What is the benefit for cells having the ATP production regulated in mitochondria compared to being from the nucleus?

What is the benefit for cells having the ATP production regulated in mitochondria compared to being from the nucleus?

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Mitochondria have their own DNA and appear to be loosely connected to the nucleus and it role.

Why are the functions of mitochondria not in the nucleus? Why doesn't the nucleus control the mitochondria's functions as it controls regulation for other chemical reactions? Are there evolutionary/competitive benefits for this separation?

For starters, see this thread.

My understanding is that the ancient predecessors of mitochondria were free-living unicellular organisms. Supposedly at one point, these mitochondria-like cells developed an endosymbiotic relationship with a larger cell. This relationship was advantageous for both cells: the smaller cell could focus on energy production, leaving tasks like homeostasis, nutrient collection, etc, to the larger cell. Over evolutionary time, this endosymbiosis caused the smaller cell to lose all functions unrelated to energy production, while the larger cell (as we now know it) came to rely heavily on the mitochondria for energy production.

So it's possible that at one time the nucleus encoded machinery for ATP production, but apparently the modularity and separation of function provided by this ancient symbiosis turned out to be successful.

Compartmentalization in Cells

Cells are not an amorphous mixture of proteins, lipids and other molecules. Instead, all cells are comprised of well-defined compartments, each specializing in a particular function. In many cases subcellular processes may be described based on whether they occur at the plasma membrane , within the cytosol or within membrane bound organelles such as the nucleus, Golgi apparatus or even vesicular components of the membrane trafficking system like lysosomes and endosomes.

Despite the morphological and functional variety of cells from different tissue types and different organisms, all cells share important similarities in their compartmental organization. These fundamental compartments, often referred to as organelles, are summarized in the drawing of the generic animal cell (central cell). Examples of specialized cell types, shown around the generic cell, include neuron, macrophage, intestine epithelial cell, adipocyte, muscle cell and osteoclast.

Compartmentalization increases the efficiency of many subcellular processes by concentrating the required components to a confined space within the cell. Where a specific condition is required to facilitate a given subcellular process, this may be locally contained so as not to disrupt the function of other subcellular compartments. For example, lysosomes require a lower pH in order to facilitate degradation of internalized material. Membrane bound proton pumps present on the lysosome maintain this condition. Similarly, a large membrane surface area is required by mitochondria to efficiently generate ATP from electron gradients across its lipid bilayer. This is achieved through the structural composition of this particular organelle.

Importantly, individual organelles may be transported throughout the cell, and this essentially localizes entire subcellular processes to regions where they are required. This has been observed in neurons, which have extremely long axonal processes and require mitochondria to generate ATP at various locations along the axon. It would be inefficient to rely on the passive diffusion of ATP down the length of the axon.

Compartmentalization can also have important physiological implications. For example, polarized epithelial cells, which possess distinct apical and basolateral membranes, can, for instance produce a secretory surface for various glands. Similarly, neuronal cells develop effective networks due to the production of dendrites and axonal processes from opposite ends of the cell body. Moreover, in the case of embryonic stem cells, cell polarization can result in distinct fates of the daughter cells.

With each organelle facilitating its own function, they may be considered as subcellular compartments in their own right. However, without a regulated supply of components to the compartment, the processes and mechanisms that produce their overall function will be impeded. With many proteins and molecular components participating in multiple subcellular processes, and therefore required throughout multiple subcellular compartments, effective transport of the protein and molecular components, either by passive diffusion or directed recruitment, is essential for the overall function of the cell.


