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

ABSTRACT: 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.

SUBMITTER: Cahill TJ

PROVIDER: S-EPMC4646246 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Cahill Thomas J TJ Leo Vincenzo V Kelly Matthew M Stockenhuber Alexander A Kennedy Nolan W NW Bao Leyuan L Cereghetti Grazia M GM Harper Andrew R AR Czibik Gabor G Liao Chunyan C Bellahcene Mohamed M Steeples Violetta V Ghaffari Safar S Yavari Arash A Mayer Alice A Poulton Joanna J Ferguson David J P DJ Scorrano Luca L Hettiarachchi Nishani T NT Peers Chris C Boyle John J Hill R Blake RB Simmons Alison A Watkins Hugh H Dear T Neil TN Ashrafian Houman H

The Journal of biological chemistry 20150914 43

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 conferr ...[more]

PMID: 26370078

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Project description:ObjectivesThe purpose of this study was to identify where ultrasmall superparamagnetic particles of iron oxide (USPIO) locate to in myocardium, develop a methodology that differentiates active macrophage uptake of USPIO from passive tissue distribution; and investigate myocardial inflammation in cardiovascular diseases.BackgroundMyocardial inflammation is hypothesized to be a key pathophysiological mechanism of heart failure (HF), but human evidence is limited, partly because evaluation is challenging. USPIO-magnetic resonance imaging (MRI) potentially allows specific identification of myocardial inflammation but it remains unclear what the USPIO-MRI signal represents.MethodsHistological validation was performed using a murine acute myocardial infarction (MI) model. A multiparametric, multi-time-point MRI methodology was developed, which was applied in patients with acute MI (n = 12), chronic ischemic cardiomyopathy (n = 7), myocarditis (n = 6), dilated cardiomyopathy (n = 5), and chronic sarcoidosis (n = 5).ResultsUSPIO were identified in myocardial macrophages and myocardial interstitium. R1 time-course reflected passive interstitial distribution whereas multi-time-point R2* was also sensitive to active macrophage uptake. R2*/R1 ratio provided a quantitative measurement of myocardial macrophage infiltration. R2* behavior and R2*/R1 ratio were higher in infarcted (p = 0.001) and remote (p = 0.033) myocardium in acute MI and in chronic ischemic cardiomyopathy (infarct: p = 0.008; remote p = 0.010), and were borderline higher in DCM (p = 0.096), in comparison to healthy controls, but were no different in myocarditis or sarcoidosis. An R2*/R1 threshold of 25 had a sensitivity and specificity of 90% and 83%, respectively, for detecting active USPIO uptake.ConclusionsUSPIO are phagocytized by cardiac macrophages but are also passively present in myocardial interstitium. A multiparametric multi-time-point MRI methodology specifically identifies active myocardial macrophage infiltration. Persistent active macrophage infiltration is present in infarcted and remote myocardium in chronic ischemic cardiomyopathy, providing a substrate for HF.

Dataset Information

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

Publications

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

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