Loss of Fis1 impairs proteostasis during skeletal muscle aging in Drosophila

Increased dysfunctional mitochondria within skeletal muscle is correlated with many aged-related physiopathological conditions. Understanding the links between mitochondrial function and muscle proteohomeostasis is necessary to develop treatments, yet the underlying connections remain unclear. The mitochondrial outer membrane protein Fis1, a yeast fission factor, may also maintain mitochondrial morphology in metazoans. Here, we found Fis1 isoform expression increased with age. Moreover, Fis1MI10520 (MiMIC insertion mutant) showed the higher ratio of damaged mitochondria during aging. These damaged mitochondria possessed compromised inner membrane structures, generated reduced ATP concentration and showed elevated ROS levels. This caused increased oxidative stress resulting in large accumulations of ubiquitinated protein and an accelerated decline in muscle function. Our findings indicate that Fis1 is crucial for Drosophila mitochondrial homeostasis, and Fis1 mutations cause aged phenotypes in young mutant flies. Further investigation into the larger homeostatic network containing Fis1 is necessary to improve understanding of how mitochondrial function changes with age.骨骼肌内功能异常线粒体的增多，与多种衰老相关的病理生理状态密切相关。阐明线粒体功能与肌肉蛋白质稳态之间的关联，是开发治疗手段的必要前提，然而其背后的内在联系仍未明确。线粒体外膜蛋白Fis1作为酵母分裂因子，在多细胞生物中或可维持线粒体形态。本研究发现，Fis1的同工型表达水平随衰老进程而上调。此外，Fis1MI10520（MiMIC插入突变体）在衰老过程中表现出更高比例的受损线粒体。这些受损线粒体的内膜结构遭到破坏，ATP生成量降低，且活性氧（Reactive Oxygen Species, ROS）水平升高。这引发了氧化应激的增强，进而导致泛素化蛋白大量积累，并使肌肉功能加速衰退。本研究结果表明，Fis1对于果蝇（Drosophila）的线粒体稳态至关重要，而Fis1突变会在年轻的突变体果蝇中引发衰老表型。未来需对包含Fis1的更大规模稳态网络展开深入研究，以增进对线粒体功能随衰老如何变化的认知。