Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice.
Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice.
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DOI：
10.1126/science.aad2459
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发表时间：
2015-12-04
期刊：
影响因子：
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通讯作者：
Dorn GW 2nd
中科院分区：
文献类型：
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作者：
Gong G;Song M;Csordas G;Kelly DP;Matkovich SJ;Dorn GW 2nd
围产期心脏代谢环境的变化使线粒体底物偏好从碳水化合物转向脂肪酸。线粒体可塑性的机制尚不清楚。在这里，我们发现PINK1-Mfn2-Parkin介导的线粒体自噬指导了小鼠的这种代谢转化。有丝分裂蛋白（Mfn） 2突变体缺乏Parkin结合所需的PINK1磷酸化位点（Mfn2 AA），抑制线粒体Parkin易位，抑制线粒体自噬，但不损害线粒体融合。心肌帕金蛋白缺失或Mfn2 AA的表达从出生开始，但断奶后没有，阻止了出生后线粒体成熟对生存至关重要。5周龄的Mfn2 AA心脏保留了胎儿线粒体转录特征，脂肪酸代谢和线粒体生物发生基因没有正常增加。心肌脂肪酰基肉碱水平和棕榈酰基肉碱诱导的心肌细胞呼吸一致下降。因此，不是转录重编程，胎儿心肌细胞线粒体经历围产期帕金森介导的线粒体自噬和被成熟的成人线粒体取代。线粒体自噬去除是发育心肌细胞线粒体可塑性和围产期心脏代谢转变的基础。
Changes in the cardiac metabolic milieu during the perinatal period redirect mitochondrial substrate preference from carbohydrates to fatty acids. Mechanisms responsible for this mitochondrial plasticity are unknown. Here we found that PINK1-Mfn2-Parkin mediated mitophagy directs this metabolic transformation in mice. A mitofusin (Mfn) 2 mutant lacking PINK1 phosphorylation sites necessary for Parkin binding (Mfn2 AA) inhibited mitochondrial Parkin translocation, suppressing mitophagy without impairing mitochondrial fusion. Cardiac Parkin deletion or expression of Mfn2 AA from birth, but not after weaning, prevented postnatal mitochondrial maturation essential to survival. Five week old Mfn2 AA hearts retained a fetal mitochondrial transcriptional signature without normal increases in fatty acid metabolism and mitochondrial biogenesis genes. Myocardial fatty acylcarnitine levels and cardiomyocyte respiration induced by palmitoylcarnitine were concordantly depressed. Thus, instead of transcriptional reprogramming, fetal cardiomyocyte mitochondria undergo perinatal Parkin-mediated mitophagy and replacement by mature adult mitochondria. Mitophagic mitochondrial removal underlies developmental cardiomyocyte mitochondrial plasticity and metabolic transitioning of perinatal hearts.