Mitochondrial Cristae: Where Beauty Meets Functionality
2016; Elsevier BV; Volume: 41; Issue: 3 Linguagem: Inglês
10.1016/j.tibs.2016.01.001
ISSN1362-4326
AutoresSara Cogliati, José Antonio Enrı́quez, Luca Scorrano,
Tópico(s)Mitochondrial Function and Pathology
ResumoMitochondrial cristae are dynamic bioenergetic compartments whose shape changes under different physiological conditions. Recent discoveries have unveiled the relation between cristae shape and oxidative phosphorylation (OXPHOS) function, suggesting that membrane morphology modulates the organization and function of the OXPHOS system, with a direct impact on cellular metabolism. As a corollary, cristae-shaping proteins have emerged as potential modulators of mitochondrial bioenergetics, a concept confirmed by genetic experiments in mouse models of respiratory chain deficiency. Here, we review our knowledge of mitochondrial ultrastructural organization and how it impacts mitochondrial metabolism. Mitochondrial cristae are dynamic bioenergetic compartments whose shape changes under different physiological conditions. Recent discoveries have unveiled the relation between cristae shape and oxidative phosphorylation (OXPHOS) function, suggesting that membrane morphology modulates the organization and function of the OXPHOS system, with a direct impact on cellular metabolism. As a corollary, cristae-shaping proteins have emerged as potential modulators of mitochondrial bioenergetics, a concept confirmed by genetic experiments in mouse models of respiratory chain deficiency. Here, we review our knowledge of mitochondrial ultrastructural organization and how it impacts mitochondrial metabolism. Mitochondria adapt their shape to sustain necessary cellular functions.Cristae are functional dynamic compartments whose shape and dimensions modulate the kinetics of chemical reactions and the structure of protein complexes.Cristae shape is maintained by the cooperation of mitochondrial-shaping proteins.Perturbations of mitochondrial-shaping proteins disrupt cristae shape and affect the structure of the OXPHOS system, impairing cellular metabolism and growth.Cristae shape could be an interesting and promising therapeutic target for modulating metabolic dysfunction. Mitochondria adapt their shape to sustain necessary cellular functions. Cristae are functional dynamic compartments whose shape and dimensions modulate the kinetics of chemical reactions and the structure of protein complexes. Cristae shape is maintained by the cooperation of mitochondrial-shaping proteins. Perturbations of mitochondrial-shaping proteins disrupt cristae shape and affect the structure of the OXPHOS system, impairing cellular metabolism and growth. Cristae shape could be an interesting and promising therapeutic target for modulating metabolic dysfunction. ‘Form ever follows function’ is a famous quote from the American architect Louis Sullivan. He reached this conclusion by observing nature, where function is determined by specific and defined structures. Mitochondria are an extraordinary example of this axiom: they are dynamic organelles that have crucial roles in many cellular processes, including apoptosis, metabolism, reactive oxygen species (ROS) detoxification, and ATP production through OXPHOS. Such a variety of functions is coupled to a highly defined but plastic structure that continuously changes according to the needs of the cell (Box 1).Box 1Mitochondrial StructureMitochondria were first described in 1857 by the Swiss anatomist Rudolf von Koelliker, who called them ‘sarcosomes’ while studying human muscle. Then, in 1898, Carl Brenda coined the name ‘mitochondrion’ from the Greek word mitos (thread) and chondros (granule). Their structure and number vary among different tissues and under different metabolic conditions. Advances in light and electron microscopy and biochemical fractionation of submitochondrial membrane resulted in the description of mitochondrial structure. Mitochondria are embedded by two membranes with different structures and functions. The outer membrane (OM) and the inner membrane (IM) can be further organized into specialized regions.The OM separates the mitochondria from the cytosol, yet it allows the passage of metabolites through the voltage-dependent anion channel (VDAC) [92Colombini M. et al.VDAC, a channel in the outer mitochondrial membrane.Ion Channels. 