictable fashion among different tissues. Consequently, mutated mtDNA accumulates at different rates among different tissues in the same individual. Thus, family members who have the identical non-working gene in mtDNA may exhibit a variety of different symptoms at different times and with varying degrees of severity.

Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of mitochondria with the non-working gene may be out-numbered by the number of mitochondria without the non-working gene. Symptoms may not appear in any given generation until a significant proportion of mitochondria have mutated mtDNA. The uneven distribution of normal and mutated mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members.

It is generally thought that a higher number of mutated mtDNA relative to normal mtDNA corresponds with more severe symptoms. However, the number of mutated mtDNA relative to the normal mtDNAs cannot be used to accurately predict if symptoms will present, which symptoms may present or symptom severity.

A few rare cases of MERRF syndrome have occurred as the result of a new spontaneous mutation in a mitochondrial gene in the affected individual. These mutations are not inherited, but may be passed down to future generations if the affected individual is female.

Affected Populations

MERRF syndrome is a rare disorder that affects males and females in equal numbers. Onset of symptoms of MERRF syndrome can occur in childhood, adolescence or early adulthood. It typically presents after a period of normal early development.

The prevalence of MERRF syndrome is unknown. However, several studies of mitochondrial disorders in European populations found that the common MT-TK mutation, m.8344A>G, has a prevalence between 0 and 1.5 per 100,000 adults in northern Finland, 0.39 per 100,000 adults in northern England, between 0 and 0.25 per 100,000 children in western Sweden and 0.7 per 100,000 individuals in northeast England. Consistent with these findings, it is widely considered that the prevalence of MERRF is likely less than 1 per 100,000 individuals.

Some researchers believe that mitochondrial myopathies may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like MERRF syndrome.

Related Disorders

MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome is a disorder that begins in childhood and affects mostly the nervous system and muscle. The most common early symptoms are seizures, recurrent headaches, loss of appetite and recurrent vomiting. Stroke-like episodes with temporary muscle weakness on one side of the body (hemiparesis) may also occur and this can lead to altered consciousness, vision and hearing loss, loss of motor skills and intellectual disability. Diabetes mellitus and paralysis of eye muscle (chronic progressive external ophthalmoplegia) are often present in isolation or in association with other symptoms. MELAS is caused by mutations in mitochondrial DNA (mtDNA). Some mutations that cause MELAS are found in mtDNA genes that are also associated with MERRF syndrome. In one patient, this syndrome has been associated with mutations in a nuclear gene, POLG1. (For more information on this disorder, choose “MELAS” as your search term in the Rare Disease Database.)

Kearns-Sayre syndrome (KSS) is a rare multisystemic disorder. An important clinical symptomatic feature is the presence of droopy eyelids (ptosis) in one or both eyes. This disease is mostly characterized by three primary findings: progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]) abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), or pigmentary retinopathy, leading to poor night vision and progressive vision loss and heart disease such as cardiomyopathy and/or progressive arrhythmia leading to complete heart block. Other findings may include muscle weakness, short stature, sensorineural hearing loss, endocrine issues such as diabetes mellitus and hypoparathyroidism (which can cause hypocalcemia) and/or the loss of ability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). In some patients, KSS may be associated with other disorders and/or conditions. KSS belongs (in part) to a group of rare disorders known as mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in genetic material (DNA) arises from a part of the cell structure (mitochondria), that produces energy (in the form of adenosine triphosphate, or ATP) causing the brain and muscles to function improperly due to lack of energy (encephalomyopathies). In these disorders, abnormally high numbers of defective mitochondria are present. In approximately 80 percent of affected individuals with KSS, tests will reveal missing genetic material (deletion) involving the unique DNA in mitochondria (mtDNA).(For more information on this disorder, choose “Kearns Sayre” as your search term in the Rare Disease Database.)

Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years, but some patients do not exhibit signs and symptoms until several years later. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia) and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome, initially described over 60 years ago. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most patients, Leigh syndrome is inherited in an autosomal recessive pattern. However, X-linked recessive and maternal inheritance, due to a mitochondrial DNA mutation, are seen in some families. (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)

Combined oxidative phosphorylation deficiency is a disease that affects many parts of the body. Onset occurs at or soon after birth in most patients, and features can include growth delay, small head (microcephaly), increased muscle tone, floppiness of the trunk and head, brain disease (encephalopathy), enlarged heart muscle (cardiomyopathy) and liver dysfunction. There are many subtypes, caused by many different gene mutations. Combined oxidative phosphorylation deficiency 27 is characterized by juvenile-onset MERRF-like severe myoclonus epilepsy with ataxia, spastic weakness that affects all four limbs (spastic tetraparesis), vision loss, hearing loss and cognitive decline. It is inherited in an autosomal recessive pattern and is caused by mutations in the CARS2 gene. (For more information on combined oxidative phosphorylation deficiencies, choose “Combined oxidative phosphorylation” as your search term in the Rare Disease Database).

POLG-related disorders are a series of conditions with overlapping symptoms. The disorders include: Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), autosomal recessive progressive external ophthalmoplegia (arPEO) and autosomal dominant progressive external ophthalmoplegia (adPEO). Symptoms and severity of these conditions vary but common features include: movement disorder including muscle spasms (myoclonus), seizures (epilepsy), impaired ability to coordinate movements (ataxia), abnormal sensation from nerve damage (peripheral neuropathy), developmental delay, decreased muscle tone (hypotonia) and muscle weakness (myopathy). These disorders are primarily inherited in an autosomal recessive pattern though some do follow an autosomal dominant pattern of inheritance. All are caused by mutations in the POLG gene.

Diagnosis

MERRF syndrome is diagnosed based on clinical findings and molecular genetic testing.

A clinical diagnosis of MERRF can be made based on the presence of four features: myoclonus (muscle spasms), generalized epilepsy (seizures), ataxia (impaired ability to coordinate movements) and abnormal muscle cells showing ragged red fibers (RRF) when a muscle biopsy is viewed microscopically.

Clinical testing may also reveal other features of MERRF syndrome. Concentrations of lactate and pyruvate are commonly elevated in blood and fluid surrounding the brain and spinal cord (cerebrospinal fluid). Concentrations of lactate and pyruvate may show large increases after moderate physical activity. The concentration of cerebrospinal fluid (CSF) protein may also be elevated in MERRF syndrome. Brain imaging techniques such as magnetic resonance imaging (MRI) may show stroke-like lesions or degeneration of cells (atrophy) and magnetic resonance spectroscopy (MRS) is used to look for lactate in the brain. Electroencephalogram (EEG) measures electrical activity in the brain and can help diagnose seizures. Electrocardiogram (EKG) may be used to diagnose heart rhythm abnormalities. Nerve conduction velocity studies may be consistent with a myopathy or a neuropathy in individuals with MERRF syndrome.