The aging process results in a gradual and progressive structural and functional deterioration of biomolecules that is associated with many pathological conditions, including cancer, neurodegenerative diseases, sarcopenia (loss of muscle mass) and liver dysfunction (Chung et al., 2009 Chung et al., 2008 Seo et al., 2006). Although several theories have been proposed to explain the fundamental mechanisms mediating these age-related diseases and conditions, the free-radical theory of aging is by far the most popular. This theory proposes that cumulative damage to biological macromolecules by oxygen radicals (reactive oxygen species ROS) leads to irreversible cell damage and an overall functional decline (Harman, 1956). The free-radical theory has also been extended to include mitochondria, as the accumulation of aging-associated mutations and deletions in mitochondrial DNA (mtDNA) can impair the function of the respiratory chain and enhance ROS production (Chomyn and Attardi, 2003 Harman, 1972). The increased ROS production can subsequently lead to a vicious cycle of exponentially increasing levels of mtDNA damage and oxidative stress in the cell (Bandy and Davison, 1990 Hiona and Leeuwenburgh, 2008 Kujoth et al., 2006 Seo et al., 2006 Seo et al., 2008) (Fig. 1). Although various genetic problems in mitochondria cause phenotypes that resemble premature aging (Wallace and Fan, 2009), additional support for this theory was provided by studies showing a direct link between mtDNA mutations and mammalian aging. In particular, mice with a proofreading-deficient version of PolgA, the catalytic subunit of mitochondrial DNA polymerase γ (POLG), accumulate mtDNA mutations that are associated with impaired respiratory-chain function and increased levels of apoptosis. These mtDNA-mutator mice, with accelerated levels of mutations, had a shorter life span and displayed age-related phenotypes [such as hair loss, kyphosis (curvature of the spine), osteoporosis and sarcopenia] at an early age (Kujoth et al., 2005 Trifunovic et al., 2004). Interestingly, these changes were not accompanied by increased levels of oxidative stress, a finding that has also been confirmed in humans (Hutter et al., 2007). This has resulted in much controversy regarding the idea that mtDNA mutations contribute to aging through increased ROS production and enhanced levels of oxidative stress in mitochondria. However, it is possible that the accumulation of mtDNA mutations that occur with age leads to alterations in cell-signaling pathways that can induce cell dysfunction and initiate apoptosis, irrespective of increased ROS production and oxidative stress in mitochondria. Whether mtDNA mutations play a causal role in the aging process is still an ongoing debate however, the fact that a functional decline in mitochondria occurs with age and that properly functioning mitochondria are crucial for longevity and minimizing age-related diseases cannot be refuted.

It is well established that mitochondria are highly motile and remarkably plastic organelles that continuously undergo fusion and fission events that actively alter their morphology. In addition, the dynamic regulation of mitochondrial fusion and fission has been shown to be an important mechanism of modulating cellular redox status, mtDNA integrity, organellar function and cell death (Liesa et al., 2009). Notably, genetic defects in the proteins involved in mitochondrial fusion and fission lead to severely altered mitochondrial shape, loss of mtDNA integrity, increased oxidative stress and apoptotic cell death it has been shown that these alterations can subsequently cause developmental abnormality, neuromuscular degeneration and metabolic disorders in humans (Chen and Chan, 2009). However, the relevance of mitochondrial fusion and fission to underlying mechanisms of aging has not been fully appreciated, in part because the molecular events that underlie the aging process have not yet been completely elucidated. In this Commentary, we discuss current knowledge of mitochondrial dynamics, structure and function in relation to key cellular events, including mitochondrial biogenesis, mtDNA homeostasis, autophagy and cell death. By providing a basic overview of mitochondrial fusion and fission events and their general function in these crucial biological processes during normal stable environmental conditions, we hope to portray how alterations in mitochondrial dynamics can contribute to the mitochondrial dysfunction that is commonly associated with aging.

Proposed model of mitochondrial dysfunction in aging. Toxic ROS generated during normal biological activity gradually impair cellular homeostatic pathways that defend against cellular stress and damage mitochondrial constituents, including the electron transfer chain (ETC) and mtDNA. Oxidative insults to mitochondria, in turn, impair the life-sustaining functions of the organelle – such as energy transduction, biogenesis of metabolites, Ca 2+ homeostasis and regulation of redox biology – with age, thereby contributing to a vicious cycle of accumulating mitochondrial damage that culminates in a mitochondrial functional crisis. This ultimately results in cell death and aging.