1996; 4: 169-202Crossref PubMed Google Scholar] and of nuclear-encoded proteins through the translocase of the OM TOM [93Pfanner N. Wiedemann N. Mitochondrial protein import: two membranes, three translocases.Curr. Opin. Cell Biol. 2002; 14: 400-411Crossref PubMed Scopus (69) Google Scholar]. Moreover, it is the platform where the β-barrel protein-sorting and assembly machinery (SAM), as well as mitochondrial-shaping proteins (Mfn1,2, Fis1) and proteins of apoptotic pathway (e.g., BAK), are located. In addition, at least two specialized regions of the OM have been described to interact with other organelles: (i) mitochondria-associated endoplasmic reticulum membrane (MAMs), which interact with the endoplasmic reticulum; and (ii) intermitochondrial junctions (IMJ), which interact with other mitochondria.The IM can be subdivided into the inner boundary membrane (IBM) and the cristae. The IBM contains the translocase inner membrane (TIM), which shuttles proteins into the matrix [94Pfanner N. Meijer M. The Tom and Tim machine.Curr. Biol. 1997; 7: R100-R103Abstract Full Text Full Text PDF PubMed Google Scholar], and proteins, such as Mia40 and Oxa1 [95Herrmann J.M. Neupert W. Protein insertion into the inner membrane of mitochondria.IUBMB Life. 2003; 55: 219-225Crossref PubMed Scopus (44) Google Scholar], which are essential for the correct assembly and localization of IM proteins. Cristae are fundamental structures for mitochondria and are not simply invaginations of the IM, as originally described by Palade in 1952. Indeed, during the 1990s, Mannella and colleagues used 3D image reconstruction of electron tomography to show that the cristae are bag-like structures, separated from the intermembrane space by narrow tubular junctions. This new structural organization suggested that cristae are specialized compartments for limiting the diffusion of molecules that are important for the OXPHOS system. A plethora of proteins that are not fully characterized regulate cristae biogenesis and structure. Among them, OPA1 and the MICOS complex are the masters of cristae dynamics [10Frezza C. et al.OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.Cell. 2006; 126: 177-189Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar, 27Pfanner N. et al.Uniform nomenclature for the mitochondrial contact site and cristae organizing system.J. Cell Biol. 2014; 204: 1083-1086Crossref PubMed Scopus (46) Google Scholar]. Mitochondria were first described in 1857 by the Swiss anatomist Rudolf von Koelliker, who called them ‘sarcosomes’ while studying human muscle. Then, in 1898, Carl Brenda coined the name ‘mitochondrion’ from the Greek word mitos (thread) and chondros (granule). Their structure and number vary among different tissues and under different metabolic conditions. Advances in light and electron microscopy and biochemical fractionation of submitochondrial membrane resulted in the description of mitochondrial structure. Mitochondria are embedded by two membranes with different structures and functions. The outer membrane (OM) and the inner membrane (IM) can be further organized into specialized regions. The OM separates the mitochondria from the cytosol, yet it allows the passage of metabolites through the voltage-dependent anion channel (VDAC) [92Colombini M. et al.VDAC, a channel in the outer mitochondrial membrane.Ion Channels. 1996; 4: 169-202Crossref PubMed Google Scholar] and of nuclear-encoded proteins through the translocase of the OM TOM [93Pfanner N. Wiedemann N. Mitochondrial protein import: two membranes, three translocases.Curr. Opin. Cell Biol. 2002; 14: 400-411Crossref PubMed Scopus (69) Google Scholar]. Moreover, it is the platform where the β-barrel protein-sorting and assembly machinery (SAM), as well as mitochondrial-shaping proteins (Mfn1,2, Fis1) and proteins of apoptotic pathway (e.g., BAK), are located. In addition, at least two specialized regions of the OM have been described to interact with other organelles: (i) mitochondria-associated endoplasmic reticulum membrane (MAMs), which interact