A molecular diagnosis of MERRF syndrome is made when an individual who has symptoms consistent with the syndrome is found to have a mutation in a mtDNA gene associated with MERRF. A molecular diagnosis can confirm a clinical diagnosis of MERRF syndrome or help clarify a diagnosis when a clinical diagnosis cannot be made because symptoms overlap with other related disorders. The mtDNA mutations associated with MERRF can usually be detected in white blood cells, but due to heteroplasmy (see Causes), other tissue samples such as skin, saliva, hair follicles, urinary sediment and skeletal muscle, may be necessary to establish a molecular diagnosis.

In individuals with a clinical diagnosis or with symptoms that are highly suggestive of MERRF syndrome, molecular genetic testing may begin with a gene-targeted approach. An individual may first be screened for the common mutation, m.8344A>G, in the MT-TK gene. If this mutation is not found, broader genetic testing may be ordered that includes sequencing all genes associated with MERRF syndrome and other genes that cause related disorders (multigene panel testing). Genetic testing in other tissue samples may also be required.

In individuals that have general symptoms, such as seizures and muscle weakness that overlap with many other inherited conditions, molecular genetic testing may begin with a very broad approach. In these patients, genetic testing may include sequencing all mtDNA (mitochondrial genome) in addition to all genes (exome sequencing) or all DNA (genome sequencing).

Clinical Testing and Work-Up

Individuals with MERRF syndrome and their at-risk relatives should be followed by an interdisciplinary team at regular intervals to monitor any new symptoms and progression of disease.

After an initial diagnosis, baseline evaluations recommended include: (1) measurement of height and weight to detect short stature, (2) neurologic evaluation with a head MRI, MRS, EEG and neuropsychiatric testing to detect differences in the brain, presence of seizures and evidence of dementia, (3) hearing (audiologic) evaluation to detect hearing impairment, (4) eye (ophthalmologic) evaluation to detect vision problems, (5) physical and occupational therapy assessments, (6) cardiac evaluation with a EKG and echocardiogram to detect heart abnormalities, and (7) fasting serum glucose and glucose tolerance test to detect diabetes mellitus.

Genetic counseling is recommended for affected individuals and their families.

Standard Therapies

No specific treatment is available for MERRF syndrome. Some medications and therapies may be helpful in managing symptoms.

Traditional anticonvulsant drugs are used to help prevent and control seizures associated with MERRF syndrome. Valproic acid should be avoided in the treatment of seizures. Levetiracetam and clonazepam have been effective in controlling myoclonus in a small number of patients. Standard treatment for heart problems (cardiomyopathies and arrhythmias) can be used per cardiologist recommendation. Hearing aids and cochlear implants can improve hearing impairments. Physical therapy, occupational therapy and aerobic exercise may help to improve muscle weakness, stiffness, and motor function.

Therapies are sometimes used to increase energy production by the mitochondria and slow the effects of the condition. Coenzyme Q10 (CoQ10) and L-carnitine have been beneficial in some patients with different mitochondrial diseases. Additionally, supplements such as ubiquinol, carnitine, alpha lipoic acid, vitamin E, vitamin B complex and creatine may be of benefit to some individuals with mitochondrial disease with muscle involvement. Efficacy of these supplements is being studied in clinical trials. Individuals with MERRF should avoid mitochondrial toxins such as aminoglycoside antibiotics, linezolid, cigarettes and alcohol.

Investigational Therapies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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      References

      Sharma H, et al. Development of mitochondrial replacement therapy: A review. Heliyon. 2020 e04643.

      Finsterer J, et al. MERRF classification: implications for diagnosis and clinical trials. Pediatric neurology. 2018 80, 8-23.

      Lorenzoni PJ, et al. When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?. Arquivos de neuro-psiquiatria. 201472(10), 803-811.

      Mancuso M, et al. Phenotypic heterogeneity of the 8344A> G mtDNA “MERRF” mutation. Neurology. 2013 80(22), 2049-2054.

      Nissenkorn A, et al, Neurologic presentations of mitochondrial disorders. J Child Neurol. 200015:44-48.

      Velez-Bartolomei F, Lee C, Enns G. MERRF. 2003 Jun 3 [Updated 2021 Jan 7]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1520/ Accessed May 5, 2021.

      Hameed S, Tadi P. (Updated 2021 Feb 7). Myoclonic Epilepsy and Ragged Red Fibers. In: StatPearls Published 2021 Jan. Available at https://www.ncbi.nlm.nih.gov/books/NBK555923/. Accessed May 5, 2021.

      McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University Entry No:545000 Last Update: 11/19/2014. https://www.omim.org/entry/545000 Accessed May 5, 2021.

      MedlinePlus. National Library of Medicine. Myoclonic epilepsy with ragged-red fibers. Reviewed May 1, 2014 http://ghr.nlm.nih.gov/condition/myoclonic-epilepsy-with-ragged-red-fibers. Accessed May 5, 2021.

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      Mutations in the MT-TK gene are the most common cause of MERRF, occurring in more than 80 percent of all cases. Less frequently, mutations in the MT-TL1, MT-TH, and MT-TS1 genes have been reported to cause the signs and symptoms of MERRF. People with mutations in the MT-TL1, MT-TH, or MT-TS1 gene typically have signs and symptoms of other mitochondrial disorders as well as those of MERRF.

      The MT-TK, MT-TL1, MT-TH, and MT-TS1 genes are contained in mitochondrial DNA (mtDNA). Mitochondria are structures within cells that use oxygen to convert the energy from food into a form cells can use through a process called oxidative phosphorylation . Although most DNA is packaged in chromosomes within the nucleus , mitochondria also have a small amount of their own DNA. The genes associated with MERRF provide instructions for making molecules called transfer RNAs , which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria. These proteins perform the steps of oxidative phosphorylation.

      Mutations that cause MERRF impair the ability of mitochondria to make proteins, use oxygen, and produce energy. These mutations particularly affect organs and tissues with high energy requirements, such as the brain and muscles. Researchers have not determined how changes in mtDNA lead to the specific signs and symptoms of MERRF.

      A small percentage of MERRF cases are caused by mutations in other mitochondrial genes, and in some cases the cause of the condition is unknown.

      Learn more about the genes and chromosome associated with Myoclonic epilepsy with ragged-red fibers

      Additional Information from NCBI Gene:


      Inheritance

      This condition is inherited in a mitochondrial pattern , which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mtDNA . Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children.

      In most cases, people with MELAS inherit an altered mitochondrial gene from their mother. Less commonly, the disorder results from a new mutation in a mitochondrial gene and occurs in people with no family history of MELAS.


      Management and Treatment

      How are mitochondrial diseases treated?

      There are no cures for mitochondrial diseases, but treatment can help reduce symptoms or slow the decline in health.

