CLUH regulates mitochondrial metabolism by controlling translation and decay of target mRNAs

Mitochondria are essential organelles that host crucial metabolic pathways and produce adenosine triphosphate. The mitochondrial proteome is heterogeneous among tissues and can dynamically change in response to different metabolic conditions. Although the transcriptional programs that govern mitochondrial biogenesis and respiratory function are well known, posttranscriptional regulatory mechanisms remain unclear. In this study, we show that the cytosolic RNA-binding protein clustered mitochondria homologue (CLUH) regulates the expression of a mitochondrial protein network supporting key metabolic programs required under nutrient deprivation. CLUH exerts its function by controlling the stability and translation of target messenger RNAs. In the absence of Cluh, mitochondria are severely depleted of crucial enzymes involved in catabolic energy-converting pathways. CLUH preserves oxidative mitochondrial function and glucose homeostasis, thus preventing death at the fetal–neonatal transition. In the adult liver, CLUH ensures maximal respiration capacity and the metabolic response to starvation. Our results shed new light on the posttranscriptional mechanisms controlling the expression of mitochondrial proteins and suggest novel strategies to tailor mitochondrial function to physiological and pathological conditions.

线粒体（mitochondria）是一类不可或缺的细胞器，承载关键代谢通路并合成三磷酸腺苷（adenosine triphosphate, ATP）。线粒体蛋白质组在不同组织间存在异质性，且可随代谢状态的改变发生动态变化。尽管调控线粒体生物发生与呼吸功能的转录程序已被广泛阐明，但转录后调控机制仍有待明确。本研究证实，胞质RNA结合蛋白（RNA-binding protein）成簇线粒体同源蛋白（clustered mitochondria homologue, CLUH）可调控一组线粒体蛋白网络的表达，该网络可支持营养匮乏条件下所需的关键代谢程序。CLUH通过控制靶信使RNA（messenger RNA, mRNA）的稳定性与翻译过程发挥其功能。在Cluh基因缺失的情况下，线粒体中参与分解代谢能量转换通路的关键酶类会出现严重耗竭。CLUH可维持线粒体氧化功能与葡萄糖稳态，从而防止机体在胎-新生儿过渡期发生死亡。在成年肝脏中，CLUH可保障最大呼吸容量与饥饿状态下的代谢应答能力。本研究结果为调控线粒体蛋白表达的转录后机制提供了新的认知，并为适配生理与病理状态下的线粒体功能改造提供了全新策略。