Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows

Blum, Thorsten B.; Hahn, Alexander; Meier, Thomas; Davies, Karen M.; Kühlbrandt, Werner

doi:10.1073/pnas.1816556116

Cited by 227 publications

(221 citation statements)

References 36 publications

(80 reference statements)

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“…4A). The CV dimer is thought to be essential to the formation of cristae by bending the IMM [51]. ATP synthase function depends on CL, which binds specifically, yet intermittently, to the IMM embedded c-ring portion of CV in the F0 region, acting as a lubricant for rotation of the CV rotor [10,52,53].…”

Section: Atp Production and Transport (Cv Ck And Adt)mentioning

confidence: 99%

“…CV localizes near the tightly curved ends of cristae, where it assembles as rows of dimers stabilizing the IMM curvature [54][55][56]. Interestingly, isolated CV reconstituted into liposomes self-assemble into rows of dimers inducing membrane curvature [51]. Compartments generated by the membrane folds of cristae allow for pools of highly concentrated protons to drive CV rotation.…”

Section: Atp Production and Transport (Cv Ck And Adt)mentioning

confidence: 99%

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Mitochondrial protein interaction landscape of SS-31

Chavez

Tang

Campbell

et al. 2019

Preprint

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Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy. Significance StatementSS-31 is a synthetic peptide that improves mitochondrial function and is currently undergoing clinical trials for treatments of heart failure, primary mitochondrial myopathy, and other mitochondrial diseases. SS-31 interacts with cardiolipin which is abundant in the inner mitochondrial membrane, but mechanistic details of its pharmacological effects are unknown. Here we apply a novel chemical cross-linking/mass spectrometry method to provide the first direct evidence for specific interactions between SS-31 and mitochondrial proteins. The identified SS-31 interactors are functional components in ATP production and 2-oxoglutarate metabolism and signaling, consistent with improved mitochondrial function resultant from SS-31 treatment. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy.

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Section: Atp Production and Transport (Cv Ck And Adt)mentioning

confidence: 99%

Section: Atp Production and Transport (Cv Ck And Adt)mentioning

confidence: 99%

Mitochondrial protein interaction landscape of SS-31

Chavez

Tang

Campbell

et al. 2019

Preprint

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“…Despite earlier assumptions that CI-V were randomly distributed within the inner mitochondrial membrane (IMM), it is now widely accepted that they form higher-order structures in vivo (2,3). The arrangement of CV in rows of V-shaped dimers has been linked to membrane bending and cristae formation (4)(5)(6), and a functional role for CV tetramers has recently been suggested (7). However, the roles of the supercomplexes (SCs) formed by CI-IV, as well as their assembly process, remain to be established (8)(9)(10).…”

mentioning

confidence: 99%

Rcf2 revealed in cryo-EM structures of hypoxic isoforms of mature mitochondrial III-IV supercomplexes

Hartley

Meunier

Pinotsis

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The organization of the mitochondrial electron transport chain proteins into supercomplexes (SCs) is now undisputed; however, their assembly process, or the role of differential expression isoforms, remain to be determined. In Saccharomyces cerevisiae, cytochrome c oxidase (CIV) forms SCs of varying stoichiometry with cytochrome bc1 (CIII). Recent studies have revealed, in normoxic growth conditions, an interface made exclusively by Cox5A, the only yeast respiratory protein that exists as one of two isoforms depending on oxygen levels. Here we present the cryo-EM structures of the III2-IV1 and III2-IV2 SCs containing the hypoxic isoform Cox5B solved at 3.4 and 2.8 Å, respectively. We show that the change of isoform does not affect SC formation or activity, and that SC stoichiometry is dictated by the level of CIII/CIV biosynthesis. Comparison of the CIV5B- and CIV5A-containing SC structures highlighted few differences, found mainly in the region of Cox5. Additional density was revealed in all SCs, independent of the CIV isoform, in a pocket formed by Cox1, Cox3, Cox12, and Cox13, away from the CIII–CIV interface. In the CIV5B-containing hypoxic SCs, this could be confidently assigned to the hypoxia-induced gene 1 (Hig1) type 2 protein Rcf2. With conserved residues in mammalian Hig1 proteins and Cox3/Cox12/Cox13 orthologs, we propose that Hig1 type 2 proteins are stoichiometric subunits of CIV, at least when within a III-IV SC.

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“…The mechanisms of mitochondrial cristae biogenesis are debated and different mechanisms for this process have been suggested [21][22][23][24][25][26][27][28] . To better analyze the formation of cristae and their structure and dynamics under different cellular conditions, a new approach for high-resolution live cell imaging of mitochondrial cristae is urgently needed.…”

Section: Discussionmentioning

confidence: 99%

Live-cell STED microscopy of mitochondrial cristae

Stephan

Roesch

Riedel

et al. 2019

Preprint

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Mitochondria are highly dynamic organelles that exhibit a complex inner architecture. They exhibit a smooth outer membrane and a highly convoluted inner membrane that forms invaginations called cristae. Imaging cristae in living cells poses a formidable challenge for light microscopy. Relying on a cell line stably expressing the mitochondrial protein Cox8A fused to the SNAP-tag and using STED (stimulated emission depletion) super-resolution microscopy, we demonstrate the visualization of cristae dynamics in cultivated human cells.

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Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows

Cited by 227 publications

References 36 publications

Mitochondrial protein interaction landscape of SS-31

Mitochondrial protein interaction landscape of SS-31

Rcf2 revealed in cryo-EM structures of hypoxic isoforms of mature mitochondrial III-IV supercomplexes

Live-cell STED microscopy of mitochondrial cristae

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