      Treatment varies from patient to patient and depends on the specific mitochondrial disease diagnosed and its severity. However, there's no way to predict a patient’s response to treatment or predict how the disease will affect that person in the long run. No two people will respond to the same treatment in the same way, even if they have the same disease.

      Treatments for mitochondrial disease may include:

      • Vitamins and supplements, including Coenzyme Q10 B complex vitamins, especially thiamine (B1) and riboflavin (B2) Alpha lipoic acid L-carnitine (Carnitor) Creatine and L-Arginine. , including both endurance exercises and resistance/strength training. These are done to increase muscle size and strength. Endurance exercises include walking, running, swimming, dancing, cycling and others. Resistance/strength training include exercises such as sit-ups, arm curls, knee extensions, weight lifting and others.
      • Conserving energy. Don’t try to do too much in a short period of time. Pace yourself.
      • Other treatments. These may include speech therapy, physical therapy, respiratory therapy and occupational therapy.

      Avoid situations that can make your medical condition worse. These include: exposure to cold and/or heat starvation lack of sleep stressful situations and use of alcohol, cigarettes and monosodium glutamate (MSG, a flavor enhancer commonly added to Chinese food, canned vegetables, soups, and processed meats).


      Affiliations

      Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, 10032, New York, USA

      Eric A. Schon, Salvatore DiMauro & Michio Hirano

      Department of Genetics and Development, Columbia University Medical Center, 701 West 168th Street, New York, 10032, New York, USA

      You can also search for this author in PubMed Google Scholar

      You can also search for this author in PubMed Google Scholar

      You can also search for this author in PubMed Google Scholar

      Corresponding author


      Conclusion

      For many years, the inheritance of mtDNA was thought to be simple and straightforward in humans. However, the recent discovery of near-universal heteroplasmy, complexity introduced by the mtDNA bottleneck and evidence of selection for and against variants in particular regions of the mtDNA shows that the situation is far more complex than we previously thought. Given the emerging evidence implicating mtDNA mutations in the pathogenesis of common late-onset diseases, and their possible contribution to the ageing process, a deeper understanding of these processes is key if we are to harness this knowledge and prevent and treat human disorders caused by mutations of mitochondrial DNA by manipulating their inheritance.


      Conclusion

      In summary, seizures occur frequently in mitochondrial disease. They may be the presenting feature but are often part of a multisystem presentation. Mitochondrial epilepsies are biochemically and genetically heterogeneous, but some of the more common causes are mtDNA mutations and mutations in POLG. A rapidly increasing number of nuclear gene defects have been linked to mitochondrial epilepsy (Table I). The pathogenesis of mitochondrial epilepsy remains poorly understood, contributing to the immense difficulties in treating this condition. Epilepsy is a poor prognostic sign in mitochondrial disease, and there is an urgent need for formal clinical trials of candidate treatments, including the ketogenic diet and novel therapeutic agents.


      A mitochondrial bioenergetic etiology of disease

      Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

      Address correspondence to: Douglas C. Wallace, Colket Translational Research Building, Room 6060, Children’s Hospital of Philadelphia, University of Pennsylvania, 3501 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4302, USA. Phone: 267.425.3034 Fax: 267.426.0978 E-mail: [email protected]

      Find articles by Wallace, D. in: JCI | PubMed | Google Scholar

      The classical Mendelian genetic perspective has failed to adequately explain the biology and genetics of common metabolic and degenerative diseases. This is because these diseases are primarily systemic bioenergetic diseases, and the most important energy genes are located in the cytoplasmic mitochondrial DNA (mtDNA). Therefore, to understand these “complex” diseases, we must investigate their bioenergetic pathophysiology and consider the genetics of the thousands of copies of maternally inherited mtDNA, the more than 1,000 nuclear DNA (nDNA) bioenergetic genes, and the epigenomic and signal transduction systems that coordinate these dispersed elements of the mitochondrial genome.

      The application of Mendelian genetic principles, using the most sophisticated technologies, has failed to adequately explain the genetics or pathophysiology of many common metabolic and degenerative diseases. This shortcoming can now be understood through the discovery that mutations in the maternally inherited mtDNA can cause many of the symptoms associated with “complex” diseases and that the mtDNA codes for the central genes of the mitochondrial energy–generating process oxidative phosphorylation (OXPHOS). Therefore, the common metabolic and degenerative diseases must be bioenergetic in origin and non-Mendelian in inheritance.

      The central player in bioenergetics is the mitochondrion. Mitochondria produce about 90% of cellular energy, regulate cellular redox status, produce ROS, maintain Ca 2+ homeostasis, synthesize and degrade high-energy biochemical intermediates, and regulate cell death through activation of the mitochondrial permeability transition pore (mtPTP). The mitochondrial genome consists of thousands of copies of the maternally inherited mtDNA plus between 1,000 and 2,000 nDNA genes. mtDNA codes for 13 OXPHOS polypeptides, plus the 22 transfer RNAs (tRNAs) and the 12S and 16S rRNAs necessary for the bacteria-like mitochondrial protein synthesis. mtDNA polypeptides encompass seven of the 45 polypeptides of OXPHOS complex I (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6), one of the 11 polypeptides of complex III (cytochrome b), three of the 13 polypeptides of complex IV (COI, COII, and COIII), and two of the approximated 17 polypeptides of complex V (ATPase6 and ATPase8). Complexes I, III, and IV constitute the electron transport chain (ETC), which oxidizes the reducing equivalents (hydrogen-derived electrons) from food with the oxygen we breathe. As the electrons flow sequentially through complexes I, III, and IV, protons are pumped out across the mitochondrial inner membrane through these complexes to generate an electrochemical gradient. This mitochondrial capacitor is the vital force and can be used to drive many biological processes, including the condensation of ADP and Pi to form ATP via complex V. Thus oxidation is coupled with phosphorylation in OXPHOS. The 1,000–2,000 nDNA mitochondrial genes, scattered across the chromosomes, code for the remaining approximately 80 OXPHOS subunits, the intermediary metabolism enzymes, and the mitochondrial biogenesis proteins ( 1 – 3 ).

      Three factors can perturb mitochondrial bioenergetics and result in disease: variation in the mtDNA sequence, variation in the sequences of nDNA-coded mitochondrial genes or in the expression of these genes, or variation in environmental calories and the caloric demands made on the organism. Since different tissues rely on mitochondrial energy to different extents, partial systemic energy deficiency can result in tissue-specific symptoms. The brain, which represents only 2% of the body weight but consumes 20% of the oxygen, is the organ most sensitive to subtle energy diminution. Other high-energy demand tissues include the heart, muscle, kidney, and endocrine system, the organs commonly affected in metabolic and degenerative diseases (Figure 1).