with the endoplasmic reticulum; and (ii) intermitochondrial junctions (IMJ), which interact with other mitochondria. The IM can be subdivided into the inner boundary membrane (IBM) and the cristae. The IBM contains the translocase inner membrane (TIM), which shuttles proteins into the matrix [94Pfanner N. Meijer M. The Tom and Tim machine.Curr. Biol. 1997; 7: R100-R103Abstract Full Text Full Text PDF PubMed Google Scholar], and proteins, such as Mia40 and Oxa1 [95Herrmann J.M. Neupert W. Protein insertion into the inner membrane of mitochondria.IUBMB Life. 2003; 55: 219-225Crossref PubMed Scopus (44) Google Scholar], which are essential for the correct assembly and localization of IM proteins. Cristae are fundamental structures for mitochondria and are not simply invaginations of the IM, as originally described by Palade in 1952. Indeed, during the 1990s, Mannella and colleagues used 3D image reconstruction of electron tomography to show that the cristae are bag-like structures, separated from the intermembrane space by narrow tubular junctions. This new structural organization suggested that cristae are specialized compartments for limiting the diffusion of molecules that are important for the OXPHOS system. A plethora of proteins that are not fully characterized regulate cristae biogenesis and structure. Among them, OPA1 and the MICOS complex are the masters of cristae dynamics [10Frezza C. et al.OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.Cell. 2006; 126: 177-189Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar, 27Pfanner N. et al.Uniform nomenclature for the mitochondrial contact site and cristae organizing system.J. Cell Biol. 2014; 204: 1083-1086Crossref PubMed Scopus (46) Google Scholar]. Mitochondria can switch from an elongated and interconnected network to a fragmented state via fusion and fission events during the so-called ‘mitochondrial life cycle’ [1Twig G. et al.Fission and selective fusion govern mitochondrial segregation and elimination by autophagy.EMBO J. 2008; 27: 433-446Crossref PubMed Scopus (1000) Google Scholar]. Through these transitions, mitochondria modulate their functions and status and allow complex quality control. Recent discoveries shed light on the correlation between the modulation of mitochondrial shape and network and the energetic state of the cell. For example, activation of the recycling autophagy pathway triggers mitochondrial elongation [2Gomes L.C. et al.During autophagy mitochondria elongate, are spared from degradation and sustain cell viability.Nat. Cell Biol. 2011; 13: 589-598Crossref PubMed Scopus (406) Google Scholar, 3Rambold A.S. et al.Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 10190-10195Crossref PubMed Scopus (231) Google Scholar], protecting mitochondria from degradation and promoting mitochondrial ATP production to increase the efficiency of energy conversion during nutrient deprivation [2Gomes L.C. et al.During autophagy mitochondria elongate, are spared from degradation and sustain cell viability.Nat. Cell Biol. 2011; 13: 589-598Crossref PubMed Scopus (406) Google Scholar]. Even upon exposure to other acute stressors, such as oxidative stress, mitochondria elongate [4Tondera D. et al.SLP-2 is required for stress-induced mitochondrial hyperfusion.EMBO. J. 2009; 28: 1589-1600Crossref PubMed Scopus (225) Google Scholar, 5Jendrach M. et al.Short- and long-term alterations of mitochondrial morphology, dynamics and mtDNA after transient oxidative stress.Mitochondrion. 2008; 8: 293-304Crossref PubMed Scopus (86) Google Scholar]. The opposite situation is found under nutrient excess, where mitochondria fragment by uncoupling OXPHOS from ATP production [6Molina A.J. et al.Mitochondrial networking protects beta-cells from nutrient-induced apoptosis.Diabetes. 2009; 58: 2303-2315Crossref PubMed Scopus (110) Google Scholar]. Oxygen tension can also modify the structure and mobility of mitochondria, especially in neurons [7Zanelli S.A. et al.Nitric oxide impairs mitochondrial movement in cortical neurons during hypoxia.J. Neurochem. 