Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency

Cogliati, Sara; Frezza, Christian; Soriano, María Eugenia; Varanita, Tatiana; Quintana-Cabrera, Rubén; Corrado, Mauro; Cipolat, Sara; Costa, Veronica; Casarin, Alberto; Gomes, Lígia C.; Perales‐Clemente, Ester; Salviati, Leonardo; Fernández‐Silva, Patricio; Enrı́quez, José Antonio; Scorrano, Luca

doi:10.1016/j.cell.2013.08.032

Cited by 1,040 publications

(999 citation statements)

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“…Instead, our data suggest that a late defect in complex I may account for the reduction of electron transport across the respiratory chain as evidenced by the decreased maximal respiration in mutant neurons and the reduction of complex I levels and activity. Functional changes in complex I were previously reported in fibroblasts with OPA1 haploinsufficiency18 or the p.G488R mutation9 and in models of acute OPA1 depletion, where respiratory efficiency was impaired when mitochondria were energized specifically with the complex I substrates, glutamate/malate 17. Therefore, in human iPSC‐derived neurons, OPA1 levels are important for the maintenance of oxidative phosphorylation, at least partly, by regulating the stability of complex I.…”

Section: Discussionmentioning

confidence: 95%

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Jonikas

Madill

Mathy

et al. 2018

Annals of Neurology

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ObjectiveDefective mitochondrial function attributed to optic atrophy 1 (OPA1) mutations causes primarily optic atrophy and, less commonly, neurodegenerative syndromes. The pathomechanism by which OPA1 mutations trigger diffuse loss of neurons in some, but not all, patients is unknown. Here, we used a tractable induced pluripotent stem cell (iPSC)‐based model to capture the biology of OPA1 haploinsufficiency in cases presenting with classic eye disease versus syndromic parkinsonism.MethodsiPSCs were generated from 2 patients with OPA1 haploinsufficiency and 2 controls and differentiated into dopaminergic neurons. Metabolic profile was determined by extracellular flux analysis, respiratory complex levels using immunoblotting, and complex I activity by a colorimetric assay. Mitochondria were examined by transmission electron microscopy. Mitochondrial DNA copy number and deletions were assayed using long‐range PCR. Mitochondrial membrane potential was measured by tetramethylrhodamine methyl ester uptake, and mitochondrial fragmentation was assessed by confocal microscopy. Exome sequencing was used to screen for pathogenic variants.ResultsOPA1 haploinsufficient iPSCs differentiated into dopaminergic neurons and exhibited marked reduction in OPA1 protein levels. Loss of OPA1 caused a late defect in oxidative phosphorylation, reduced complex I levels, and activity without a significant change in the ultrastructure of mitochondria. Loss of neurons in culture recapitulated dopaminergic degeneration in syndromic disease and correlated with mitochondrial fragmentation.InterpretationOPA1 levels maintain oxidative phosphorylation in iPSC‐derived neurons, at least in part, by regulating the stability of complex I. Severity of OPA1 disease associates primarily with the extent of OPA1‐mediated fusion, suggesting that activation of this mechanism or identification of its genetic modifiers may have therapeutic or prognostic value. Ann Neurol 2018;83:915–925

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Section: Discussionmentioning

confidence: 95%

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Jonikas

Madill

Mathy

et al. 2018

Annals of Neurology

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“…Mitochondrial cristae morphology also influences respiratory chain organization. 40,49 GB disrupts cristae junctions through an unknown mechanism, which likely contributes to mitochondrial dysfunction and ROS production.…”

Section: Discussionmentioning

confidence: 99%

“…Cristae morphology is a critical determinant of ETC organization and respiratory efficiency. 40 We therefore examined whether GB treatment might also affect the shape of cristae. By electron microscopy, we observed that in GB-treated mitochondria many of the cristae appeared to have lost their junction (Figures 6h and i).…”