      Bioenergetic paradigm for metabolic and degenerative diseases, cancer, and aging. Mitochondrial OXPHOS can be perturbed by nDNA genetic alterations and/or epigenomic regulation, by mtDNA ancient adaptive of recent deleterious mutations, or by variation in the availability of calories and in caloric demands. Alterations in mitochondrial structure and function can impair OXPHOS, which in turn can reduce energy production, alter cellular redox state, increase ROS production, deregulate Ca 2+ homeostasis, and ultimately activate the mtPTP, leading to apoptosis. These and other consequences of OXPHOS perturbation can destabilize mtDNA. This results in progressive accumulation of somatic mtDNA mutations and decline of mitochondrial function, which accounts for aging and the delayed-onset and progressive course of degenerative diseases. As energy output declines, the most energetic tissues are preferentially affected, resulting in degenerative diseases of the central nervous system, heart, muscle, and kidney. Aberrant mitochondrial caloric metabolism also leads to metabolic deregulation, endocrine dysfunction, and symptoms such as diabetes, obesity, and cardiovascular disease. The release into the blood stream of mtDNA mutant N-formylmethionine polypeptides plus the mtDNA can initiate the inflammatory response, contributing to autoimmune diseases (e.g., multiple sclerosis and type I diabetes) and possibly also to the inflammatory component of late-onset degenerative diseases. Finally, cancer cells must manage energy resources to permit rapid replication ( 95 ). Figure adapted with permission from Cold Spring Harbor Press ( 55 ).

      Since the first report of an inherited mtDNA disease mutation 25 years ago ( 4 ), hundreds of clinically relevant mtDNA mutations have been identified. These can either be polypeptide mutations or protein synthesis mutations, the latter altering the tRNA or rRNA genes ( 3 , 5 ). There are three clinically relevant classes of mtDNA mutations: recent deleterious mutations that result in matrilineal disease, ancient adaptive variants that predispose to the common diseases, and somatic mutations that accumulate in tissues with age and provide the aging clock (Figure 1).

      Recent deleterious mutations and maternally inherited diseases. A prime example of a pathogenic mtDNA polypeptide missense mutation is the NADH dehydrogenase subunit 4 (ND4) nt 11,778 G>A mutation (histidine 340 to arginine), or ND4 G11778A (R340H), that causes Leber hereditary optic neuropathy (LHON) ( 4 ). LHON is characterized by acute or subacute midlife blindness that is two to five times more likely to affect males than females, even though all maternal relatives generally have close to 100% mutant mtDNAs (homoplasmic) ( 6 ).

      The two most common mtDNA protein synthesis mutations cause myoclonic epilepsy and ragged red fiber disease (MERRF) (tRNA Lys A8344G) ( 7 , 8 ) and mitochondrial encephalomyopathy and stroke-like episodes (MELAS) (tRNA Leu(UUR) A3243G) ( 9 ). These more severe mtDNA mutations produce multisystem neuromuscular diseases, and the mutant mtDNAs are generally mixed within the cell with normal (wild-type) mtDNAs (heteroplasmic) ( 3 , 5 ). As a heteroplasmic cell replicates, the percentages of mutant and normal mtDNAs are randomly distributed into the daughter cells (replicative segregation). Consequently, the mtDNA genotype can drift during both meiotic and mitotic cell division. Meiotic replicative segregation can cause maternal relatives to harbor different percentages of mutant mtDNAs, have different degrees of the energetic defect, and manifest widely different phenotypes. For example, when the MELAS-causing tRNA Leu(UUR) A3243G mutant is present in 10%–30% of the mtDNAs, the individual will develop type I or type II diabetes mellitus, but when the mutant is present at higher percentages, myopathy, cardiomyopathy, and stroke-like episodes will develop. Mitotic segregation can give rise to an individual with significantly different percentages of mutant mtDNAs in different tissues when derived from a heteroplasmic oocyte, further contributing to phenotypic variability ( 3 , 5 , 7 , 8 ).

      The milder mtDNA variants can affect caloric metabolism and result in metabolic abnormalities such as diabetes and obesity and/or affect the most energy-demanding organs such as the brain and lead to late-onset degenerative diseases, such as psychiatric disorders, Parkinson disease (PD), and Alzheimer disease (AD). The more severe mtDNA mutations, like MERRF and MELAS, cause progressive multisystem diseases, frequently resulting in premature death. The most severe mtDNA mutations can lead to lethal childhood diseases, such as Leigh syndrome ( 3 ).

      Ancient adaptive mtDNA variants: common variants that predispose to common diseases. Population-specific mtDNA polymorphisms have been linked to predisposition to a broad range of metabolic and degenerative diseases ( 3 , 10 , 11 ). These variants are generally ancient, having accumulated along radiating maternal lineages during the human expansion out of Africa. By superimposing the human mtDNA mutational tree on the geographic locations of indigenous populations that harbor the various mtDNA types, mtDNA polymorphisms have been used to reconstruct the origins and ancient migrations of women (Figure 2).

      Radiation of human mtDNA as women migrated out of Africa to colonize Eurasia, Australia, and the Americas. The uniparentally inherited mtDNA can only change by sequential accumulation of mutations along radiating female lineages. Therefore, the mtDNA mutational tree and ancient migrations of women were reconstructed by sequencing mtDNAs from indigenous populations and correlating their regional clusters of related haplotypes (haplogroups) with the population’s geographic location. The haplogroups are regional because they were founded by regionally adaptive functional variants. The mtDNA tree originates in Africa, and all African mtDNAs are classified together as macrohaplogroup L. From haplogroup L3, two mtDNA lineages, M and N, arose in Ethiopia and successfully left Africa to colonize the rest of the world about 65,000–70,000 YBP. The founder mtDNA of macrohaplogroup N harbored two mtDNA missense mutations, ND3 G10398A (A114T) and ATP6 G8701A (A59T), whereas the founder of macrohaplogroup M did not harbor major functional mutations ( 3 , 15 ). Early M and N emigrants from Africa moved through Southeast Asia, ending in Australia ( 96 , 97 ). N mtDNAs also moved north from Africa into the Middle East to generate submacrohaplogroup R and European-specific haplogroups H, J, T, U, Uk, and V (from R) and I, W, and X (from N). N and R gave rise to Asian haplogroups A+Y and B+F, respectively. M moved north out of Southeast Asia to colonize Asia, generating haplogroups C and D and multiple M haplogroups. Haplogroups A, B, C, D, and X subsequently migrated to the Americas. The mtDNA mutation rate is 2.2%–2.9% per million years (numbers within the figure denote YBP). Figure adapted with permission from MITOMAP ( 5 ).

      mtDNA has a very high mutation rate, yet codes for the most important mitochondrial energy genes. This should be a lethal combination. However, mammalian females have evolved an intraovarian selection system that destroys the proto-oocytes with the most severe mitochondrial defects ( 12 , 13 ), a process that may account for atresia. Therefore, mild mtDNA variants are continuously being introduced into populations with minimum genetic load. Those variants can be beneficial for a population within a specific regional energetic environment and be selectively enriched in that regional population. Since different mtDNA variants are adaptive in different environments, different mtDNAs became enriched in different populations. The subsequent accumulation of random mtDNA mutations on the founding adaptive mtDNA produced regional clusters of related mtDNA haplotypes, known as haplogroups.