Proposed model of mitochondrial dysfunction in aging. Toxic ROS generated during normal biological activity gradually impair cellular homeostatic pathways that defend against cellular stress and damage mitochondrial constituents, including the electron transfer chain (ETC) and mtDNA. Oxidative insults to mitochondria, in turn, impair the life-sustaining functions of the organelle – such as energy transduction, biogenesis of metabolites, Ca 2+ homeostasis and regulation of redox biology – with age, thereby contributing to a vicious cycle of accumulating mitochondrial damage that culminates in a mitochondrial functional crisis. This ultimately results in cell death and aging.

Key Differences Between Mitochondria and Chloroplast

Following are the key difference between the two most important organelles of the cell:

  1. Mitochondria are the large, membrane-bound, bean-shaped organelle found in almost all kind of eukaryotic organism, also known as ‘powerhouse of the cell’. Mitochondria are responsible for cellular respiration and energy metabolism. Conversely, Chloroplast is found only in green plants and in few algae, they are the sites of photosynthesis. This organelle of the cell is much more complex and larger than the mitochondria.
  2. Mitochondria are present in the cells of all types of aerobic organisms like plants and animals, whereas Chloroplast is present in green plants and some algae, protists like Euglena. Mitochondria is the colourless, bean shape organelles. Chloroplasts are green colour and disc shape organelles.
  3. Mitochondria and Chloroplast have two chambers inside them which is the matrix and the cristae in mitochondria, stroma, and thylakoids in a chloroplast.
  4. The inner membrane of mitochondria is folded into cristae while that of a chloroplast, rises into flattened sacs called as thylakoids.
  5. The thylakoid membrane in chloroplast contains carotenoids, chlorophyll, and photosynthetic pigments, but these are absent in mitochondria. Mitochondria convert sugar (glucose) into chemical energy called as ATP (adenosine triphosphate), it uses oxygen and release energy by breaking the organic food and in turn produces carbon dioxide along with water. In chloroplast the solar energy is stored, this organelle helps in storing the energy, further it also uses carbon dioxide and water to make glucose. Chloroplast liberates or releases oxygen.
  6. Mitochondria are the site for beta oxidative, photorespiration, oxidative phosphorylation, ETC Chloroplast is the site for the photorespiration and photosynthesis.


  • Both are double membrane structure.
  • Both the organelle contains their DNA and RNA.
  • They both provide energy to the cell.
  • Both the organelles contain enzyme and coenzyme.
  • There is the involvement of the oxygen and carbon dioxide.
  • Another unique feature is that both the organelles can move from one place to another within the cell.


From the above article, we came to know that, being one of the most important parts of the eukaryotic cell, both the organelles are essential and contribute equally to the growth and function of the cell. It is also concluded that earlier mitochondria were the free-living aerobic bacteria, which became part of the eukaryotic cell due to some process.

Chloroplast, is not the part of all eukaryotic cell, as it is found in green plants and few algae. As these play the main role in process photosynthesis, through which plant prepare their food with the help of sunlight.

The mitochondrion is often referred as the cellular powerhouse because the organelle oxidizes organic acids and NADH derived from nutriments, converting around 40% of the Gibbs free energy change of these reactions into ATP, the major energy currency of cell metabolism. Mitochondria are thus microscopic furnaces that inevitably release heat as a by-product of these reactions, and this contributes to body warming, especially in endotherms like birds and mammals. Over the last decade, the idea has emerged that mitochondria could be warmer than the cytosol, because of their intense energy metabolism. It has even been suggested that our own mitochondria could operate under normal conditions at a temperature close to 50 °C, something difficult to reconcile with the laws of thermal physics.