2006; 97: 724-736Crossref PubMed Scopus (38) Google Scholar]. Taken together, these recent discoveries show that mitochondrial shape and bioenergetics are intimately linked, providing a defined framework to study the crucial biological problem of the relation between form and function. Mitochondria reorganize their internal structure by modifying the shape of the cristae. Nearly 50 years ago, Hackenbrock noted that, in response to low ADP concentrations, the inner membrane morphology changed from a ‘condensed’ state, characterized by a contracted and dense matrix compartment and wide cristae, to an ‘orthodox’ state, with an expanded, less dense matrix and a more compact cristae compartment [8Hackenbrock C.R. Ultrastructural bases for metabolically linked mechanical activity in mitochondria. I. Reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria.J. Cell Biol. 1966; 30: 269-297Crossref PubMed Google Scholar]. However, these pioneering observations remained confined to the aficionados of mitochondrial bioenergetics and were considered to be an in vitro artifact of isolated organelles incubated in nonphysiological sugar-containing media, until the discovery of the dynamic rearrangement of cristae shape that occurs during programmed cell death. This so-called ‘cristae remodeling’ occurs during apoptosis to allow the complete release of cytochrome c [9Scorrano L. et al.A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis.Dev. Cell. 2002; 2: 55-67Abstract Full Text Full Text PDF PubMed Scopus (654) Google Scholar]. This occurs through the proapoptotic members of the B cell lymphoma (BCL)-2 family, which widen cristae junctions and invert cristae curvature [9Scorrano L. et al.A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis.Dev. Cell. 2002; 2: 55-67Abstract Full Text Full Text PDF PubMed Scopus (654) Google Scholar, 10Frezza C. et al.OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.Cell. 2006; 126: 177-189Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar], ultimately impacting mitochondrial bioenergetics [11Cogliati S. et al.Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency.Cell. 2013; 155: 160-171Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar]. The discovery of this cristae-remodeling process showed that dynamic ultrastructural mitochondrial changes occur in pathophysiology and paved the way to discover the molecular mechanism controlling cristae shape. Moreover, it resulted in the hypothesis that the cell and the organelle can exploit changes in mitochondrial ultrastructure to modulate enzymatic activity. This concept has precedent in cell biology; for example, cells use swelling and shrinking processes to regulate their anabolic and metabolic functions, such as glycogen synthesis, maintenance of pH, and activation of Cdc42 [12Nalbant P. et al.Activation of endogenous Cdc42 visualized in living cells.Science. 2004; 305: 1615-1619Crossref PubMed Scopus (222) Google Scholar]. In a crucial proof-of-principle study, Orwar and colleagues used a solitary-vesicle model with the same size volume of mitochondria to demonstrate that the shape and volume of vesicles affects the reaction rate of several enzymes in the Krebs cycle [13Lizana L. et al.Controlling the rates of biochemical reactions and signaling networks by shape and volume changes.Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 4099-4104Crossref PubMed Scopus (0) Google Scholar], providing a biophysical basis for how changes in mitochondrial compartments can regulate the embedded biochemical reactions. Biological examples of this process exist: in the amoeba Chaos carolinensis, upon fasting, the cristae transition from random tubular to ordered (paracrystalline) larger cubic structures [14Deng Y. et al.Fasting induces cyanide-resistant respiration and oxidative stress in the amoeba Chaos carolinensis: implications for the cubic structural transition in mitochondrial membranes.Protoplasma. 2002; 219: 160-167Crossref PubMed Scopus (37) Google Scholar], perhaps to protect the membrane from oxidants and prevent mitochondrial damage, as demonstrated in the large vesicles [15Li Q.T. et al.Lipid peroxidation in small and large phospholipid unilamellar vesicles induced by water-soluble free radical sources.Biochem. Biophys. Res. Commun. 