      Because of the complexity of mitochondrial physiology, a mtDNA variant might be beneficial early in reproductive life, but deleterious postreproductively. Such variants are said to be antagonistically pleiotropic. For example, increased ROS production might help fight infection in the young but cause lifelong chronic oxidative stress that predisposes to development of age-related degenerative diseases.

      The human mtDNA tree originated in Africa about 130,000–200,000 years before present (YBP) and gave rise to a series of African-specific haplogroups, which in aggregate form African macrohaplogroup L (Figure 2). Of all the African mtDNAs, only two mtDNA lineages, macrohaplogroups M and N, successfully left Africa (about 65,000–70,000 YBP) and colonized the rest of the world. In one migration, M and N left Africa and traveled along the tropical Southeast Asian coast, ultimately reaching Australia.

      Macrohaplogroup N mtDNAs also moved north into the Middle East and radiated to create submacrohaplogroup R. Both N and R lineages spread into Europe to generate the eight to nine European-specific haplogroups.

      In Asia, macrohaplogroup N radiated to form haplogroups A and Y, and the N-derived R lineage generated haplogroups B and F. From Southeast Asia, macrohaplogroup M moved northward to form an array of Asian-specific mtDNA haplogroups (C, D, and M1∼M40). Ultimately, haplogroups A, B, C, D, and X migrated into the Americas to found the Native American populations (Figure 2).

      A major environmental barrier to the migration of sub-Saharan Africans into Eurasia must have been the cold of the northern latitudes. To survive, early humans would have needed to produce more core body heat. This might have been achieved by mtDNA mutations that decreased the “coupling efficiency” of OXPHOS. This would require that more calories be burned to generate the same amount of ATP. Since a calorie is a unit of heat, reduced coupling efficiency would increase the core body temperature and resistance to cold, but would necessitate a higher-calorie diet ( 2 , 14 ).

      Prior to moving out of Ethiopia, the founding macrohaplogroup N mtDNA acquired two functional variants, ND3 G10398A (A114T) and ATP6 G8701A (A59T) ( 3 , 15 ), which changed the mitochondrial membrane potential and Ca 2+ metabolism (ref. 16 and Figure 3). These mutations likely contributed to cold resistance in the temperate zone. Macrohaplogroup M, in contrast, stayed in the tropics, so cold-adaptive variants were not initially fixed in this lineage.

      Relationship between ancient adaptive mtDNA variants and predisposition to metabolic and degenerative diseases. African haplogroup L3 gave rise to macrohaplogroups M and N, which colonized Europe and Asia. N differed from M in harboring the ND3 G10398A (A114T) and ATP6 G8701A (A59T) variants. In Europe, N gave rise to haplogroup H, and H acquired the tRNA Gln A4336G variant to generate H5a, which predisposes to AD, PD, and both AD and PD ( 17 ). The ND1 A3397G (M31V) missense mutation arose twice in Europeans, once on H5a and once independently, and in both cases was associated with predisposition to both AD and PD ( 17 ). Both tRNA Gln A4336G and ND1 A3397G (M31V) mutations are likely to reduce mitochondrial complex I activity, augmenting the founding N variants. The ND1 T3394C (Y30H) mutation, which is adjacent to the ND1 M31 codon, arose on N and M mtDNAs. When arising on N haplogroups B and F, the ND1 T3394C (Y30H) variant is associated with complex I deficiency and increased penetrance of the primary LHON mutations. However, complex I activity is also modulated by N haplogroup background, with haplogroup F mtDNAs having lower complex I activity than haplogroup B mtDNAs, consistent with haplogroup F predisposition to diabetes ( 23 ). The ND1 T3394C (Y30H) mutation has arisen on several M mtDNAs, with all haplogroup M9 mtDNAs having the 3394C allele. Both M9 and 3394C mtDNAs increase in frequency with altitude in Tibet. Finally, M9 complex I activity is equal to or greater than that of any of the N haplogroups with the wild-type T3394 allele ( 20 ). Asterisks indicate that the stated complex I activity is predicted, based on the known genotype and complex I activities determined for cell lines harboring ND1 T3394C (Y30H)–containing mtDNAs.

      The most common European N-R–derived mtDNA haplogroup is H. In Europe, haplogroup H acquired additional functional variants, one of which arose between 8,500 and 17,000 YBP in the tRNA Gln gene (tRNA Gln A4336G), creating subhaplogroup H5a. Today, this variant is found in only 0.4% of the general European population, but is present in 3.3% of AD patients, 5.3% of PD patients, and 6.8% of patients with both AD and PD (ref. 17 and Figure 3). The retention of this variant in the European population may be an example of antagonistic pleiotropy. A second European mtDNA variant observed in patients with both AD and PD is a missense mutation in the ND1 gene: ND1 A3397G (M31V). This variant arose twice, once in the tRNA Gln A4336G lineage, and once independently (ref. 17 and Figure 3).

      A related ND1 variant, ND1 T3394C (Y30H), changes the amino acid adjacent to M31. When arising on macrohaplogroup N mtDNAs, this variant is associated with increased penetrance of the milder primary LHON mtDNA mutations ( 18 , 19 ). Yet when this same ND1 T3394C (Y30H) variant arose on macrohaplogroup M mtDNAs, it became enriched in high-altitude Tibetans. Haplogroup M9 mtDNA with the ND1 T3394C (Y30H) variant is present at less than 2% at sea level, but increases to about 35% of the mtDNAs in the highest Tibetan villages (ref. 20 and Figure 3).

      The ND1 T3394C (Y30H) variant results in a 15%–28% reduction in complex I–specific activity when arising on macrohaplogroup N mtDNAs, which explains its enhancement of LHON mutation penetrance. However, the specific activity of complex I can also vary among different macrohaplogroup N haplogroups by up to 30%, independent of their 3394 allele. Even more surprising, the 3394C allele, when present in the M9 haplogroup mtDNA, is associated with complex I activity equal to or greater than any of the macrohaplogroup N mtDNAs with the wild-type T3394 (Y30) variant (ref. 20 and Figure 3).

      Similar physiological differences have been documented between European haplogroup H and Uk mtDNAs ( 11 , 21 ). Therefore, the metabolic consequences of a particular mtDNA nucleotide variant can be strongly influenced by genetic and environmental context.

      The clinical relevance of mtDNA haplogroup variation has been repeatedly demonstrated through case-control studies on a wide variety of metabolic and degenerative diseases, cancer, and aging ( 3 , 10 , 11 , 22 ), and the physiological associations are being elucidated. For example, haplogroup F mtDNAs are associated with low complex I activity ( 20 ) and predilection to diabetes ( 23 ). Hence, ancient mtDNA variants and haplogroups are likely the long-sought common variants that predispose to common diseases.