Section: Gb-induced Ros Requires a Functional Respiratory Chainmentioning

confidence: 99%

Granzyme B-induced mitochondrial ROS are required for apoptosis

et al. 2014

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Caspases and the cytotoxic lymphocyte protease granzyme B (GB) induce reactive oxygen species (ROS) formation, loss of transmembrane potential and mitochondrial outer membrane permeabilization (MOMP). Whether ROS are required for GBmediated apoptosis and how GB induces ROS is unclear. Here, we found that GB induces cell death in an ROS-dependent manner, independently of caspases and MOMP. GB triggers ROS increase in target cell by directly attacking the mitochondria to cleave NDUFV1, NDUFS1 and NDUFS2 subunits of the NADH: ubiquinone oxidoreductase complex I inside mitochondria. This leads to mitocentric ROS production, loss of complex I and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junctions. Furthermore, we have also found that GB-induced mitocentric ROS are necessary for optimal apoptogenic factor release, rapid DNA fragmentation and lysosomal rupture. Interestingly, scavenging the ROS delays and reduces many of the features of GB-induced death. Consequently, GB-induced ROS significantly promote apoptosis. Cell Death and Differentiation (2015) 22, 862-874; doi:10.1038/cdd.2014.180; published online 31 October 2014To induce cell death, human granzyme B (GB) activates effector caspase-3 or acts directly on key caspase substrates, such as the proapoptotic BH3 only Bcl-2 family member Bid, inhibitor of caspase-activated DNase (ICAD), poly-(ADPribose) polymerase-1 (PARP-1), lamin B, nuclear mitotic apparatus protein 1 (NUMA1), catalytic subunit of the DNAdependent protein kinase (DNA-PKcs) and tubulin. [1][2][3] Consequently, caspase inhibitors have little effect on human GB-mediated cell death and DNA fragmentation. 2 GB causes reactive oxygen species (ROS) production, dissipation of the mitochondrial transmembrane potential (ΔΨm) and MOMP, which leads to the release of apoptogenic factors such as cytochrome c (Cyt c), HtrA2/Omi, endonuclease G (Endo G), Smac/Diablo and apoptosis-inducing factor, from the mitochondrial intermembrane space to the cytosol. [4][5][6][7][8][9][10][11] Interestingly, cells deficient for Bid, Bax and Bak are still sensitive to human GB-induced cell death, 5,11-13 suggesting that human GB targets the mitochondria in another way that needs to be characterized. Altogether, much attention has been focused on the importance of MOMP in the execution of GB-mediated cell death, leaving unclear whether ROS production is a bystander effect or essential to the execution of GBinduced apoptosis. The mitochondrial NADH: ubiquinone oxidoreductase complex I is a key determinant in steadystate ROS production. This 1 MDa complex, composed of 44 subunits, 14 couples the transfer of two electrons from NADH to ubiquinone with the translocation of four protons to generate the ΔΨm. The importance of ROS has been previously demonstrated for caspase-3 and granzyme A (GA) pathways through the cleavage of NDUFS1 and NDUFS3, respectively. [15][16][17][18] GA induces cell death in a Bcl-2-insensitive and caspase-and MOMP-indepen...

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“…The inner membrane dynamin-like GTPase Opa1 mediates inner membrane mitochondrial fusion and morphology (13,15,16). Inner membrane proteases such as Oma1 cleave long membrane-bound Opa1 forms (Opa1-L) into short soluble forms (Opa1-S).…”

Section: Journal Of Biological Chemistry 24883mentioning

confidence: 99%

StarD7 Protein Deficiency Adversely Affects the Phosphatidylcholine Composition, Respiratory Activity, and Cristae Structure of Mitochondria

Horibata

Ando

Zhang

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerPhosphatidylcholine (PC) is a major phospholipid of mitochondria, comprising 40 -50% of both the outer and the inner membranes. However, PC must be imported from its production organelles because mitochondria lack the enzymes essential for PC biosynthesis. In a previous study, we found that StarD7 mediates the intracellular transfer of PC to mitochondria. Therefore, in this study, we analyzed the contribution of StarD7 to the maintenance of mitochondrial phospholipid content and function using siRNA-mediated knockdown and knock-out (KO) of the StarD7 gene in HEPA-1 cells. Real time analysis of respiratory activity demonstrated that the oxygen consumption rate and activity of mitochondrial complexes were impaired in StarD7-KD cells. To confirm these results, we established StarD7-KO HEPA-1 cells by double nicking using CRISPR/Cas9n. As expected, StarD7-KD and -KO cells showed a significant reduction in mitochondrial PC content. The ATP level and growth rate of KO cells were notably lower compared with wild-type cells when cultured in glucose-free galactosecontaining medium to force cells to rely on mitochondrial ATP production. In KO cells, the level of the MTCO1 protein, a primary subunit of complex IV, was reduced without a concomitant decrease in its mRNA, but the level was restored when StarD7-I was overexpressed. StarD7-KO cells showed impaired formation of the mitochondrial supercomplexes and exhibited a disorganized cristae structure, with no changes in optic atrophy 1 protein. These findings indicate that StarD7 plays important roles in maintaining the proper composition of mitochondrial phospholipids as well as mitochondrial function and morphogenesis.

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Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency

Cited by 1,040 publications

References 50 publications

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

Granzyme B-induced mitochondrial ROS are required for apoptosis

StarD7 Protein Deficiency Adversely Affects the Phosphatidylcholine Composition, Respiratory Activity, and Cristae Structure of Mitochondria

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