Here, using our combined expertise in biology and physics, we exhaustively review the reports that led to the concept of a hot mitochondrion, which is essentially based on the development and use of a variety of molecular thermosensors whose intrinsic fluorescence is modified by temperature. Then, we discuss the physical concepts of heat diffusion, including mechanisms like phonons scattering, which occur in the nanoscale range. Although most of approaches with thermosensors studies present relatively sparse data and lack absolute temperature calibration, overall, they do support the hypothesis of hot mitochondria. However, there is no convincing physical explanation that would allow the organelle to maintain a higher temperature than its surroundings. We nevertheless proposed some research directions, mainly biological, that might help throw light on this intriguing conundrum.

Physical and Functional Communication

In adult cardiomyocytes mitochondria mobility is limited with mitochondria moving along microtubule networks (Frederick and Shaw, 2007). In most mammalian cells mitochondria generally cluster around the nucleus (Yoon, 2004), but mitochondria can be at different cytoplasmic locations leading to mitochondrial heterogeneity within different cell types (Kuznetsov et al., 2009 Piquereau et al., 2013). In cardiomyocytes, this heterogenous population can be divided up into three separate populations, characterized by their location within the cardiomyofibers: subsarcolemmal mitochondria (SSM), intermyofibrillar mitochondria (IFM) or perinuclear mitochondria (PNM) (Shimada et al., 1984). Electron microscopy and transmission electron microscopy show these distinct populations of mitochondria as the morphology is unique for both their location and function (Shimada et al., 1984 Manneschi and Federico, 1995 Vendelin et al., 2005 Wikstrom et al., 2009). SSM are located just under the surface sarcolemma and possess closely packed cristae. Holmuhamedov and colleagues characterized and assessed SSM, finding that SSM have a high sensitivity to Ca 2+ overload-mediated inhibition of ATP synthesis (Holmuhamedov et al., 2012). PNM are clustered at nuclear pores between and around the two nuclei commonly found in cardiomyocytes. Due to their well-developed curved cristae, PNM have little matrix area that allows for higher ATP production (Hackenbrock, 1966). Lu and coworkers provide us with one of the few studies on PNM and found that PNM morphology is more spherical than IFM and SSM, where the lack of myofibrillar constraints allows for the PNM spherical shape and its high mobility. This group also determined that PNM are physically closer to protein synthesis sites for perinuclear mitochondrial biogenesis, indicating that PNM are involved in transcription and translation processes (Piquereau et al., 2013 Lu et al., 2019). Lastly, IFM are very well organized, as they lay closely parallel to contractile myofilaments. This highly organized structure may cause IFMs to be restricted in their position and mobility however it also provides bioenergetic support needed for contraction and mitochondrial interaction with the cytoskeleton and the SR (Wilding et al., 2006). IFM form an interface with the SR, which allows molecules to be transported between the SR and mitochondria for effective signal transduction (Eisner et al., 2013).

The SR is of extreme importance in cardiomyocytes, as it critically regulates excitation-contraction coupling by releasing its stored Ca 2+ via the type 2 ryanodine receptor (RyR2) (Fu et al., 2006 Figure 2). To understand the release of Ca 2+ by the SR, we will discuss the SR compartments. Structurally, the SR is a diverse organelle, consisting of junctional, corbular, and network SR. These components of the SR form a complex tubular network where the network SR is formed by a series of interconnected tubules that are located in the region between the transverse-tubules (T-tubules) (Figure 2). The junctional SR is the domain where specialized junctions are formed with the sarcolemma T-tubules, allowing the SR to bring its ryanodine sensitive Ca 2+ channels (RyRs) in close range with the sarcolemma voltage-gated L-type Ca 2+ channels (Franzini-Armstrong and Protasi, 1997 Franzini-Armstrong et al., 1999 Figure 2). The corbular SR expresses RyRs as well, however it does not form junctions with the sarcolemma (Vega et al., 2011). The membrane depolarization, as a result of excitation-contraction (EC), causes the L-type Ca 2+ channels to open up close to the junctional SR (jSR). This results in a small amount of Ca 2+ entering the limited cytosolic space that separates the SR and the T-tubule sarcolemma. This increase in Ca 2+ concentration exceeds the threshold for the RyR2 to be activated through a mechanism of Ca 2+ -induced Ca 2+ release (CICR) (Figure 2 Fabiato, 1983). This activation of a small number of clustered RyR2 affects the concentration of intracellular calcium, inducing �lcium sparks” (Cheng et al., 1993). When multiple “sparks” are activated by the EC, a rise of intracellular calcium can be detected in the dyadic cleft (Sharma et al., 2000), thereby initiating myocardial contractions.