      Somatic mtDNA mutations. mtDNA also accumulates mutations within tissues with age. mtDNA deletions that occur early in development can become widely disseminated throughout the body and cause spontaneous mitochondrial myopathy ( 24 ). However, mtDNA deletions ( 25 – 28 ) and base substitutions ( 29 , 30 ) can arise in tissues throughout life, and their accumulation has been shown to modulate aging and longevity ( 31 – 33 ). Therefore, the accumulation of somatic mtDNA mutations may be the aging clock.

      The rate of accumulation of somatic mtDNA mutations can be modulated by nuclear or cytoplasmic genetic variants and by environmental factors (Figure 1). For example, factors that increase mitochondrial ROS production would increase the mtDNA mutation rate and lead to premature organ failure. Increased mtDNA somatic mutation levels have been documented in ischemic heart disease ( 34 ), AD brains ( 35 – 37 ), PD brains ( 38 , 39 ), Huntington disease brains ( 40 ), and Down syndrome with dementia (DSAD) brains ( 37 ). In AD and DSAD brains, elevated somatic mtDNA base substitution mutations have been correlated with reduced mtDNA copy number and ND6 transcript levels ( 37 ).

      As somatic mtDNA mutations accumulate, they change the amino acid sequences of the mtDNA-coded mitochondrial N-formylmethionine–initiated polypeptides. These bacterial-like variant polypeptides can then be seen as foreign and initiate an inflammatory response. This may contribute to the inflammation frequently observed in late-stage degenerative diseases (Figure 1 and refs. 38 , 41 – 43 ).

      Bioenergetic disease can also result from mutations in any one of the hundreds of nDNA genes that code for mitochondrial proteins. Mutations in more than 200 nDNA gene loci have already been reported to cause mitochondrial bioenergetic dysfunction ( 3 , 44 ).

      Structural and metabolic nDNA-coded mitochondrial genes. In addition to mutations in the nDNA-coded enzymes of mitochondrial intermediary metabolism, which exhibit classical Mendelian transmission, pathogenic mutations have been identified in multiple nDNA-coded OXPHOS structural and assembly factor genes. When both copies of a chromosomal gene are mutated, severe OXPHOS defects can occur and cause devastating pediatric disease, the most commonly recognized phenotype being Leigh syndrome ( 3 , 44 ).

      Diseases of nDNA-mtDNA interactions. Mutations in the nDNA-coded mtDNA biogenesis genes can cause degenerative diseases by destabilizing mtDNA biogenesis, resulting in multiple mtDNA deletions and/or mtDNA depletion ( 3 , 44 ). Pathogenic mutations have been reported in mtDNA polymerase γ (POLG) ( 45 ), Twinkle helicase ( 46 ), mitochondrial deoxyguanosine kinase and thymidine kinase 2 ( 47 , 48 ), cytosolic thymidine phosphorylase ( 49 ), and the heart-muscle adenine nucleotide (ADP/ATP) translocator (ANT1) ( 50 , 51 ), to name a few ( 3 ). Mitochondrial disease can also result from the incompatible interaction of two otherwise nonpathogenic nDNA and mtDNA genetic variants ( 52 ).

      Alterations in nDNA-coded mitochondrial gene expression and the epigenome. While mtDNA mutations have permitted humans to adapt to stable regional environmental energetic differences, many energy resources and demands fluctuate cyclically, for example, seasonal changes in temperature and food supply. Adaptation to this type of energetic variation is accomplished by changes in the levels of mitochondrially generated high-energy intermediates, such as acetyl-CoA and ATP, and in the mitochondrial modulation of the cellular redox state. As these mitochondrial bioenergetic parameters fluctuate with the environment, they drive posttranslational modification of the proteins of the epigenome and the signal transduction pathways. In this way, the expression of the hundreds of nDNA-coded bioenergetic genes is coupled to environmental fluctuations through mitochondrial energy flux ( 53 – 55 ).

      This new bioenergetic perspective provides a framework to reevaluate the genetics and pathophysiology of “complex” diseases, such as PD, AD, autism spectrum disorders (ASDs), and psychiatric disorders. In PD, numerous nDNA loci that have been linked to developing movement disorders are directly involved in modulating mitochondrial integrity and function ( 38 ). For example, mutations in parkin (PARK2) and PTEN-induced kinase 1 (PINK1 also known as PARK6) impede mitochondrial autophagy (mitophagy), which leads to the accumulation of mitochondrial damage ( 38 , 56 , 57 ). The resulting increased mtDNA somatic mutation rate degrades the mtDNA in the basal ganglion and substantia nigra, ultimately resulting in neuronal dysfunction, cell death, and movement disorders ( 26 , 39 , 58 ).

      In AD, Aβ toxicity is generally assumed to be the cause, yet systemic mitochondrial defects have been repeatedly reported ( 1 ). At high concentrations, Aβ oligomerizes and is toxic ( 59 ), specifically inhibiting mitochondrial function ( 38 , 60 ). However, at low concentrations, monomeric Aβ is protective of mitochondrial function ( 38 ). Therefore, Aβ appears to be bifunctional. From this perspective, under normal conditions, Aβ functions to protect the mitochondria and associated neurons and synapses and is induced in response to mitochondrial stress, possibly mitochondrial ROS production. However, when mitochondrial dysfunction becomes so severe that neuronal function is irreversibly impaired, Aβ induction becomes excessive and leads to Aβ oligomerization. The oligomerized Aβ then inhibits mitochondrial function, activates the mtPTP, and destroys the neuron with the defective mitochondria, thus eliminating noise from the neuronal information network.

      Early-onset AD, then, is the result of mutations in APP or the presenilins, which aberrantly increase Aβ levels, leading to premature Aβ aggregation and destruction of potentially repairable mitochondria, neurons, and synapses. Late-onset AD, in contrast, is the result of chronic mitochondrial stress, perhaps mediated by ROS toxicity, Ca 2+ overload, or other factors. Increased chronic mitochondrial oxidative stress can result from a variety of factors that partially inhibit OXPHOS, including the tRNA Gln A4336G and ND1 A3397G (M31V) variants. Excessive mitochondrial Ca 2+ exposure can also increase mitochondrial ROS production and activate the mtPTP. Mitochondrially destined Ca 2+ is released from the endoplasmic reticulum within the mitochondria-associated membranes (MAMs), and MAMs harbor the presenilin complexes ( 61 , 62 ). Inappropriate MAM Ca 2+ regulation can cause chronic mitochondrial stress by increasing mitochondrial ROS production and Ca 2+ activation of the mtPTP. These and other stressors could cause the premature accumulation of neuronal somatic mtDNA mutations, bioenergetic decline, mutant mtDNA peptide–induced inflammation, synaptic loss, and dementia ( 38 ).

