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首页> 外文期刊>Autophagy >In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy
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In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy

机译：在哺乳动物骨骼肌中，蛋白激酶CSNK2 / CK2对蛋白质激酶的磷酸化进行控制

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In yeast, Tom22, the central component of the TOMM (translocase of outer mitochondrial membrane) receptor complex, is responsible for the recognition and translocation of synthesized mitochondrial precursor proteins, and its protein kinase CK2-dependent phosphorylation is mandatory for TOMM complex biogenesis and proper mitochondrial protein import. In mammals, the biological function of protein kinase CSNK2/CK2 remains vastly elusive and it is unknown whether CSNK2-dependent phosphorylation of TOMM protein subunits has a similar role as that in yeast. To address this issue, we used a skeletal muscle-specific Csnk2b/Ck2-conditional knockout (cKO) mouse model. Phenotypically, these skeletal muscle Csnk2b cKO mice showed reduced muscle strength and abnormal metabolic activity of mainly oxidative muscle fibers, which point towards mitochondrial dysfunction. Enzymatically, active muscle lysates from skeletal muscle Csnk2b cKO mice phosphorylate murine TOMM22, the mammalian ortholog of yeast Tom22, to a lower extent than lysates prepared from controls. Mechanistically, CSNK2-mediated phosphorylation of TOMM22 changes its binding affinity for mitochondrial precursor proteins. However, in contrast to yeast, mitochondrial protein import seems not to be affected in vitro using mitochondria isolated from muscles of skeletal muscle Csnk2b cKO mice. PINK1, a mitochondrial health sensor that undergoes constitutive import under physiological conditions, accumulates within skeletal muscle Csnk2b cKO fibers and labels abnormal mitochondria for removal by mitophagy as demonstrated by the appearance of mitochondria-containing autophagosomes through electron microscopy. Mitophagy can be normalized by either introduction of a phosphomimetic TOMM22 mutant in cultured myotubes, or by in vivo electroporation of phosphomimetic Tomm22 into muscles of mice. Importantly, transfection of the phosphomimetic Tomm22 mutant in muscle cells with ablated Csnk2b restored their oxygen consumption rate comparable to wild-type levels. In sum, our data show that mammalian CSNK2-dependent phosphorylation of TOMM22 is a critical switch for mitophagy and reveal CSNK2-dependent physiological implications on metabolism, muscle integrity and behavior.
机译：在酵母中，Tom22，Tomm（外线粒体膜）受体复合物的Tomm（千晶酶）的中央分量负责合成线粒体前体蛋白的识别和转移，其蛋白激酶CK2依赖性磷酸化对于Tomm复合物生物发生和适当的是强制性的线粒体蛋白质进口。在哺乳动物中，蛋白质激酶CSNK2 / CK2的生物学功能仍然难以难以捉摸，并且尚不清楚CSNK2依赖性磷酸化是否与酵母中的酵母相似的作用。为了解决这个问题，我们使用了骨骼肌特异性CSNK2B / CK2条件淘汰（CKO）鼠标模型。表型，这些骨骼肌CSNK2B CKO小鼠表现出肌肉强度降低，主要是氧化肌肉纤维的异常代谢活性，这指向线粒体功能障碍。酶促，活性肌肉裂解物，来自骨骼肌CSNK2B CKO小鼠的磷酸酯鼠TOMM22，哺乳动物ORETPOOLOG的酵母TOM22，低于由对照制备的裂解物。机械地，CSNK2介导的Tomm22的磷酸化改变了对线粒体前体蛋白的结合亲和力。然而，与酵母形成鲜明对比，线粒体蛋白质进口似乎不会在体外使用从骨骼肌CSNK2B CKO小鼠的肌肉中分离的线粒体影响。 Pink1是一种在生理条件下进行组织型进口的线粒体健康传感器，积累在骨骼肌CSNK2B CKO纤维中，并通过电子显微镜的外观的外观所证明的含有线粒体的自噬物的出现所证明的用于除去的线粒体异常线粒体。通过在培养的肌管中引入磷光染素Tomm22突变体或通过将磷酸化Tomm22的体内电穿孔成小鼠的肌肉，可以通过引入培养基。重要的是，用烧蚀的CSNK2B转染肌细胞中的肌细胞细胞中的抗染色率恢复了与野生型水平相当的氧消耗率。总而言之，我们的数据显示Tomm22的哺乳动物CSNK2依赖性磷酸化是乳化物的关键开关，并揭示了对新陈代谢，肌肉完整性和行为的CSNK2依赖性生理影响。

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