Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.

线粒体动力学在细胞命运决策以及控制 mtDNA 水平和分布中起着关键作用。然而，将线粒体膜重塑和质量控制与 mtDNA 拷贝数 （CN） 调节联系起来的分子机制仍然难以捉摸。在这里，我们证明线粒体内膜 （IMM） 蛋白线粒体裂变过程 1 （MTFP1） 负向调节 IMM 融合。此外，通过调节 MTFP1 水平操纵线粒体融合导致 mtDNA CN 调节。从机制上讲，我们发现 MTFP1 抑制线粒体融合，以从网络的其余部分分离和排除受损的 IMM 亚结构域。随后，外周裂变确保它们分离成富含 MTFP1 的小线粒体 （SMEM），这些线粒体以自噬依赖性方式靶向降解。值得注意的是，MTFP1 依赖性 IMM 质量控制对于基础类核循环至关重要，因此可以维持细胞内足够的 mtDNA 水平。