Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and Its Containment by Suppressing Mitofusin

Abstract

Rationale Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood. Objective We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in Drosophila heart tubes. Methods and Results Transcriptional profiling of Parkin knockout mouse hearts revealed compensatory upregulation of multiple related E3 ubiquitin ligases. Because Drosophila lack most of these redundant genes, we examined heart tubes of parkin knockout flies and observed accumulation of enlarged hollow donut mitochondria with dilated cardiomyopathy, which could be rescued by cardiomyocyte-specific Parkin expression. Identical abnormalities were induced by cardiomyocyte-specific Parkin suppression using 2 different inhibitory RNAs. Parkin-deficient cardiomyocyte mitochondria exhibited dysmorphology, depolarization, and reactive oxygen species generation without calcium cycling abnormalities, pointing to a primary mitochondrial defect. Suppressing cardiomyocyte mitochondrial fusion in Parkin-deficient fly heart tubes completely prevented the cardiomyopathy and corrected mitochondrial dysfunction without normalizing mitochondrial dysmorphology, demonstrating a central role for mitochondrial fusion in the cardiomyopathy provoked by impaired mitophagy. Conclusions Parkin deficiency and resulting mitophagic disruption produces cardiomyopathy in part by contamination of the cardiomyocyte mitochondrial pool through fusion between improperly retained dysfunctional/senescent and normal mitochondria. Limiting mitochondrial contagion by inhibiting organelle fusion shows promise for minimizing organ dysfunction produced by defective mitophagic signaling.

Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Against Energy Stress

“…Interestingly, downregulation of Beclin1 did not affect GD-induced increases in mitochondrial foreshortening (Online Figure VC) but significantly increased GD-induced cell death (Online Figure VD). Thus, although evidence suggests that unopposed fusion of mitochondria alone can induce cell death, 27 suppression of autophagy alone may also induce cardiomyocyte death even when mitochondrial foreshortening is not affected.…”

“…Furthermore, 1-time treatment with mdivi-1 reduced I/R injury even in Drp1-hetCKO mice, suggesting that mdivi-1 most likely has a Drp1-independent antiapoptotic function. Along this same line, mdivi-1 affects other molecules besides Drp1, including delayed rectifier K + channels, 27 raising the issue of specificity of the chemical inhibitor. Fourth, mitochondrial localization of Drp1 is positively regulated by protein kinase A, 30 calcineurin, 30 PUMA, 31 Bax/Bak, 32 ceramide, 33 and O-linked-β-N-acetylglucosamine modification, 34 and is negatively regulated by miR-499 35 and Pim1.…”

The role of mitochondria in cardiac development and protection

“…The mitochondrial network is under constant remodeling by fusion and fission. Mitochondrial fission, budding off parts of the mitochondrial network, is essential for the identification of dysfunctional and senescent parts of the mitochondrial network and their removal by autophagy [46,73]. In addition, mitochondrial fusion is required for mitochondrial maintenance; it is not only essential for cardiomyocyte differentiation [74], but also for the healthy function of an adult heart [4,75].…”

Superoxide Dismutase (SOD) Genes and Aging in Drosophila

“…Over-expression of Cu/ZnSOD in the muscle and other tissues (twist-GAL4 driver) was reported to rescue the life-span shortening effect of a mutation in the parkin gene (Saini et al 2010), and over-expression of MnSOD was reported to reduce the developmental defects caused by a PINK1 gene mutation (Koh et al 2012). Over-expression of either Cu/ZnSOD or MnSOD was found to reduce the toxic effects of poly-Q-containing proteins in the Drosophila heart (Melkani et al 2013), and to reduce the toxic effects of disrupted mitochondrial fusion in the heart (Dorn et al 2011;Bhandari et al 2014). Over-expression of MnSOD increased survival of flies expressing the mutant protein associated with human spinal cerebellar ataxia type 12 (Wang et al 2011).…”