Resistance of Dynamin-related Protein 1 Oligomers to Disassembly Impairs Mitophagy, Resulting in Myocardial Inflammation and Heart Failure

We have reported previously that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy. The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and t...

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Published in:	The Journal of biological chemistry Vol. 290; no. 43; pp. 25907 - 25919
Main Authors:	Cahill, Thomas J., Leo, Vincenzo, Kelly, Matthew, Stockenhuber, Alexander, Kennedy, Nolan W., Bao, Leyuan, Cereghetti, Grazia, Harper, Andrew R., Czibik, Gabor, Lao, Chunyan, Bellahcene, Mohamed, Steeples, Violetta, Ghaffari, Safar, Yavari, Arash, Mayer, Alice, Poulton, Joanna, Ferguson, David J.P., Scorrano, Luca, Hettiarachchi, Nishani T., Peers, Chris, Boyle, John, Hill, R. Blake, Simmons, Alison, Watkins, Hugh, Dear, T. Neil, Ashrafian, Houman
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 23-10-2015 American Society for Biochemistry and Molecular Biology
Subjects:	Animals Biopolymers - genetics Biopolymers - metabolism Biopolymers - physiology cardiomyopathy Cells, Cultured Dynamins - genetics Dynamins - metabolism Dynamins - physiology heart failure Heart Failure - etiology Heart Failure - physiopathology Mice mitochondria mitochondrial metabolism Mitophagy Molecular Bases of Disease Mutation Myocarditis - etiology Myocarditis - physiopathology Oxidative Phosphorylation heart failure mitophagy cardiomyopathy mitochondria mitochondrial metabolism
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Summary:	We have reported previously that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy. The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and to define the cellular sequelae leading to heart failure in the Python monogenic dilated cardiomyopathy model. We found that the C452F mutation increased Drp1 GTPase activity. The mutation also conferred resistance to oligomer disassembly by guanine nucleotides and high ionic strength solutions. In a mouse embryonic fibroblast model, Drp1 C452F cells exhibited abnormal mitochondrial morphology and defective mitophagy. Mitochondria in C452F mouse embryonic fibroblasts were depolarized and had reduced calcium uptake with impaired ATP production by oxidative phosphorylation. In the Python heart, we found a corresponding progressive decline in oxidative phosphorylation with age and activation of sterile inflammation. As a corollary, enhancing autophagy by exposure to a prolonged low-protein diet improved cardiac function in Python mice. In conclusion, failure of Drp1 disassembly impairs mitophagy, leading to a downstream cascade of mitochondrial depolarization, aberrant calcium handling, impaired ATP synthesis, and activation of sterile myocardial inflammation, resulting in heart failure. Background: The C452F mutation in the mitochondrial fission protein Drp1 leads to heart failure through an unknown mechanism. Results: C452F impairs Drp1 disassembly, leading to impaired mitophagy, failed bioenergetics, and inflammation. Conclusion: Drp1-mediated mitochondrial fission is essential for normal cardiac function. Significance: Mutations in mitochondrial quality control proteins are a likely cause of human cardiomyopathy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Supported by National Institutes of Health Grant R01-GM067180. Both authors contributed equally to this work. Supported by Medical Research Council Project Grant MR/J010448/1 and Wellcome Trust Project Grant 0948685/Z/10/Z. Supported by a National Institutes for Health Research Academic Clinical Fellowship.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M115.665695