Mitochondrial contagion induced by Parkin deficiency in Drosophila hearts and its containment by suppressing mitofusin.
Mitochondrial contagion induced by Parkin deficiency in Drosophila hearts and its containment by suppressing mitofusin.
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DOI：
10.1161/circresaha.114.302734
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发表时间：
2014-01-17
影响因子：
20.1
通讯作者：
Dorn GW 2nd
中科院分区：
文献类型：
--
作者：
Bhandari P;Song M;Chen Y;Burelle Y;Dorn GW 2nd
功能失调的帕金森介导的衰老或受损线粒体的线粒体自噬剔除是帕金森病的主要病理过程，也是心肌病的潜在遗传机制。尽管帕金森氏病和心力衰竭之间存在流行病学关联，但帕金森氏病和有丝分裂质量控制在维持正常心脏稳态中的作用尚不清楚。我们使用种系突变体和心脏特异性RNA干扰来询问心肌细胞线粒体的Parkin调控，并检查果蝇心管中线粒体自噬和线粒体动力学之间的功能串扰。Parkin基因敲除小鼠心脏的转录谱显示了多种相关E3泛素连接酶的代偿上调。由于果蝇缺乏这些冗余基因，我们检测了帕金基因敲除果蝇的心脏管，观察到扩张型心肌病患者的空心甜甜圈线粒体增大，这可以通过心肌细胞特异性帕金基因表达来挽救。使用2种不同的抑制rna抑制心肌细胞特异性Parkin诱导相同的异常。帕金森缺乏症心肌细胞线粒体表现出畸形、去极化和活性氧生成，但没有钙循环异常，这表明线粒体存在原发性缺陷。抑制帕金森病果蝇心管心肌细胞线粒体融合可完全预防心肌病，并在不使线粒体畸形正常化的情况下纠正线粒体功能障碍，这表明线粒体融合在线粒体自噬受损引起的心肌病中起着核心作用。帕金森氏缺乏症及其导致的线粒体自噬中断产生心肌病，部分原因是由于保留不当的功能失调/衰老线粒体与正常线粒体融合而污染了心肌细胞线粒体池。通过抑制细胞器融合来限制线粒体感染，有望减少由有缺陷的线粒体自噬信号产生的器官功能障碍。
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. 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. 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. 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.