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Calcium Transport and Signaling in Mitochondria

Roberto Bravo‐Sagua, Valentina Parra, Camila López‐Crisosto, Paula Díaz, Andrew F. G. Quest, Sergio Lavandero

10.1002/cphy.c160013

Source: Volume 7, Issue 2, April 2017

Published online: March 2017

Full Article on Wiley Online Library



ABSTRACT

Calcium (Ca2+) is a key player in the regulation of many cell functions. Just like Ca2+, mitochondria are ubiquitous, versatile, and dynamic players in determining both cell survival and death decisions. Given their ubiquitous nature, the regulation of both is deeply intertwined, whereby Ca2+ regulates mitochondrial functions, while mitochondria shape Ca2+ dynamics. Deregulation of either Ca2+ or mitochondrial signaling leads to abnormal function, cell damage or even cell death, thereby contributing to muscle dysfunction or cardiac pathologies. Moreover, altered mitochondrial Ca2+ homeostasis has been linked to metabolic diseases like cancer, obesity, and pulmonary hypertension. In this review article, we summarize the mechanisms that coordinate mitochondrial and Ca2+ responses and how they affect human health. © 2017 American Physiological Society. Compr Physiol 7:623‐634, 2017.

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Figure 1. Figure 1. Mitochondrial structure and bioenergetics. The OMM and IMM define the mitochondrial matrix and the intermembrane space, respectively. In the matrix, the citric acid cycle takes place, which involves the oxidation of acetyl‐CoA molecules to yield carbon dioxide (CO2), ATP, and reducing equivalents, in the form of NADH and FADH2. Both molecules fuel the ETC located in the IMM. A chain of redox reactions executed by the ETC is used to pump protons (H+) from the matrix to the intermembrane space, thereby generating an electrochemical gradient that creates the transmembrane potential (ΔΨmt). Because of its redox activity, the ETC generates ROS. Accumulated H+ in the intermembrane space then enter the matrix through the ATP synthase, which uses H+ translocation as a driving force for ATP synthesis.
Figure 2. Figure 2. Remodeling of the mitochondrial network. (A) For mitochondrial fission, Drp‐1 binds to the mitochondrial surface by interaction with Fis‐1 and other proteins. There, Drp‐1 forms a ring that constricts mitochondria, thus dividing them in two. (B) Mitochondrial fusion initiates with the interaction of two mitochondrial surfaces by homo or heterotypic formation of mitofusin dimers (Mfn‐1/2). This process leads to outer membrane fusion. Then, Opa‐1 drives the remodeling of mitochondrial cristae, thus allowing for inner membrane fusion. (C) Four main components are required for mitogenesis: mitochondrial DNA (mtDNA), mtDNA‐encoded proteins, nucleus‐encoded proteins, and lipids. (D) For mitophagy, mitochondrial fission generates small mitochondria, which are then engulfed by an isolation membrane. Mitochondria are thus trapped inside a vesicle that later fuses with lysosomes, leading to their enzymatic degradation.
Figure 3. Figure 3. ER‐to‐mitochondria Ca2+ transfer occurs at mitochondria‐associated ER membranes (MAM), where specialized Ca2+ channels reside. Opening of inositol triphosphate receptors (IP3R) at the ER surface leads to Ca2+ release from the ER lumen, forming a local microdomain of high [Ca2+]. Nearby mitochondria take up Ca2+ using their mitochondrial potential (ΔΨmt) as the driving force. Ca2+ crosses the OMM through the channel VDAC1, and the IMM via mitochondrial Ca2+ uniporter (MCU). MICU1 forms part of the MCU complex, which acts as a gatekeeper, allowing Ca2+ entry into mitochondria only in the presence of high [Ca2+].