Figure 2. Sarcoplasmic reticulum-mitochondria communications. Sarcoplasmic reticulum (SR) is in close proximity to T-tubules and mitochondria. Depicted are the channels involved in Ca 2+ flux by which SR regulates excitation-contraction coupling and Ca 2+ signaling with mitochondria. Microdomains where Ca 2+ exchanges occur are shown. Ryanodine Receptor 2 (RyR2) and L-Type Ca 2+ Channels located at the t-tubule-SR interface voltage-dependent anion-selective channel proteins (VDAC) colocalize with RyR2 and also with L-Type Ca 2+ channels, Mitochondrial Calcium Uniporter Complex (MCUC) is mainly located at the SR-Mito interface, Rapid modes of Ca 2+ uptake (RaM), ryanodyne receptor type 1 (mRyR1), Mitochondrial Na + /Ca 2+ exchanger (NCLX) is located at the opposite side of MCUC near the sarcoplasmic/endoplasmic reticulum Ca2+ ATPases (SERCA). Mitofusin1/2 (MFN1/2) function as SR-mitochondrial tethers (Created with

Interestingly, it has been reported that L-type Ca 2+ channels regulate mitochondrial functions through actin filaments (Viola and Hool, 2010). Viola and colleagues demonstrated that Ca 2+ influx through this channel increases superoxide production, NADH levels, metabolism and also mitochondrial membrane potential in a calcium independent pathway (Viola et al., 2009). The cytoplasmic β-subunit of the L-type Ca 2+ channel is anchored to the actin cytoskeleton. Disruption of this tether decreases Ca 2+ flux, leading to poor oxygen consumption and ATP production by the mitochondria (Viola et al., 2009). Moreover, this group found that cardiomyocytes isolated from mdx mice (a mouse model of Duschennes muscular dystrophy that in patients causes dilated cardiomyopathy) had impaired communication between L-type Ca 2+ and mitochondria through an alteration in the cytoskeletal network that led to a decrease in metabolic functions (Viola et al., 2014). They were the first to show a physical and functional association between L-type Ca 2+ and VDAC through F-actin (Viola et al., 2013, 2014 Figure 2). They further reported that mdx cardiomyocytes maintain a higher level of resting calcium and L-type Ca 2+ channel activation plays a role in the observed mitochondrial calcium changes all of which may promote DCM (Viola et al., 2013).

Interactions between the SR and mitochondria play a key role in cardiomyocyte contraction and multiple studies have provided us with evidence of mitochondrial Ca 2+ uptake, and thus increased mitochondrial Ca 2+ levels, in response to SR-mediated Ca 2+ release (Bassani et al., 1992 Negretti et al., 1993 Szalai et al., 2000). As mentioned previously, cardiac mitochondria uptake cytosolic Ca 2+ through MCUC. However, this channel requires at least a concentration of 2𠄵 μM of free Ca 2+ in the SR’s bulk in order to be activated (Kirichok et al., 2004). This Ca 2+ concentration is reached only within specific microdomains at the SR-mitochondria interface (Figure 2). Specifically, in such extremely structured cells, MCUC is expressed more in areas in close contact with the jSR, which contain Ca 2+ -releasing RyR2 channels (Figure 2 De La Fuente et al., 2016). Moreover, Ca 2+ fluxes must be tightly regulated. De la Fuente and colleagues demonstrated that MCUC and NCLX are spatially excluded in cardiac mitochondria (Figure 2) in order to optimize Ca 2+ signals and sustain mitochondrial metabolism required for cardiomyocyte contraction, while also reducing the energy required for mitochondrial membrane potential depolarization (De La Fuente et al., 2016, 2018). It remains controversial whether mitochondrial Ca 2+ uptake occurs quickly and synchronously with the cytosolic Ca 2+ fluctuations in a beat to beat model (Garc໚-Pérez et al., 2008) or if it increases slowly (Griffiths et al., 1997). The differences between these two models rely on the experimental approach used in terms of probes, stimulation and species (De la Fuente and Sheu, 2019).