2000; 273: 72-76Crossref PubMed Scopus (38) Google Scholar]. In addition, upon different energetic states in mouse heart and muscle, adjacent mitochondria form intermitochondrial junctions (IMJs), where cristae density is higher and cristae are aligned in the same orientation. The authors hypothesized that IMJs allow exchange between mitochondria. Although more work is needed to understand the physiological role of IMJs, these findings underscore the notion of cristae as a dynamic energetic compartment [16Picard M. et al.Trans-mitochondrial coordination of cristae at regulated membrane junctions.Nat. Commun. 2015; 6: 6259Crossref PubMed Scopus (10) Google Scholar]. Cristae are the site of OXPHOS: 94% of complex III and ATP synthase [17Gilkerson R.W. et al.The cristal membrane of mitochondria is the principal site of oxidative phosphorylation.FEBS Lett. 2003; 546: 355-358Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar] and approximately 85% of total cytochrome c are stored in this compartment [9Scorrano L. et al.A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis.Dev. Cell. 2002; 2: 55-67Abstract Full Text Full Text PDF PubMed Scopus (654) Google Scholar] (Box 2). Evolutionarily, there is a molecular correlation between the core cristae-shaping machinery, the emergence of cristae, and the OXPHOS system [18Munoz-Gomez S.A. et al.Ancient homology of the mitochondrial contact site and cristae organizing system points to an endosymbiotic origin of mitochondrial cristae.Curr. Biol. 2015; 25: 1489-1495Abstract Full Text Full Text PDF PubMed Google Scholar], further supporting the concept that cristae are the true bioenergetic membrane of the mitochondrion. The OXPHOS system comprises four different complexes that are further assembled into supercomplexes (SC, Box 2).Box 2The Structure of the OXPHOS SystemThe OXPHOS system comprises protein complexes that couple the oxidation of reducing equivalents (NADH and FADH2) to the pumping of protons across the inner membrane, generating a proton electrochemical gradient that is then used by ATP synthase to synthesize ATP. NADH and FADH2 enter the electron transport chain through Complex I and Complex II, respectively, and the electrons are then transferred stepwise to coenzyme Q and from there to Complex III, cytochrome c, and finally to Complex IV, which passes them to molecular oxygen.The functional organization of the OXPHOS complexes has been widely debated. According to the latest model, known as the ‘plasticity model’, OXPHOS complexes are present as both single complexes and supercomplexes (SCs) of different composition and stoichiometry [96Acin-Perez R. et al.Respiratory active mitochondrial supercomplexes.Mol. Cell. 2008; 32: 529-539Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar].SCs have been described in mammals, yeast, plants, and algae [97Schagger H. Pfeiffer K. The ratio of oxidative phosphorylation complexes I-V in bovine heart mitochondria and the composition of respiratory chain supercomplexes.J. Biol. Chem. 2001; 276: 37861-37867Abstract Full Text Full Text PDF PubMed Google Scholar, 98Krause F. et al.Supramolecular organization of cytochrome c oxidase- and alternative oxidase-dependent respiratory chains in the filamentous fungus Podospora anserina.J. Biol. Chem. 2004; 279: 26453-26461Crossref PubMed Scopus (84) Google Scholar, 99Marques I. et al.Supramolecular organization of the respiratory chain in Neurospora crassa mitochondria.Eukaryot. Cell. 2007; 6: 2391-2405Crossref PubMed Scopus (50) Google Scholar, 100Chaban Y. et al.Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation.Biochim. Biophys. Acta. 2014; 1837: 418-426Crossref PubMed Scopus (35) Google Scholar]. Updated results demonstrate that the major SCs identified comprise complex I+III, I+III+IV, and III+IV [96Acin-Perez R. et al.Respiratory active mitochondrial supercomplexes.Mol. Cell. 2008; 32: 529-539Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 97Schagger H. Pfeiffer K. The ratio of oxidative phosphorylation complexes I-V in bovine heart mitochondria and the composition of respiratory chain supercomplexes.J. Biol. Chem. 2001; 276: 37861-37867Abstract Full Text Full Text PDF PubMed Google Scholar, 101Stroh A. et al.Assembly of respiratory complexes I, III, and IV into NADH oxidase supercomplex stabilizes complex I in Paracoccus denitrificans.J. Biol. Chem. 2004; 279: 5000-5007Crossref PubMed Scopus (139) Google Scholar, 102Dudkina N.V. et al.Structure of a mitochondrial supercomplex formed by respiratory-chain complexes I and III.Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 3225-3229Crossref PubMed Scopus (195) Google Scholar]. This organization allows a more efficient transport of electrons. Most Complex I is found to be associated with SCs, where its stability is enhanced. Complex II is essentially unassociated with SCs, because only a small fraction migrates at high molecular weights in native gels and it is not yet clear whether the high-molecular-weight species truly represent assembly into SCs or if they are only comigrating with other complexes [96Acin-Perez R. et al.Respiratory active mitochondrial supercomplexes.Mol. Cell. 2008; 32: 529-539Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 103Eubel H. et al.New insights into the respiratory chain of plant mitochondria. Supercomplexes and a unique composition of complex II.Plant Physiol. 2003; 133: 274-286Crossref PubMed Scopus (200) Google Scholar, 104Muster B. et al.Respiratory chain complexes in dynamic mitochondria display a patchy distribution in life cells.PLoS ONE. 2010; 5: e11910Crossref PubMed Scopus (33) Google Scholar]. ATP synthase can be found as a monomer or as a dimer, and is thought to not associate with any other complex. The interaction between complex III and IV [105Strogolova V. et al.Rcf1 and Rcf2, members of the hypoxia-induced gene 1 protein family, are critical components of the mitochondrial cytochrome bc1-cytochrome c oxidase supercomplex.Mol. Cell. Biol. 2012; 32: 1363-1373Crossref PubMed Scopus (55) Google Scholar, 106Chen Y.C. et al.Identification of a protein mediating respiratory supercomplex stability.Cell Metab. 2012; 15: 348-360Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 107Lapuente-Brun E. et al.Supercomplex assembly determines electron flux in the mitochondrial electron transport chain.Science. 2013; 340: 1567-1570Crossref PubMed Scopus (126) Google Scholar] is modulated by specific assembly factors: Rcf1 and 2 in yeast and SCAFI in mammals. Depending on the mouse strain, SCAFI is present as a long-active or short-inactive isoform, impacting SCs composition and oxygen consumption performance. This lends a possible molecular explanation to the variable respiratory complex organization observed in the brains of different mouse strains [108Buck K.J. et al.Genetic variability of respiratory complex abundance, organization and activity in mouse brain.Genes Brain Behav. 2014; 13: 135-143Crossref PubMed Scopus (0) Google Scholar]. In the fungal aging model Podospora anserina, ablation of the Saccharomyces cerevisiae homolog Rcf1 destabilizes complex IV and reduces the amount of complex IV-containing SCs, impairing mitochondrial respiration and generating oxidative stress, ultimately leading to a shorter lifespan [109Fischer F. et al.RCF1-dependent respiratory supercomplexes are integral for lifespan-maintenance in a fungal ageing model.Sci. Rep. 2015; 5: 12697Crossref PubMed Google Scholar]. Another modulator of the SCs assembly is MCJ/DnaJC15, which has been characterized as a negative modulator of complex I activity and assembly of SCs [110Hatle K.M. et al.MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations.Mol. Cell. Biol. 2013; 33: 2302-2314Crossref PubMed Scopus (16) Google Scholar]. The OXPHOS system comprises protein complexes that couple the oxidation of reducing equivalents (NADH and FADH2) to the pumping of protons across the inner membrane, generating a proton electrochemical gradient that is then used by ATP synthase to synthesize ATP. NADH and FADH2 enter the electron transport chain through Complex I and Complex II, respectively, and the electrons are then transferred stepwise to coenzyme Q and from there to Complex III, cytochrome c, and finally to Complex IV, which passes them to molecular oxygen. The functional organization of the OXPHOS complexes has been widely debated. According to the latest model, known as the ‘plasticity model’, OXPHOS complexes are present as both single complexes and supercomplexes (SCs) of