Figure 4. Figure 4. Ca2+ regulates mitochondrial function and dynamics. (A) In the mitochondrial matrix, Ca2+ stimulates the citric acid cycle via activation of PDH by relieving inhibition mediated by PDH kinase. Also, Ca2+ activates isocitrate and oxoglutarate dehydrogenases (IDH and OGDH, respectively). Moreover, Ca2+ promotes intramitochondrial cAMP formation, which leads to PKA‐mediated stimulation of ATP synthesis. (B) However, mitochondrial Ca2+ overload leads to the loss of the mitochondrial potential (ΔΨmt) and opening of the mitochondrial permeability transition pore (MPTP), which releases apoptotic factors into the cytoplasm, such as cytochrome c. (C) Sites of high Ca2+ concentration in the cytoplasm induce mitochondrial clustering, because Ca2+ dampens mitochondrial movement along microtubules by inhibition of the miro/milton complex, which couples mitochondria to molecular motors such as kinesin. (D) Ca2+ also stimulates mitochondrial fission, via activation of the phosphatase calcineurin A, which dephosphorylates and thus activates Drp‐1. Active Drp‐1 then induces mitochondrial fragmentation through formation of a constriction ring around mitochondria.
Figure 5. Figure 5. The dynamics of the mitochondrial network shape Ca2+ signals within the cell. (A) Their movement along microtubules allows for the clustering or dispersion of mitochondria. Clustered mitochondria are more efficient in preventing local Ca2+ elevations, basically because there are more mitochondria present for Ca2+ uptake. (B) Mitochondrial localization in close proximity to sites of Ca2+ release permits more efficient Ca2+ uptake, because the mitochondria are exposed to higher [Ca2+] that generate a greater chemical gradient to drive Ca2+ uptake. (C) Elongated mitochondria are also better Ca2+ buffers, due to the increase in available matrix volume for Ca2+ diffusion. This capacity for internal ion diffusion turns mitochondria into “Ca2+ conducting wires” throughout the cell. (D) Appropriate regulation of mitochondrial volume has been shown to be critical for mitochondrial Ca2+ buffering, as forced mitochondrial expansion or fragmentation reduce their Ca2+ uptake capacity.
Figure 6. Figure 6. Alterations in mitochondrial Ca2+ uptake contribute to development of various diseases. (A) Decreased ER‐mitochondria coupling and mitochondrial fragmentation are detrimental for Ca2+ uptake and mitochondrial function, thus leading to neurodegenerative diseases such as Alzheimer's. Altered mitochondrial cristae and network fragmentation also lead to inadequate Ca2+ buffering, thus rendering neurons susceptible to excitotoxic cell death, as is the case for Charcot‐Marie Tooth type 2 (CMT2) and ADOA. (B) In skeletal muscle, extensive mitochondrial fragmentation sensitizes cells to Ca2+‐mediated damage provoked by repetitive Ca2+ increases typical of muscle physiology. Furthermore, loss of mitochondrial connectivity decreases Akt signaling, which causes insulin resistance. Ultimately, altered mitochondrial morphology leads to abnormal propagation of Ca2+ waves, rendering cells unsuitable for muscle contraction, as in amyotrophic lateral sclerosis. (C) In cardiac myocytes, mitochondrial fragmentation also impairs the Akt pathway, thereby reducing insulin sensitivity. Excessive mitochondrial fragmentation together with decreased ER‐mitochondria coupling also contributes to cardiac hypertrophy by decreasing mitochondrial Ca2+ uptake. This alteration reduces metabolic efficiency, which triggers tissue remodeling to maintain cardiac function. (D) Excessive ER‐mitochondrial coupling results in augmented mitochondrial Ca2+, which induces oxidative stress that impairs mitochondrial function. In hepatocytes, mitochondrial oxidative damage leads to decreased glucose metabolism, which favors the development of obesity. Decreased ER‐to‐mitochondria Ca2+ transfer, on the other hand, depresses mitochondrial Ca2+ uptake, thus preventing mitochondrial Ca2+ overload required to trigger apoptosis. In pulmonary artery smooth muscle cells, apoptosis resistance leads to an imbalance in cell number, resulting in increased vascular resistance and PAH. Finally, both increased and decreased mitochondrial Ca2+ uptake have been proposed to participate in cancer progression. Cells with predominantly oxidative metabolism due to increased [Ca2+]mito are more efficient in energy generation, but prone to mutations due to oxidative DNA damage. In contrast, cells with depressed mitochondrial function are more resistant to apoptosis and produce intermediary metabolites that fuel the metabolism of oxidative cells. Such symbiosis between both cancer cell types is thought to be crucial for tumor cell growth and adaptation.


