芬兰赫尔辛基大学Anu Suomalainen小组发现线粒体肌肉疾病中线粒体自噬的镶嵌式功能障碍。2022年1月13日，《细胞—代谢》杂志在线发表了这项成果。

研究人员发现，有丝分裂有助于老年小鼠和人类患者骨骼肌的线粒体功能障碍。早期疾病阶段的特点是肌肉纤维有中心核，这些核周围的有丝分裂现象增强。然而，渐进的线粒体功能障碍会停止有丝分裂，并破坏溶酶体的平衡。有趣的是，即使在相邻的肌肉纤维中，激活或停止的有丝分裂也是以镶嵌的方式发生的，这表明细胞自主的调节。雷帕霉素能恢复线粒体的周转，从而表明在疾病晚期线粒体回收对mTOR的依赖。

这些证据表明：（1）有丝分裂是哺乳动物肌肉中与年龄有关的线粒体病变的标志；（2）有丝分裂的镶嵌式停止是解释成年发病的线粒体疾病和正常衰老中镶嵌式呼吸链缺陷和致病性mtDNA变体积累的一种机制；（3）增强有丝分裂是治疗肌肉线粒体功能障碍的一种有希望的治疗方法。

据介绍，有丝分裂是一种消除受损线粒体的质量控制机制，但它在哺乳动物的病理生理学和衰老中的意义仍不清楚。

附：英文原文

Title: Mosaic dysfunction of mitophagy in mitochondrial muscle disease

Author: Takayuki Mito, Amy E. Vincent, Julie Faitg, Robert W. Taylor, Nahid A. Khan, Thomas G. McWilliams, Anu Suomalainen

Issue&Volume: 2022-01-13

Abstract: Mitophagy is a quality control mechanism that eliminates damaged mitochondria, yet its significance in mammalian pathophysiology and aging has remained unclear. Here, we report that mitophagy contributes to mitochondrial dysfunction in skeletal muscle of aged mice and human patients. The early disease stage is characterized by muscle fibers with central nuclei, with enhanced mitophagy around these nuclei. However, progressive mitochondrial dysfunction halts mitophagy and disrupts lysosomal homeostasis. Interestingly, activated or halted mitophagy occur in a mosaic manner even in adjacent muscle fibers, indicating cell-autonomous regulation. Rapamycin restores mitochondrial turnover, indicating mTOR-dependence of mitochondrial recycling in advanced disease stage. Our evidence suggests that (1) mitophagy is a hallmark of age-related mitochondrial pathology in mammalian muscle, (2) mosaic halting of mitophagy is a mechanism explaining mosaic respiratory chain deficiency and accumulation of pathogenic mtDNA variants in adult-onset mitochondrial diseases and normal aging, and (3) augmenting mitophagy is a promising therapeutic approach for muscle mitochondrial dysfunction.

DOI: 10.1016/j.cmet.2021.12.017

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00636-7