线粒体基因组转录调控机制研究进展

Advances on the regulatory mechanisms of mitochondrial genome transcription

线粒体是半自主细胞器,具有自身的基因组(mtDNA)和独特的复制转录机制。线粒体不仅是细胞能量工厂,也是细胞代谢、信号转导和表观调控的枢纽。目前对核基因组编码线粒体基因的转录调控已有较多认识,mtDNA的转录调控机制研究则处于起步状态。线粒体转录复合体包括线粒体RNA聚合酶POLRMT (mitochondrial RNA polymerase)、转录因子TFAM (mitochondrial transcription factor A)以及TFB2M(mitochondrial transcription factor B2)等。近年研究发现,线粒体转录复合体互作因子调节mtDNA的转录强度。此外,线粒体转录复合体的翻译后修饰或mtDNA的化学修饰也是调控线粒体转录的重要机制。一些核因子在转位至线粒体后也会调控线粒体转录过程,最终影响线粒体代谢和细胞呼吸水平。由于mtDNA编码电子传递链的关键蛋白,线粒体转录异常与肿瘤、心血管疾病、糖尿病、衰老等多种人类疾病密切相关。现阶段对mtDNA转录复合体的结构和生化活性已有初步认识,但细胞如何协调mtDNA转录和线粒体代谢活性仍是尚待解决的生物学问题。本文旨在总结近年线粒体转录调控机制的研究进展及其生理病理意义,并展望可能的药物靶点及临床前景。

Mitochondria are semi-autonomous organelles with specific genomes(mtDNA). They maintain machineries that are specialized for mtDNA replication and transcription. In addition to their role as cellular powerhouses, mitochondria are also hubs for cell metabolism, signal transduction and epigenetic regulation. To date, the transcriptional regulation of nuclear genome-encoded mitochondrial genes has been extensively understood. However, the knowledge of transcriptional regulation of mtDNA is still in its infancy. Mitochondrial transcription complex consists of POLRMT(mitochondrial RNA polymerase), TFAM(mitochondrial transcription factor A) and TFB2M(mitochondrial transcription factor B2). Recent studies found that protein interactors of transcription complex regulated mtDNA transcription efficiency. Post-translational modifications of mitochondrial transcription complex and chemical modifications of mtDNA were also important mechanisms for regulating mitochondrial transcription. Some nuclear factors were found to translocate into mitochondria and alter mtDNA transcription, ultimately affecting mitochondrial metabolism and cellular respiration. mtDNA encodes key proteins in the electron transport chain, hence mitochondrial transcription abnormalities are closely related to multiple human diseases, such as tumors, cardiovascular diseases, diabetes and aging. At present, the structure and biochemical activity of mitochondrial genome transcription complex have been preliminarily recognized. How cells coordinate mtDNA transcription and mitochondrial metabolic activity remains a key biological question. This review summaries recent progresses in mitochondrial transcriptional regulation and its pathophysiological significance, with a highlight of potential druggable targets and their clinic potential.