Figure 1. Mitochondrial structure and bioenergetics. The OMM and IMM define the mitochondrial matrix and the intermembrane space, respectively. In the matrix, the citric acid cycle takes place, which involves the oxidation of acetyl‐CoA molecules to yield carbon dioxide (CO2), ATP, and reducing equivalents, in the form of NADH and FADH2. Both molecules fuel the ETC located in the IMM. A chain of redox reactions executed by the ETC is used to pump protons (H+) from the matrix to the intermembrane space, thereby generating an electrochemical gradient that creates the transmembrane potential (ΔΨmt). Because of its redox activity, the ETC generates ROS. Accumulated H+ in the intermembrane space then enter the matrix through the ATP synthase, which uses H+ translocation as a driving force for ATP synthesis.


Figure 2. Remodeling of the mitochondrial network. (A) For mitochondrial fission, Drp‐1 binds to the mitochondrial surface by interaction with Fis‐1 and other proteins. There, Drp‐1 forms a ring that constricts mitochondria, thus dividing them in two. (B) Mitochondrial fusion initiates with the interaction of two mitochondrial surfaces by homo or heterotypic formation of mitofusin dimers (Mfn‐1/2). This process leads to outer membrane fusion. Then, Opa‐1 drives the remodeling of mitochondrial cristae, thus allowing for inner membrane fusion. (C) Four main components are required for mitogenesis: mitochondrial DNA (mtDNA), mtDNA‐encoded proteins, nucleus‐encoded proteins, and lipids. (D) For mitophagy, mitochondrial fission generates small mitochondria, which are then engulfed by an isolation membrane. Mitochondria are thus trapped inside a vesicle that later fuses with lysosomes, leading to their enzymatic degradation.


Figure 3. ER‐to‐mitochondria Ca2+ transfer occurs at mitochondria‐associated ER membranes (MAM), where specialized Ca2+ channels reside. Opening of inositol triphosphate receptors (IP3R) at the ER surface leads to Ca2+ release from the ER lumen, forming a local microdomain of high [Ca2+]. Nearby mitochondria take up Ca2+ using their mitochondrial potential (ΔΨmt) as the driving force. Ca2+ crosses the OMM through the channel VDAC1, and the IMM via mitochondrial Ca2+ uniporter (MCU). MICU1 forms part of the MCU complex, which acts as a gatekeeper, allowing Ca2+ entry into mitochondria only in the presence of high [Ca2+].


Figure 4. Ca2+ regulates mitochondrial function and dynamics. (A) In the mitochondrial matrix, Ca2+ stimulates the citric acid cycle via activation of PDH by relieving inhibition mediated by PDH kinase. Also, Ca2+ activates isocitrate and oxoglutarate dehydrogenases (IDH and OGDH, respectively). Moreover, Ca2+ promotes intramitochondrial cAMP formation, which leads to PKA‐mediated stimulation of ATP synthesis. (B) However, mitochondrial Ca2+ overload leads to the loss of the mitochondrial potential (ΔΨmt) and opening of the mitochondrial permeability transition pore (MPTP), which releases apoptotic factors into the cytoplasm, such as cytochrome c. (C) Sites of high Ca2+ concentration in the cytoplasm induce mitochondrial clustering, because Ca2+ dampens mitochondrial movement along microtubules by inhibition of the miro/milton complex, which couples mitochondria to molecular motors such as kinesin. (D) Ca2+ also stimulates mitochondrial fission, via activation of the phosphatase calcineurin A, which dephosphorylates and thus activates Drp‐1. Active Drp‐1 then induces mitochondrial fragmentation through formation of a constriction ring around mitochondria.