      ASDs have also proven enigmatic when viewed from a classical Mendelian perspective. Yet the genetics and pathophysiology of ASDs are fully consistent with the expectations for mild mitochondrial dysfunction. Like LHON ( 6 ), in ASDs, males are four times more likely than females to be affected ( 63 , 64 ). Mitochondrial metabolic defects have been repeatedly reported in ASD patients, and mtDNA mutations have been found in several ASD pedigrees ( 63 , 65 – 67 ).

      Elevated Ca 2+ levels have also been observed in ASD brains, and the excess Ca 2+ could activate the neuronal aspartate/glutamate carrier of the mitochondrial NADH shuttle system ( 68 ) and the tricarboxylic acid cycle dehydrogenases ( 69 , 70 ). Both of these effects would drive excessive reducing equivalents into the ETC, stimulating mitochondrial ROS production, oxidative stress, mitochondrial damage, and synaptic loss. Mutations in the CACNA1C Ca 2+ channel gene have been shown to cause the syndromic ASD Timothy syndrome ( 71 ), and mutations in the CACNA1F Ca 2+ channel gene have been reported in ASD patients ( 72 ).

      Copy number variants (CNVs) are also increased in number in autism patients ( 73 , 74 ), and CNVs that remove a copy of the PARK2 or ubiquitin protein ligase E3A (UBE3A) genes have been observed repeatedly ( 75 , 76 ). Since loss of PARK2 would impair mitochondrial quality control ( 77 ), and mutations in UBE3A are associated with hippocampal mitochondrial defects in Angelman syndrome, another syndromic ASD ( 78 ), these observations also implicate bioenergetics in ASDs.

      Since there are more than 1,000 nDNA mitochondrial genes, and partial mitochondrial defects can be sufficient to cause neurodegenerative disease, random CNVs that delete one copy of a nDNA mitochondrial gene could be sufficient to predispose to the neurological symptoms of ASD. Indeed, in one study, an ASD subject with one CNV had near-normal OXPHOS function, while another patient with 13 CNVs had a severe OXPHOS defect ( 67 ).

      Another surprise from the Mendelian perspective has been that genetic elements linked to ASDs are also associated with other neuropsychiatric disorders ( 79 , 80 ). However, this would be predicted if neuropsychiatric disorders share a common bioenergetic pathophysiological mechanism. Mitochondrial dysfunction has been documented in psychiatric disorders ( 81 ), evidence of matrilineal bias in transmission has been reported ( 82 , 83 ), and mtDNA haplogroups and brain mtDNA somatic mutations have been observed in patients with psychiatric conditions ( 21 , 28 ).

      To prove that mitochondrial defects cause metabolic and degenerative diseases, mitochondrial gene mutations have been introduced into the mouse, and metabolic and degenerative disease phenotypes have been observed ( 84 ). The introduction of mtDNA mutations into the mouse germline has proven particularly instructive.

      To introduce a mtDNA mutation into the mouse, an appropriate mtDNA mutation must be isolated in a cultured mouse cell line and the mutant mtDNA transferred into the mouse female germline, most commonly mediated by mouse female embryonic stem cell (mfESC) transmitochondrial cybrids ( 85 ). Introduction into the mouse of a mtDNA harboring a 12S rRNA chloramphenicol resistance (CAP R ) mutation ( 86 , 87 ) resulted in chimeric CAP R mice with cataracts, retinal dysfunction, and optic nerve hamartomas. Homoplasmic CAP R transgenic mice had stunted growth, mitochondrial myopathy, and cardiomyopathy and died prematurely ( 87 ).

      Introduction of mtDNAs harboring a homoplasmic mtDNA with a COI T6589C (V421A) missense mutation that were also heteroplasmic for a ND6 13886 insertion C frameshift mutation resulted in animals that rapidly and directionally lost the frameshift mtDNA within three generations. This observation revealed the existence of the prefertilization ovarian selective system, which eliminates proto-oocytes with the most deleterious mtDNA mutations ( 12 , 88 ). The mice that remained after segregation of the ND6 13886 insertion C frameshift mtDNA were homoplasmic for the COI T6589C (V421A) missense mutation. These animals had a 50% reduction in complex IV activity and developed mitochondrial myopathy and cardiomyopathy ( 12 ).

      Introduction into the mouse of an ND6 G13997A (P25L) mtDNA mutation, which is functionally equivalent to the human ND6 G14600A (P25L) mutation reported to cause optic atrophy when heteroplasmic and Leigh syndrome when homoplasmic ( 89 ), resulted in animals with all of the anatomically possible physiological and pathological features of LHON. The physiological effects of the mutation on neurons were analyzed using synaptosomes from the mouse LHON model brain. This revealed that the optic atrophy mutation did not diminish synaptic ATP levels, but instead chronically increased mitochondrial ROS production. If this is the case for other LHON mutations, it suggests that the delayed onset of acute vision loss may be the result of cumulative oxidative damage ( 90 ).

      A heteroplasmic mtDNA rearrangement mutation has also been introduced into the mouse. This resulted in mice with complex IV–negative (COX-negative) muscle and heart myofibers, renal dysfunction ( 91 ), and infertility ( 92 ). Therefore, both base substitution and mtDNA rearrangement mutations are sufficient to cause degenerative diseases.

      To determine the consequences of much milder mitochondrial defects, mice were created in which two normal but different mouse mtDNAs were mixed within the female germline, thus subverting maternal inheritance. The mtDNAs were from NZB and 129 mice and differed at 91 nt positions encompassing 15 missense mutations, 5 tRNA mutations, 7 rRNA mutations, and 11 control region mutations. All mice were maintained on the C57BL/6J nuclear background ( 93 ). As previously observed ( 94 ), the heteroplasmy levels within the tissues of individual animals segregated, with NZB mtDNAs predominating in liver and kidney, and 129 mtDNAs in spleen and pancreas. However, the tail, muscle, heart, and brain heteroplasmy levels remained relatively stable. In mating experiments, the NZB mtDNAs were progressively lost from the maternal lineage, with the rate of segregation being greatest when the mtDNAs were at relatively equal percentages.

      By random segregation and selective breeding, the heteroplasmic mice were used to derive three mouse lines: homoplasmic NZB, homoplasmic 129, and heteroplasmic NZB-129. These three different mtDNA genotype strains were then examined for behavioral alterations. While the homoplasmic NZB and homoplasmic 129 mice were essentially the same and phenotypically normal, the heteroplasmic NZB-129 mice were markedly different. The heteroplasmic NZB-129 animals were hypoactive during the normally active dark period, in association with reduced food intake and respiratory exchange ratio, but were hyperexcitable under stress conditions. Even more remarkably, the heteroplasmic mice showed a striking learning defect, being slow to learn and quick to forget ( 93 ).