It should be noted that at the microdomain level, the molecular bridge permitting Ca 2+ exchange between SR-Mitochondria is formed by RyR2 and VDAC2 channels (Figure 2 Min et al., 2012). Moreover, in aged cardiomyoctes the physical interaction between RyR2 and VDAC is significantly reduced, leading to lower mitochondrial Ca 2+ uptake, thereby promoting oxidative stress and energy impairment (Fernandez-Sanz et al., 2014). However, this event is independent of RyR2 and VDAC expression levels and does not correlate with MFN2 levels (Fernandez-Sanz et al., 2014).

It has become widely accepted that mitochondrial dysfunction is associated with heart disease (Bonora et al., 2019). Pathological SR-dependent Ca 2+ leak through RyR2 channels is involved in excessive mitochondrial Ca 2+ uptake (Santulli et al., 2015 Ruiz-Meana et al., 2019). Santulli et al. were the first to show using a murine model that a feedback loop exists between SR and mitochondria where Ca 2+ leak through RyR2 channels causes mitochondrial Ca 2+ overload and ROS burst that enhances Ca 2+ leak and thereby worsening mitochondrial dysfunction (Santulli et al., 2015). Moreover, in human and murine senescent cardiomyocytes, the SR-mitochondria Ca 2+ exchange is significantly impaired due to RyR2 glycation (Ruiz-Meana et al., 2019). These aged cardiomyocytes display a deficient dicarbonyl detoxification pathway initiating Ca 2+ leak through RyR2 channels and further increasing mitochondrial Ca 2+ uptake. Taken together, this mechanism is involved in the transition from a healthy cardiomyocyte to a failing cardiomyocyte, as it may induce bioenergetic deficit through mitochondrial damage leading to mitochondrial dysfunction (Ruiz-Meana et al., 2019).

It is important to mention that MCUC is not the only manner in which mitochondrial Ca 2+ uptake occurs in cardiomyocytes. Three different approaches of MCU-knockout mice (global constitutive, cardiac-specific, dominant negative overexpression) have been developed (Pan et al., 2013 Kwong et al., 2015 Luongo et al., 2015). These models demonstrate that MCUC is dispensable for heart function in basal cardiac activity, while under 𠇏ight-or-flight” conditions MCU deletion shows inhibition of acute mitchondrial Ca 2+ uptake. Moreover, these mice are highly protected from mPTP opening during ischemia-reperfusion injury. Therefore, in basal resting conditions, mitochondrial Ca 2+ influx for maintaining ATP production and cardiac metabolism occurs through other channels such as rapid modes of Ca 2+ uptake (RaM) (Buntinas et al., 2001) and ryanodyne receptor type 1 (mRyR1) (Beutner et al., 2001, 2005 Figure 2) both of which are located in the IMM. RaM displays a faster Ca 2+ uptake compared to MCUC (Buntinas et al., 2001), while mRyR1 opens at lower cytosolic Ca 2+ concentrations (Beutner et al., 2001, 2005).

