Biogenesis and Dynamics of Mitochondria during the Cell Cycle: Significance of 3′UTRs

Nowadays, we are facing a renaissance of mitochondria in cancer biology. However, our knowledge of the basic cell biology and on the timing and mechanisms that control the biosynthesis of mitochondrial constituents during progression through the cell cycle of mammalian cells remain largely unknown. Herein, we document the in vivo changes on mitochondrial morphology and dynamics that accompany cellular mitosis, and illustrate the following key points of the biogenesis of mitochondria during progression of liver cells through the cycle: (i) the replication of nuclear and mitochondrial genomes is synchronized during cellular proliferation, (ii) the accretion of OXPHOS proteins is asynchronously regulated during proliferation being the synthesis of β-F1-ATPase and Hsp60 carried out also at G2/M and, (iii) the biosynthesis of cardiolipin is achieved during the S phase, although full development of the mitochondrial membrane potential (ΔΨm) is attained at G2/M. Furthermore, we demonstrate using reporter constructs that the mechanism regulating the accretion of β-F1-ATPase during cellular proliferation is controlled at the level of mRNA translation by the 3′UTR of the transcript. The 3′UTR-driven synthesis of the protein at G2/M is essential for conferring to the daughter cells the original phenotype of the parental cell. Our findings suggest that alterations on this process may promote deregulated β-F1-ATPase expression in human cancer.

当下，癌症生物学领域正迎来线粒体研究的复兴。然而，我们对于哺乳动物细胞在细胞周期进程中，调控线粒体组分生物合成的基础细胞生物学机制、时机与过程的认知仍存在大量空白。本文中，我们记录了伴随细胞有丝分裂发生的体内线粒体形态与动力学变化，并阐明了肝细胞周期进程中线粒体生物发生的核心要点：(i) 细胞增殖过程中，细胞核与线粒体基因组的复制呈现同步化特征；(ii) 氧化磷酸化（OXPHOS）蛋白的积累在增殖过程中受到异步调控，其中β-F1-ATP酶与热休克蛋白60（Hsp60）的合成还可在G2/M期进行；(iii) 心磷脂的生物合成发生于S期，但线粒体膜电位（ΔΨm）的完全成熟则在G2/M期实现。进一步地，我们通过报告基因构建体证实，细胞增殖过程中调控β-F1-ATP酶积累的机制，是通过转录本的3′非翻译区（3′UTR）在mRNA翻译层面实现的。该3′UTR介导的G2/M期蛋白合成，对子代细胞继承亲代细胞的原始表型至关重要。我们的研究结果提示，这一过程的异常可能会促进人类癌症中β-F1-ATP酶表达的失调。