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. 2015 Dec 4;350(6265):aad0116.
doi: 10.1126/science.aad0116.

Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice

Timothy Wai  1 , Jaime García-Prieto  2 , Michael J Baker  3 , Carsten Merkwirth  3 , Paule Benit  4 , Pierre Rustin  4 , Francisco Javier Rupérez  5 , Coral Barbas  5 , Borja Ibañez  6 , Thomas Langer  7
Affiliations

Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice

Timothy Wai et al. Science. .

Abstract

Mitochondrial morphology is shaped by fusion and division of their membranes. Here, we found that adult myocardial function depends on balanced mitochondrial fusion and fission, maintained by processing of the dynamin-like guanosine triphosphatase OPA1 by the mitochondrial peptidases YME1L and OMA1. Cardiac-specific ablation of Yme1l in mice activated OMA1 and accelerated OPA1 proteolysis, which triggered mitochondrial fragmentation and altered cardiac metabolism. This caused dilated cardiomyopathy and heart failure. Cardiac function and mitochondrial morphology were rescued by Oma1 deletion, which prevented OPA1 cleavage. Feeding mice a high-fat diet or ablating Yme1l in skeletal muscle restored cardiac metabolism and preserved heart function without suppressing mitochondrial fragmentation. Thus, unprocessed OPA1 is sufficient to maintain heart function, OMA1 is a critical regulator of cardiomyocyte survival, and mitochondrial morphology and cardiac metabolism are intimately linked.

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Comment in

  • METABOLISM. Mitochondria shape cardiac metabolism.
    Gottlieb RA, Bernstein D. Gottlieb RA, et al. Science. 2015 Dec 4;350(6265):1162-3. doi: 10.1126/science.aad8222. Science. 2015. PMID: 26785456 No abstract available.
  • 'Mitotherapy' for Heart Failure.
    Sanchis-Gomar F, Lippi G, Lucia A. Sanchis-Gomar F, et al. Trends Mol Med. 2016 Apr;22(4):267-269. doi: 10.1016/j.molmed.2016.02.007. Epub 2016 Mar 7. Trends Mol Med. 2016. PMID: 26965961

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