As discussed above, in cardiomyocytes SR-mitochondria Ca 2+ transfer occurs mainly in areas of direct physical contact. However, the proteins involved in the tethering have been poorly investigated in the heart. Currently, mitofusin 2 (MFN2) is the protein that has been suggested to tether this physical interaction (Figure 2 Papanicolaou et al., 2011 Chen et al., 2012). It remains a matter of discussion whether MFN2 acts as a tether or a spacer at the ER/SR-mito interface. Two different MFN2-KO mouse models have been generated showing opposite results. When the gene deletion is made after birth the distance of SR-mitochondria increased leading to a rise of Ca 2+ concentration in the SR (Chen et al., 2012). Moreover, isopronenterol stimulation of cardiomyocytes, display an increase in cytosolic Ca 2+ concentrations and lower mitochondrial Ca 2 uptake. Of note, this model does not show mitochondrial bioenergetic impairment (Chen et al., 2012). On the other hand, if the gene is deleted at the embryonic stage, there are no differences in the SR-mitochondria distance and therefore, no alterations in Ca 2+ fluxes. This result may be due to compensatory remodeling (Papanicolaou et al., 2012). Each of these mouse models demonstrates mitochondrial morphology alterations, contractile depression and cardiac hypertrophy in the adults. However, more studies are needed to investigate the role of MFN2 in tethering SR-mitochondria and also to determine whether other proteins may be involved in this tethering (Figure 2).

Energy status and cell death

As documented for a number of mammalian cell lines, a drop in ATP is commonly associated with apoptosis[(Bossy-Wetzel et al., 1998 de Graaf et al., 2002 Izyumov et al., 2004 Marton et al., 1997 Vander Heiden et al., 1999)exceptions exist (e.g. Atlante et al.,2005)]. This relationship with ATP level exists despite the fact that there are a number of steps in the apoptotic pathway that actually require ATP (see below, `Specific requirements for ATP in cell death'). However, it is appropriate to point out that a major drop in cellular ATP can occur without limiting the activities of many of these steps, due to the micromolar Km values for the enzymes involved (cf. Skulachev, 2006) and the rather high ATP binding affinities for non-catalytic proteins that participate in the process (Riedl et al.,2005). Further, the amount of ATP needed to permit the progression of apoptosis is actually quite small, and the source of ATP is not critical,e.g. it can be produced from either glycolysis or oxidative phosphorylation(Nicotera et al., 2000 Skulachev, 2006). Thus,modest compromise in mitochondrial function (and a concomitant drop in ATP)does not necessarily dictate that necrosis will be favored and apoptosis disfavored. Nevertheless it is true that necrotic cell death is typically observed under conditions of severe ATP depletion in mammalian systems(Atlante et al., 2005 Eguchi et al., 1997 Leist et al., 1997 Nicotera et al., 2000 Nicotera et al., 1998 Nicotera and Melino,2004).

Skulachev and colleagues have studied the interplay in HeLa cells between cellular ATP levels and the occurrence of apoptosis versus necrosis(Izyumov et al., 2004). These authors report that not only is the magnitude of the ATP drop important for favoring one form of cell death over the other, but also the length of time HeLa cells experience compromised ATP levels is a determining factor, with longer exposures being more conducive to necrosis. Such linkages to both the duration and degree of ATP depression were first shown for Jurkat cells(Leist et al., 1997), an immortalized line of human T lymphocytes. When interpreting cell death studies with immortalized cell lines, a cautionary note it is that such cells typically display an altered metabolic poise (more glycolytic based), and the features of cell death are apt to differ from primary cells or tissues.

