Zc3h10 is a novel mitochondrial regulator

Mitochondria are the energy-generating hubs of the cell. In spite of considerable advances, our understanding of the factors that regulate the molecular circuits that govern mitochondrial function remains incomplete. Using a genome-wide functional screen, we have identified the poorly characterized protein Zinc finger CCCH-type containing 10 (Zc3h10) as regulator of mitochondrial physiology. We show that Zc3h10 is upregulated during physiological mitochondriogenesis such as myoblasts differentiation into myotubes. Zc3h10 overexpression boosts mitochondrial function and promotes myoblasts differentiation. On the other hand, depletion of Zc3h10 results in impaired myoblasts differentiation, mitochondrial dysfunction, reduced expression of electron transport chain (ETC) subunits and blunted TCA cycle flux. Notably, we have identified a loss-of-function mutation of Zc3h10 in humans (Tyr105 to Cys105) that is associated with increased body mass index, fat mass, fasting glucose and triglycerides. Isolated peripheral blood mononuclear cells from Cys105 homozygotes display reduced oxygen consumption rate, some ETC subunit expression and decreased levels of some TCA cycle metabolites that derive in mitochondrial dysfunction. Finally, our study identifies Zc3h10 as a novel mitochondrial regulator. Gene expression profiling in C2C12 myotubes depleted for Zc3h10 and controls

线粒体是细胞的能量生成枢纽。尽管该领域已取得长足进展，我们对调控线粒体功能的分子通路的相关调控因子仍缺乏完整认知。本研究通过全基因组功能筛选，将功能尚未被充分阐明的CCCH型锌指蛋白10（Zinc finger CCCH-type containing 10，Zc3h10）鉴定为线粒体生理功能的调控因子。研究发现，Zc3h10在生理性线粒体生成过程中表达上调，如成肌细胞向肌管分化的过程中。过表达Zc3h10可增强线粒体功能，并促进成肌细胞分化。反之，敲低Zc3h10会导致成肌细胞分化受损、线粒体功能异常、电子传递链（electron transport chain，ETC）亚基表达下调，以及三羧酸（TCA）循环通量降低。值得注意的是，本研究在人类体内发现了Zc3h10的功能丧失型突变（Tyr105突变为Cys105），该突变与体重指数、脂肪量、空腹血糖及甘油三酯水平升高显著相关。从Cys105纯合子个体中分离的外周血单个核细胞，其氧消耗速率降低、部分ETC亚基表达水平下调，同时部分与线粒体功能异常相关的TCA循环代谢物含量出现下降。最后，本研究将Zc3h10鉴定为一种新型线粒体调控因子。针对敲低Zc3h10的C2C12肌管及对照样本的基因表达谱分析