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.

骨骼肌中功能失调的线粒体数量增加与众多衰老相关的生理病理状态密切相关。为了研发治疗手段，有必要理解线粒体功能与肌肉蛋白质稳态之间的联系，然而，其潜在的联系尚不明确。线粒体外膜蛋白Fis1，作为酵母分裂因子，也可能在多细胞生物中维持线粒体形态。在本研究中，我们发现Fis1异构体的表达随年龄增长而增加。此外，Fis1MI10520（MiMIC插入突变体）在衰老过程中表现出更高的损伤线粒体比率。这些损伤线粒体具有受损的内膜结构，产生减少的ATP浓度，并表现出升高的活性氧（ROS）水平。这导致氧化应激增加，进而引起泛素化蛋白的大量积累和肌肉功能的加速下降。我们的研究结果表明，Fis1对果蝇的线粒体稳态至关重要，且Fis1突变会导致年轻突变果蝇的衰老表型。为进一步探究包含Fis1在内的更大稳态网络，有必要深入了解线粒体功能随年龄变化的机制。