Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation-Induced Cardiac Proteotoxicity.
Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation-Induced Cardiac Proteotoxicity.
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DOI：
10.1161/jaha.118.009289
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发表时间：
2018-07-09
影响因子：
5.4
通讯作者：
Bhuiyan MS
中科院分区：
文献类型：
--
作者：
Alam S;Abdullah CS;Aishwarya R;Miriyala S;Panchatcharam M;Peretik JM;Orr AW;James J;Robbins J;Bhuiyan MS
结蛋白丝蛋白将收缩性肌原纤维装置与线粒体、细胞核和肌膜连接起来。人类结蛋白基因突变会导致心脏病、重构和心力衰竭，但其病理生理机制仍不清楚。心肌细胞特异性过度表达突变结蛋白（7 个氨基酸缺失 R172-E178，D7-Des Tg）会导致电子致密聚集体的积累和与心功能障碍相关的肌原纤维变性。尽管大量研究表明这些改变的超微结构变化会导致心肌收缩力受损，但心肌细胞死亡的分子机制仍然难以捉摸。在本研究中，我们报告 D7-Des Tg 小鼠心脏经历与线粒体裂变调节蛋白表达增加相关的异常线粒体裂变。从 D7-Des Tg 心脏分离的线粒体显示线粒体呼吸减少和细胞凋亡增加。在培养的心肌细胞中，腺病毒感染导致突变结蛋白的过度表达，导致线粒体裂变增加、线粒体呼吸抑制和细胞毒性激活。线粒体分裂抑制剂 mdivi-1 对线粒体分裂的抑制显着改善了线粒体呼吸，并抑制了与心肌细胞中 D7-Des 过度表达相关的细胞毒性。异常的线粒体分裂导致 D7-Des Tg 心脏线粒体呼吸缺陷和细胞凋亡。使用线粒体分裂抑制剂抑制异常线粒体分裂可显着保留线粒体功能并减少凋亡细胞死亡。综上所述，我们的研究表明，适应不良的异常线粒体分裂会导致与细胞功能障碍相关的细胞功能障碍。
Desmin filament proteins interlink the contractile myofibrillar apparatus with mitochondria, nuclei and the sarcolemma. Mutations in the human desmin gene cause cardiac disease, remodeling, and heart failure but the pathophysiological mechanisms remain unknown. Cardiomyocyte‐specific overexpression of mutated desmin (a 7 amino acid deletion R172‐E178, D7‐Des Tg) causes accumulations of electron‐dense aggregates and myofibrillar degeneration associated with cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause impairment of cardiac contractility, the molecular mechanism of cardiomyocyte death remains elusive. In the present study, we report that the D7‐Des Tg mouse hearts undergo aberrant mitochondrial fission associated with increased expression of mitochondrial fission regulatory proteins. Mitochondria isolated from D7‐Des Tg hearts showed decreased mitochondrial respiration and increased apoptotic cell death. Overexpression of mutant desmin by adenoviral infection in cultured cardiomyocytes led to increased mitochondrial fission, inhibition of mitochondrial respiration, and activation of cellular toxicity. Inhibition of mitochondrial fission by mitochondrial division inhibitor mdivi‐1 significantly improved mitochondrial respiration and inhibited cellular toxicity associated with D7‐Des overexpression in cardiomyocytes. Aberrant mitochondrial fission results in mitochondrial respiratory defects and apoptotic cell death in D7‐Des Tg hearts. Inhibition of aberrant mitochondrial fission using mitochondrial division inhibitor significantly preserved mitochondrial function and decreased apoptotic cell death. Taken together, our study shows that maladaptive aberrant mitochondrial fission causes desminopathy‐associated cellular dysfunction.