different composition and stoichiometry [96Acin-Perez R. et al.Respiratory active mitochondrial supercomplexes.Mol. Cell. 2008; 32: 529-539Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar]. SCs have been described in mammals, yeast, plants, and algae [97Schagger H. Pfeiffer K. The ratio of oxidative phosphorylation complexes I-V in bovine heart mitochondria and the composition of respiratory chain supercomplexes.J. Biol. Chem. 2001; 276: 37861-37867Abstract Full Text Full Text PDF PubMed Google Scholar, 98Krause F. et al.Supramolecular organization of cytochrome c oxidase- and alternative oxidase-dependent respiratory chains in the filamentous fungus Podospora anserina.J. Biol. Chem. 2004; 279: 26453-26461Crossref PubMed Scopus (84) Google Scholar, 99Marques I. et al.Supramolecular organization of the respiratory chain in Neurospora crassa mitochondria.Eukaryot. Cell. 2007; 6: 2391-2405Crossref PubMed Scopus (50) Google Scholar, 100Chaban Y. et al.Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation.Biochim. Biophys. Acta. 2014; 1837: 418-426Crossref PubMed Scopus (35) Google Scholar]. Updated results demonstrate that the major SCs identified comprise complex I+III, I+III+IV, and III+IV [96Acin-Perez R. et al.Respiratory active mitochondrial supercomplexes.Mol. Cell. 2008; 32: 529-539Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 97Schagger H. Pfeiffer K. The ratio of oxidative phosphorylation complexes I-V in bovine heart mitochondria and the composition of respiratory chain supercomplexes.J. Biol. Chem. 2001; 276: 37861-37867Abstract Full Text Full Text PDF PubMed Google Scholar, 101Stroh A. et al.Assembly of respiratory complexes I, III, and IV into NADH oxidase supercomplex stabilizes complex I in Paracoccus denitrificans.J. Biol. Chem. 2004; 279: 5000-5007Crossref PubMed Scopus (139) Google Scholar, 102Dudkina N.V. et al.Structure of a mitochondrial supercomplex formed by respiratory-chain complexes I and III.Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 3225-3229Crossref PubMed Scopus (195) Google Scholar]. This organization allows a more efficient transport of electrons. Most Complex I is found to be associated with SCs, where its stability is enhanced. Complex II is essentially unassociated with SCs, because only a small fraction migrates at high molecular weights in native gels and it is not yet clear whether the high-molecular-weight species truly represent assembly into SCs or if they are only comigrating with other complexes [96Acin-Perez R. et al.Respiratory active mitochondrial supercomplexes.Mol. Cell. 2008; 32: 529-539Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 103Eubel H. et al.New insights into the respiratory chain of plant mitochondria. Supercomplexes and a unique composition of complex II.Plant Physiol. 2003; 133: 274-286Crossref PubMed Scopus (200) Google Scholar, 104Muster B. et al.Respiratory chain complexes in dynamic mitochondria display a patchy distribution in life cells.PLoS ONE. 2010; 5: e11910Crossref PubMed Scopus (33) Google Scholar]. ATP synthase can be found as a monomer or as a dimer, and is thought to not associate with any other complex. The interaction between complex III and IV [105Strogolova V. et al.Rcf1 and Rcf2, members of the hypoxia-induced gene 1 protein family, are critical components of the mitochondrial cytochrome bc1-cytochrome c oxidase supercomplex.Mol. Cell. Biol. 2012; 32: 1363-1373Crossref PubMed Scopus (55) Google Scholar, 106Chen Y.C. et al.Identification of a protein mediating respiratory supercomplex stability.Cell Metab. 2012; 15: 348-360Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 107Lapuente-Brun E. et al.Supercomplex assembly determines electron flux in the mitochondrial electron transport chain.Science. 2013; 340: 1567-1570Crossref PubMed Scopus (126) Google Scholar] is modulated by specific assembly factors: Rcf1 and 2 in yeast and SCAFI in mammals. Depending on the mouse strain, SCAFI is present as a long-active or short-inactive isoform, impacting SCs composition and oxygen consumption performance. This lends a possible molecular explanation to the variable respiratory complex organization ob
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