OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand
Cristae, the organized invaginations of the mitochondrial inner membrane, respond structurally to the energetic demands of the cell. The mechanism by which these dynamic changes are regulated and the consequences thereof are largely unknown. Optic atrophy 1 (OPA1) is the mitochondrial GTPase respons...
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Published in | The EMBO journal Vol. 33; no. 22; pp. 2676 - 2691 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Blackwell Publishing Ltd
18.11.2014
Nature Publishing Group UK BlackWell Publishing Ltd |
Subjects | |
Online Access | Get full text |
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Summary: | Cristae, the organized invaginations of the mitochondrial inner membrane, respond structurally to the energetic demands of the cell. The mechanism by which these dynamic changes are regulated and the consequences thereof are largely unknown. Optic atrophy 1 (OPA1) is the mitochondrial GTPase responsible for inner membrane fusion and maintenance of cristae structure. Here, we report that OPA1 responds dynamically to changes in energetic conditions to regulate cristae structure. This cristae regulation is independent of OPA1's role in mitochondrial fusion, since an OPA1 mutant that can still oligomerize but has no fusion activity was able to maintain cristae structure. Importantly, OPA1 was required for resistance to starvation‐induced cell death, for mitochondrial respiration, for growth in galactose media and for maintenance of ATP synthase assembly, independently of its fusion activity. We identified mitochondrial solute carriers (SLC25A) as OPA1 interactors and show that their pharmacological and genetic blockade inhibited OPA1 oligomerization and function. Thus, we propose a novel way in which OPA1 senses energy substrate availability, which modulates its function in the regulation of mitochondrial architecture in a SLC25A protein‐dependent manner.
Synopsis
Metabolic stress causes inner mitochondrial membrane fusion protein OPA1 to interact with solute carriers and to oligomerize to regulate cristae shape, thereby maintaining mitochondrial activity under low energy availability.
OPA1 dynamically responds to energy substrate availability, mediating changes in cristae ultrastructure.
OPA1‐mediated cristae changes are required for cell adaptation to metabolic demand, independently of OPA1 fusion activity.
SLC25A proteins interact with OPA1 and modulate its function.
OGC (SLC25A11) affects how OPA1 oligomerizes in response to starvation, mediating changes in mitochondrial function.
Graphical Abstract
Metabolic stress causes inner mitochondrial membrane fusion protein OPA1 to interact with solute carriers and to oligomerize to regulate cristae shape, thereby maintaining mitochondrial activity under low energy availability. |
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Bibliography: | istex:224723C1FD2F4D4A0DBCBA469A00DA9524219985 Shelby Hayter Pass the Baton Graduate Fellowship Suplementary Figure S1Suplementary Figure S2Suplementary Figure S3Suplementary Figure S4Suplementary Figure S5Suplementary Figure S6Suplementary Figure S7Suplementary Figure S8Suplementary Figure S9Suplementary Table S1Suplementary Table S2Legends for Supplementary FiguresSource Data for Supplementary Figure S1Source Data for Supplementary Figure S7Review Process FileSource Data for Figure 1Source Data for Figure 2Source Data for Figure 3Source Data for Figure 4Source Data for Figure 5Source Data for Figure 6Source Data for Figure 7 Heart and Stroke Foundation Heart and Stroke Society of Canada ArticleID:EMBJ201488349 ark:/67375/WNG-DXH929C2-6 Heart and Stroke Foundation of Canada - No. T7185 Canadian Institutes of Health Research - No. MOP50471; No. MOP57810 Ontario Graduate Scholarship Parkinson's Research Consortium Parkinson's Society of Canada Research Fellowship Brain Canada/Krembil Foundation ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Subject Categories Membrane & Intracellular Transport; Metabolism |
ISSN: | 0261-4189 1460-2075 |
DOI: | 10.15252/embj.201488349 |