Figure 5. The dynamics of the mitochondrial network shape Ca2+ signals within the cell. (A) Their movement along microtubules allows for the clustering or dispersion of mitochondria. Clustered mitochondria are more efficient in preventing local Ca2+ elevations, basically because there are more mitochondria present for Ca2+ uptake. (B) Mitochondrial localization in close proximity to sites of Ca2+ release permits more efficient Ca2+ uptake, because the mitochondria are exposed to higher [Ca2+] that generate a greater chemical gradient to drive Ca2+ uptake. (C) Elongated mitochondria are also better Ca2+ buffers, due to the increase in available matrix volume for Ca2+ diffusion. This capacity for internal ion diffusion turns mitochondria into “Ca2+ conducting wires” throughout the cell. (D) Appropriate regulation of mitochondrial volume has been shown to be critical for mitochondrial Ca2+ buffering, as forced mitochondrial expansion or fragmentation reduce their Ca2+ uptake capacity.


Figure 6. Alterations in mitochondrial Ca2+ uptake contribute to development of various diseases. (A) Decreased ER‐mitochondria coupling and mitochondrial fragmentation are detrimental for Ca2+ uptake and mitochondrial function, thus leading to neurodegenerative diseases such as Alzheimer's. Altered mitochondrial cristae and network fragmentation also lead to inadequate Ca2+ buffering, thus rendering neurons susceptible to excitotoxic cell death, as is the case for Charcot‐Marie Tooth type 2 (CMT2) and ADOA. (B) In skeletal muscle, extensive mitochondrial fragmentation sensitizes cells to Ca2+‐mediated damage provoked by repetitive Ca2+ increases typical of muscle physiology. Furthermore, loss of mitochondrial connectivity decreases Akt signaling, which causes insulin resistance. Ultimately, altered mitochondrial morphology leads to abnormal propagation of Ca2+ waves, rendering cells unsuitable for muscle contraction, as in amyotrophic lateral sclerosis. (C) In cardiac myocytes, mitochondrial fragmentation also impairs the Akt pathway, thereby reducing insulin sensitivity. Excessive mitochondrial fragmentation together with decreased ER‐mitochondria coupling also contributes to cardiac hypertrophy by decreasing mitochondrial Ca2+ uptake. This alteration reduces metabolic efficiency, which triggers tissue remodeling to maintain cardiac function. (D) Excessive ER‐mitochondrial coupling results in augmented mitochondrial Ca2+, which induces oxidative stress that impairs mitochondrial function. In hepatocytes, mitochondrial oxidative damage leads to decreased glucose metabolism, which favors the development of obesity. Decreased ER‐to‐mitochondria Ca2+ transfer, on the other hand, depresses mitochondrial Ca2+ uptake, thus preventing mitochondrial Ca2+ overload required to trigger apoptosis. In pulmonary artery smooth muscle cells, apoptosis resistance leads to an imbalance in cell number, resulting in increased vascular resistance and PAH. Finally, both increased and decreased mitochondrial Ca2+ uptake have been proposed to participate in cancer progression. Cells with predominantly oxidative metabolism due to increased [Ca2+]mito are more efficient in energy generation, but prone to mutations due to oxidative DNA damage. In contrast, cells with depressed mitochondrial function are more resistant to apoptosis and produce intermediary metabolites that fuel the metabolism of oxidative cells. Such symbiosis between both cancer cell types is thought to be crucial for tumor cell growth and adaptation.
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Article Title: Calcium Transport and Signaling in Mitochondria
 

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Roberto Bravo‐Sagua, Valentina Parra, Camila López‐Crisosto, Paula Díaz, Andrew F. G. Quest, Sergio Lavandero. Calcium Transport and Signaling in Mitochondria. Compr Physiol 2017, 7: 623-634. doi: 10.1002/cphy.c160013