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

Cahill, Thomas J.; Leo, Vincenzo C.; Kelly, Meghan; Stockenhuber, Alexander; Kennedy, Nolan W.; Bao, Lei; Cereghetti, Grazia M.; Harper, Andrew R.; Czibik, Gabor; Liao, Chunyan; Bellahcene, Mohamed; Steeples, Violetta; Ghaffari, Sahar; Yavari, Arash; Mayer, Alice; Poulton, Joanna; Djp., Ferguson; Scorrano, Luca; Hettiarachchi, Nishani T.; Peers, Chris; Boyle, J; Hill, Rolla B.; Simmons, Alisha; Watkins, Hugh; Dear, T. Neil; Ashrafian, Houman

doi:10.1074/jbc.m115.665695

Cited by 54 publications

(37 citation statements)

References 46 publications

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“…Human Drp1 (isoform 1) was expressed and purified as a His-tagged fusion construct as previously described (Cahill et al, 2015). Specifically, plasmid encoding Drp1 isoform 1 was transformed into Escherichia coli BL21 (DE3).…”

Section: Methods Detailsmentioning

confidence: 99%

The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species

et al. 2017

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SUMMARY Mitochondrial fission mediated by the GTPase dynamin-related protein-1 (Drp1) is an attractive drug target in numerous maladies that range from heart disease to neurodegenerative disorders. The compound mdivi-1 is widely reported to inhibit Drp1-dependent fission, elongate mitochondria, and mitigate brain injury. Here, we show that mdivi-1 reversibly inhibits mitochondrial Complex I-dependent O2 consumption and reverse electron transfer-mediated reactive oxygen species (ROS) production at concentrations (e.g. 50 μM) used to target mitochondrial fission. Respiratory inhibition is rescued by bypassing Complex I using yeast NADH dehydrogenase Ndi1. Unexpectedly, respiratory impairment by mdivi-1 occurs without mitochondrial elongation, is not mimicked by Drp1 deletion, and is observed in Drp1-deficient fibroblasts. In addition, mdivi-1 poorly inhibits recombinant Drp1 GTPase activity (Ki>1.2 mM). Overall, results suggest that mdivi-1 is not a specific Drp1 inhibitor. The ability of mdivi-1 to reversibly inhibit Complex I and modify mitochondrial ROS production may contribute to effects observed in disease models.

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Section: Methods Detailsmentioning

confidence: 99%

The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species

et al. 2017

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“…Cardiomyopathy caused by a Drp1 mutation in the same domain, C452F in so-called Python mice [46,47], is likewise associated with GTPase abnormalities and defective Drp1 assembly and further supports deep sequencing efforts to uncover disease-related Drp1 mutants in otherwise unexplained clinical cardiomyopathy.…”

Section: Mitochondrial Fission and Experimental Heart Diseasementioning

confidence: 96%

Mitochondrial fission/fusion and cardiomyopathy

Dorn

2016

Current Opinion in Genetics & Development

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Mitochondria are highly abundant in and essential to the beat-to-beat contractile performance of hearts. However, relatively few cardiac diseases have been attributed to primary mitochondrial dysfunction. The paucity of evidence for “primary mitochondrial cardiac diseases” may be because such an entity doesn’t exist. Alternately, the consequences of mitochondrial dysfunction on hearts may be so severe that long-term viability is severely impaired and affected individuals are therefore not included in standard genetic screens of adult heart disease subjects. Here, I review accumulating experimental evidence that impairing mitochondrial fission or fusion causes cardiomyopathy in otherwise normal mice, and consider how these data could motivate screening of perinatal cardiomyopathy subjects for damaging mutations of mitochondrial fission and fusion factors.

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“…However, the role of mitochondrial fission appears to be context-dependent. A Drp1 mutation (C452F) in mice leads to autosomal dominant dilated cardiomyopathy and heart failure with impaired mitochondrial dynamics and mitophagy[56, 57]. Cardiac specific deletion of Drp1 uniformly produces large and elongated dysfunctional mitochondria, leading to heart failure and premature death in several different studies[58–62], which underscores the importance of mitochondrial fission in maintaining cardiac homeostasis at baseline.…”

Section: Mitochondrial Dynamics In the Diabetic Heartmentioning

confidence: 99%

Mitochondrial quality control in the diabetic heart

Liang

Kobayashi

2016

Journal of Molecular and Cellular Cardiology

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Diabetes is a well known risk factor for heart failure. Diabetic heart damage is closely related to mitochondrial dysfunction and increased ROS generation. However, clinical trials have shown no effects of antioxidant therapies on heart failure in diabetic patients, suggesting that simply antagonizing existing ROS by antioxidants is not sufficient to reduce diabetic cardiac injury. A potentially more effective treatment strategy may be to enhance the overall capacity of mitochondrial quality control to maintain a pool of healthy mitochondria that are needed for supporting cardiac contractile function in diabetic patients. Mitochondrial quality is controlled by a number of coordinated mechanisms including mitochondrial fission and fusion, mitophagy and biogenesis. The mitochondrial damage consistently observed in the diabetic hearts indicates a failure of the mitochondrial quality control mechanisms. Recent studies have demonstrated a crucial role for each of these mechanisms in cardiac homeostasis and have begun to interrogate the relative contribution of insufficient mitochondrial quality control to diabetic cardiac injury. In this review, we will present currently available literature that links diabetic heart disease to the dysregulation of major mitochondrial quality control mechanisms. We will discuss the functional roles of these mechanisms in the pathogenesis of diabetic heart disease and their potentials for targeted therapeutical manipulation.

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

Cited by 54 publications

References 46 publications

The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species

The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species

Mitochondrial fission/fusion and cardiomyopathy

Mitochondrial quality control in the diabetic heart

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