Zc3h10 controls mitochondrial function coupling iron and cardiolipin homeostasis [RNA-seq]. Mus musculus

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 a nuclear RNA binding protein that controls the fate of Slc25a37 and Prelid3a mRNA transcripts, two nuclear-encoded mitochondrial proteins central for iron and cardiolipin homeostasis. Depletion of Zc3h10 results in mitochondrial dysfunction and reduced TCA cycle flux. Notably, we have identified a loss-of-function mutation of Zc3h10 in humans (Tyr105 to Cys105) that is associated with decreased mitochondrial function, increased body mass index, fat mass, fasting glucose and triglycerides. Cells from Cys105 homozygotes display alterations in Slc25a37 and Prelid3a levels and defects in mitochondrial iron and cardiolipin homeostasis that derive in mitochondrial dysfunction. Overall design: Profiling of 4sU-labeled and total RNA in wild-type and Zc3h10 depleted C2C12 myoblasts

线粒体是细胞的能量生成枢纽。尽管已有诸多研究进展，但我们对调控线粒体功能的分子环路相关因子的认知仍不全面。本研究通过全基因组功能筛选，将功能尚未明确的锌指CCCH型包含蛋白10（Zinc finger CCCH-type containing 10, Zc3h10）鉴定为线粒体生理功能的调控因子。研究表明，Zc3h10是一种核内RNA结合蛋白，可调控Slc25a37与Prelid3a的mRNA转录本命运；这两种由核编码的线粒体蛋白分别在铁离子与心磷脂稳态中发挥核心作用。敲低Zc3h10会导致线粒体功能障碍，并降低三羧酸循环（TCA cycle）通量。值得注意的是，本研究在人类中发现了Zc3h10的功能丧失型突变（Tyr105突变为Cys105），该突变与线粒体功能下降、体质量指数升高、脂肪量增加、空腹血糖及甘油三酯水平上升相关。携带Cys105纯合突变的个体细胞中，Slc25a37与Prelid3a的表达水平发生改变，同时存在线粒体铁离子与心磷脂稳态缺陷，最终引发线粒体功能障碍。实验整体设计：对野生型与Zc3h10敲低的C2C12成肌细胞中的4-硫尿苷（4sU）标记RNA及总RNA进行转录组谱分析。