      Extensive biochemical studies of the heteroplasmic NZB-129 mice have failed to detect a significant OXPHOS defect. Therefore, even extremely subtle bioenergetic dysfunction is sufficient to cause neuropsychiatric symptoms. This can account for why maternal inheritance of the mtDNA is strictly imposed throughout most of the eukaryotic kingdom and might explain why it has been so difficult to determine the pathophysiological basis of neuropsychiatric disorders.

      Elucidation of the novel genetics of mtDNA and the demonstration of its central role in bioenergetics has provided a new set of genetic rules and physiological parameters for understanding the intraspecific genetic variation of relevance to human health and disease. This bioenergetic perspective not only provides a coherent theory for the etiology of the “complex” metabolic and degenerative diseases, it suggests powerful new approaches for their presymptomatic diagnoses, reliable prognosis, and effective treatment and prevention ( 10 ). However, reaping the benefits of these new insights will require a major redirection of the way we think about medical genetics and origin of disease. If we can change, the bioenergetic perspective promises to reduce the burden of chronic diseases and markedly improve global health span.

      The author thanks Marie Lott for assistance. This work was supported by NIH grants NS21328, NS070298, AG24373, and DK73691 and by Simon Foundation grant 205844 awarded to D.C. Wallace.

      Conflict of interest: The author’s research has received some support from Glaxo-Smith Kline.

      Reference information: J Clin Invest. 2013123(4):1405–1412. doi:10.1172/JCI61398.


      Three-Parent Babies and The Truth Behind Mitochondrial Replacement Therapy

      Most of us have heard in a biology class that DNA is found in the cell’s nucleus. While this statement is mostly true, some DNA also resides in the mitochondria. The human nuclear genome consists of more than 3 billion base pairs, while the human mitochondrial genome clocks in at slightly fewer than seventeen thousand base pairs. It is clear that in terms of quantity, mitochondrial DNA (mtDNA) pales in comparison to nuclear DNA. However, mitochondrial DNA is nevertheless an integral part of the genetic code. So what exactly is it that makes mitochondrial DNA so special?

      For one, it is usually passed exclusively from mother to child. However, in contradiction to this, a recent study has shown that fathers are also capable of passing on mtDNA to their children in some cases. Dr. Taosheng Huang, a pediatrician at Cincinnati Children’s Hospital Medical Center, discovered that a four-year-old patient of his carried two sets of mtDNA—one from his mother and one from his father. Despite this new discovery, Sophie Breton, a mitochondrial geneticist, explains that “maternal inheritance of mitochondrial DNA is still the norm.” It is easy to think that because mtDNA has historically been maternally inherited, everyone has the same mtDNA. However, this is not true, due to mutations being picked up over time as mtDNA was passed down. Eventually, this led to the existence of slightly different mtDNA sequences across individuals.

      Due to the way mtDNA is passed on, there are certain diseases which can only be inherited maternally. One example is mitochondrial myopathies, encephalopathy, lactic acidosis, and stroke (MELAS), which causes serious nervous and muscular system problems. Mutations in mtDNA can also cause myoclonic epilepsy with ragged red fibers (MERRF), which is characterized by sudden spasms, and Leber’s hereditary optic neuropathy (LHON), which results in vision loss during childhood or young adulthood. To further complicate matters, mtDNA exhibits heteroplasmy, meaning that each cell may contain several variants of mtDNA. Because of this, mitochondrially inherited conditions can vary widely in severity, age of onset, and symptoms because each cell may contain a different ratio of normal mtDNA to abnormal mtDNA. This also creates a lot of variance between organs, as organs throughout the body may have differing levels of heteroplasmy.

      Fortunately, the advent of mitochondrial replacement therapy (MRT) has proven to be very promising for couples who would like to have biological children without passing on a mitochondrial disease. MRT involves using healthy mitochondria from a donor egg from which the nucleus is removed. The mother’s nucleus is then transferred into the cell, and in vitro fertilization (IVF) is used to produce “ an embryo that contains nuclear DNA from the father and the mother with healthy mtDNA from the donor.” This way, women with mtDNA mutations are still able to have children of their own who will almost certainly not inherit said mutations. Due to the fact that genetic material from three individuals is combined during MRT, the resultant offspring is sometimes referred to as a “three-parent baby.”

      As of now, MRT is only legal in the United Kingdom. The FDA in the United States has not approved human clinical trials for IVF involving donor mitochondria. However, for some couples, this procedure is their only chance to have a healthy biological child of their own. Evan and Kristelle Shulman are one of these couples. They lost their son Noah soon after his birth due to a mitochondrial disease and later found out that his condition was a result of mutations present in seventy to eighty percent of Kristelle’s mitochondria, though she herself is not symptomatic. The Shulmans’ only option to guarantee a healthy child is through MRT, but they are unable to undergo the procedure, since it is currently illegal in the United States. Dr. Michio Hirano is able to perform MRT for the Shulmans and five other couples in similar situations, but unfortunately, he cannot transfer the embryos for fertilization with the current laws in place. Until then, the embryos will remain frozen.

      Why is it such a big deal to legalize MRT? After all, it has the potential to help so many couples, right? Though this is true, there are also several associated ethical concerns which lead to the technique being viewed with apprehension by many scientists and bioethicists. For one, there is, as with any procedure, the possibility of unforeseen effects down the road. Though these repercussions are not known at the moment, Professor Joanna Poulton at the University of Oxford explains that “replacing the nucleus [of an egg cell] d oes not prevent development into a baby, but it causes damage to the cell that probably requires radical reorganization.” She goes on to state that this replacement could possibly result in an increased risk of diabetes later on in life. Another ethical concern regarding MRT is that its effects will be passed down through multiple generations, giving it the potential to change the human gene pool over time. Though nucleotide sequences are not being altered as in the case of CRISPR, MRT and its associated alterations will nevertheless persist throughout future generations. A safeguard currently being discussed in order to minimize the risk of future complications of MRT is to, following the procedure, implant only male embryos for possible pregnancy. This way, potential adverse effects of MRT on the mtDNA will be less likely to be passed on to future generations. A third concern relates to the high costs of MRT. With the procedure ranging from $25k-50k, a societal divide may form between those able to afford this therapy and improve their children’s lives, and those who would like to have this opportunity but cannot afford it. Also related to MRT’s price point is the concern regarding the donors themselves. Mitochondrial donors receive significant compensation, and this might fuel the exploitation of disadvantaged women in the donor business.

      All in all, mitochondrial DNA accounts for only a small portion of the human genome, but mutations within it can be just as adverse as those occurring in nuclear DNA. The breakthrough of mitochondrial replacement therapy appears to be a solution to diseases inherited mitochondrially however, as with any new biotechnology, it is accompanied by several ethical concerns. Stringent regulation of the use of MRT, as well as delving deeper into its possible side effects, will hopefully allow a balanced and ethical use of this technology in the coming years.


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