Structure of a mitochondrial ATP synthase with bound native cardiolipin

Muhleip, A.; McComas, Sarah; Amunts, Alexey

doi:10.7554/elife.51179

Cited by 84 publications

(122 citation statements)

References 82 publications

(134 reference statements)

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“…In line with this model, cardiolipin is found enriched in contact sites , and proteins involved in cardiolipin synthesis share strong genetic interactions with MICOS components . Cardiolipin also affects oligomerization of the F 1 F o ‐ATP synthase, possibly by a direct interaction . Cardiolipin‐deficient mitochondria from Drosophila flight muscle display loss of ATP synthase dimers and oligomers and a random distribution , in contrast to the localization of higher order ATP synthase assemblies in regions of high curvature in wild‐type mitochondria.…”

Section: Nonbilayer‐forming Phospholipidsmentioning

confidence: 67%

Shaping the mitochondrial inner membrane in health and disease

et al. 2020

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Colina-Tenorio L, Horten P, Pfanner N, Rampelt H (University of Freiburg, Freiburg, Germany). Shaping the mitochondrial inner membrane in health and disease (Review Symposium). J Intern Med 2020; 287: 645-664.Mitochondria play central roles in cellular energetics, metabolism and signalling. Efficient respiration, mitochondrial quality control, apoptosis and inheritance of mitochondrial DNA depend on the proper architecture of the mitochondrial membranes and a dynamic remodelling of inner membrane cristae. Defects in mitochondrial architecture can result in severe human diseases affecting predominantly the nervous system and the heart. Inner membrane morphology is generated and maintained in particular by the mitochondrial contact site and cristae organizing system (MICOS), the F 1 F o -ATP synthase, the fusion protein OPA1/Mgm1 and the nonbilayer-forming phospholipids cardiolipin and phosphatidylethanolamine. These protein complexes and phospholipids are embedded in a network of functional interactions. They communicate with each other and additional factors, enabling them to balance different aspects of cristae biogenesis and to dynamically remodel the inner mitochondrial membrane. Genetic alterations disturbing these membrane-shaping factors can lead to human pathologies including fatal encephalopathy, dominant optic atrophy, Leigh syndrome, Parkinson's disease and Barth syndrome.

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Section: Nonbilayer‐forming Phospholipidsmentioning

confidence: 67%

Shaping the mitochondrial inner membrane in health and disease

et al. 2020

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“…Together, the specific elements add ~0.7 MDa to the type III ATP synthase dimer, doubling its size compared to bacterial counterparts. For the conserved subunits, we adopted the yeast nomenclature 19 , and type III specific subunits are named ATPTT1-13 according to descending molecular weight, as previously proposed 21 , 27 (Supplementary Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization

et al. 2020

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Mitochondrial ATP synthases form functional homodimers to induce cristae curvature that is a universal property of mitochondria. To expand on the understanding of this fundamental phenomenon, we characterized the unique type III mitochondrial ATP synthase in its dimeric and tetrameric form. The cryo-EM structure of a ciliate ATP synthase dimer reveals an unusual U-shaped assembly of 81 proteins, including a substoichiometrically bound ATPTT2, 40 lipids, and co-factors NAD and CoQ. A single copy of subunit ATPTT2 functions as a membrane anchor for the dimeric inhibitor IF1. Type III specific linker proteins stably tie the ATP synthase monomers in parallel to each other. The intricate dimer architecture is scaffolded by an extended subunit-a that provides a template for both intra- and inter-dimer interactions. The latter results in the formation of tetramer assemblies, the membrane part of which we determined to 3.1 Å resolution. The structure of the type III ATP synthase tetramer and its associated lipids suggests that it is the intact unit propagating the membrane curvature.

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“…While there have been some notable cases of CL being resolved directly in crystal structures (e.g. the ADP/ATP carrier [ 74 , 93 ], cytochrome bc 1 [ 94 ], and cytochrome c oxidase [ 95 ]), the cryo-electron microscopy ‘resolution revolution’ [ 96 ] means that there are now many more membrane protein structures with CL resolved, such as the yeast respiratory supercomplexes [ 97 , 98 ], mammalian Complex I [ 99 , 100 ], and ATP synthase [ 101 ]. As such, there are not to my knowledge any structures of mitochondrial proteins resolved in the presence of MLCL.…”

Section: Discussionmentioning

confidence: 99%

Monolysocardiolipin (MLCL) interactions with mitochondrial membrane proteins

Duncan

2020

Biochemical Society Transactions

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Monolysocardiolipin (MLCL) is a three-tailed variant of cardiolipin (CL), the signature lipid of mitochondria. MLCL is not normally found in healthy tissue but accumulates in mitochondria of people with Barth syndrome (BTHS), with an overall increase in the MLCL:CL ratio. The reason for MLCL accumulation remains to be fully understood. The effect of MLCL build-up and decreased CL content in causing the characteristics of BTHS are also unclear. In both cases, an understanding of the nature of MLCL interaction with mitochondrial proteins will be key. Recent work has shown that MLCL associates less tightly than CL with proteins in the mitochondrial inner membrane, suggesting that MLCL accumulation is a result of CL degradation, and that the lack of MLCL–protein interactions compromises the stability of the protein-dense mitochondrial inner membrane, leading to a decrease in optimal respiration. There is some data on MLCL–protein interactions for proteins involved in the respiratory chain and in apoptosis, but there remains much to be understood regarding the nature of MLCL–protein interactions. Recent developments in structural, analytical and computational approaches mean that these investigations are now possible. Such an understanding will be key to further insights into how MLCL accumulation impacts mitochondrial membranes. In turn, these insights will help to support the development of therapies for people with BTHS and give a broader understanding of other diseases involving defective CL content.

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Structure of a mitochondrial ATP synthase with bound native cardiolipin

Cited by 84 publications

References 82 publications

Shaping the mitochondrial inner membrane in health and disease

Shaping the mitochondrial inner membrane in health and disease

Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization

Monolysocardiolipin (MLCL) interactions with mitochondrial membrane proteins

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