If placed in the perspective of the overall energy budget for a cell, the ATP requirements for operating the cell death pathways are likely to be small. The main consumers of cellular energy in the basal state are three processes.(1) The metabolic cost of active transport by the Na + /K + -ATPase for the maintenance of ion gradients averages 36% [range 15–58% (Covi and Hand, 2007)] of the basal metabolic rate across many cell types(Hand and Hardewig, 1996 Rolfe and Brown, 1997). Similarly, the cost of maintaining the proton gradient across the mitochondrial inner membrane, i.e. offsetting the proton leak, is also estimated to be quite substantial, accounting for 20–40% of the respiration rate of hepatocytes isolated from a rat and a lizard(Brand et al., 1994). Thus,over half the cell's energy can be devoted to processes of ion transport alone. (2) Under resting conditions, the metabolic cost of protein synthesis ranges between 18 and 26% in various tissues and cell types(Hawkins, 1991), and even higher values are observed for tissues during growth or increased biosynthetic activity (Land et al., 1993). The cost of ubiquitin-dependent protein degradation is sizable as well(Land and Hochachka, 1994).(3) Finally, DNA transcription and replication are responsible for up to 10%of basal cellular metabolism (Rolfe and Brown, 1997). Consequently, initiation and execution of apoptosis are unlikely to represent even a noticeable fraction of the energy budget. In the latter phases of cell death, when various physiological processes have been disrupted, the relative cost of cell death processes within the cellular energy budget undoubtedly increases. Unfortunately, a quantitative inventory of how much ATP is utilized during apoptosis is not available(Chiarugi, 2005).

Key points

The intestinal epithelium is a constantly renewing monolayer of cells undergoing continuous steps of proliferation, differentiation and finally cell death, representing an excellent model system to study stem cell regulation.

Intestinal epithelial cells (IECs) are key players in intestinal diseases such as IBD and colorectal cancer (CRC), constituting a dynamic interface between microbiota and host.

Mitochondrial function and metabolism determine and regulate IEC properties, such as differentiation status and proliferation.

Mitochondrial unfolded protein response (MT-UPR) coordinates mitochondrial function, metabolism and cellular phenotype and is activated in various diseases, including IBD and CRC.

MT-UPR might act as a sensor of the luminal and host environment, orchestrating epithelial tissue responses.

Determining the proliferative and regenerative capacity of IECs, the MT-UPR constitutes an attractive target for future therapeutic approaches for intestinal diseases.

Mitochondrial quality control in pulmonary fibrosis

Mechanisms underlying the pathogenesis of pulmonary fibrosis remain incompletely understood. Emerging evidence suggests changes in mitochondrial quality control are a critical determinant in many lung diseases, including chronic obstructive pulmonary disease, asthma, pulmonary hypertension, acute lung injury, lung cancer, and in the susceptibility to pulmonary fibrosis. Once thought of as the kidney-bean shaped powerhouses of the cell, mitochondria are now known to form interconnected networks that rapidly and continuously change their size to meet cellular metabolic demands. Mitochondrial quality control modulates cell fate and homeostasis, and diminished mitochondrial quality control results in mitochondrial dysfunction, increased reactive oxygen species (ROS) production, reduced ATP production, and often induces intrinsic apoptosis. Here, we review the role of the mitochondria in alveolar epithelial cells, lung macrophages, and fibroblasts within the context of pulmonary fibrosis.

We would like to thank Rita Teodoro for critical reading of the manuscript. We thank Telmo Pereira from the Microscopy Facility at CEDOC for technical support the Fly Facility at CEDOC CONGENTO: consortium for genetically tractable organisms (LISBOA-01-0145-FEDER-022170) the Vienna Drosophila Resource Center and Bloomington Drosophila Stock Center (NIH P40OD018537) for stocks used in this study the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242.

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Keywords: mitochondrial dynamics, germ stem cell, oxidative phosphorylation, differentiation, oogenesis, fertility, Drosophila melanogaster

Citation: Garcez M, Branco-Santos J, Gracio PC and Homem CCF (2021) Mitochondrial Dynamics in the Drosophila Ovary Regulates Germ Stem Cell Number, Cell Fate, and Female Fertility. Front. Cell Dev. Biol. 8:596819. doi: 10.3389/fcell.2020.596819

Received: 20 August 2020 Accepted: 30 November 2020
Published: 28 January 2021.

Susana Solá, University of Lisbon, Portugal

Yuan Wang, Michigan State University, United States
Maria Fernanda Forni, Yale University, United States

Copyright © 2021 Garcez, Branco-Santos, Gracio and Homem. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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