Department of Animal Sciences, Purdue University, West Lafayette, IN, USA.
College of Animal Science and Technology, Southwest University, Chongqing, China.
FASEB J. 2021 Apr;35(4):e21426. doi: 10.1096/fj.202002464R.
Mitochondrial remodeling through fusion and fission is crucial for progenitor cell differentiation but its role in myogenesis is poorly understood. Here, we characterized the function of mitofusin 2 (Mfn2), a mitochondrial outer membrane protein critical for mitochondrial fusion, in muscle progenitor cells (myoblasts). Mfn2 expression is upregulated during myoblast differentiation in vitro and muscle regeneration in vivo. Targeted deletion of Mfn2 gene in myoblasts (Mfn2 ) increases oxygen-consumption rates (OCR) associated with the maximal respiration and spare respiratory capacity, and increased levels of reactive oxygen species (ROS). Skeletal muscles of Mfn2 mice exhibit robust mitochondrial swelling with normal mitochondrial DNA content. Additionally, mitochondria isolated from Mfn2 muscles have reduced OCR at basal state and for complex I respiration, associated with decreased levels of complex I proteins NDUFB8 (NADH ubiquinone oxidoreductase subunit B8) and NDUFS3 (NADH ubiquinone oxidoreductase subunit S3). However, Mfn2 has no obvious effects on myoblast differentiation, muscle development and function, and muscle regeneration. These results demonstrate a novel role of Mfn2 in regulating mitochondrial complex I protein abundance and respiratory functions in myogenic progenitors and myofibers.
线粒体通过融合和分裂进行重塑对于祖细胞分化至关重要，但它在肌发生中的作用尚不清楚。在这里，我们研究了线粒体融合所必需的线粒体外膜蛋白——线粒体融合蛋白 2（Mfn2）在肌肉祖细胞（成肌细胞）中的功能。Mfn2 的表达在体外成肌细胞分化和体内肌肉再生过程中上调。在成肌细胞中靶向敲除 Mfn2 基因（Mfn2 -/-）会增加与最大呼吸和备用呼吸能力相关的耗氧率（OCR），并增加活性氧（ROS）水平。Mfn2 小鼠的骨骼肌表现出明显的线粒体肿胀，线粒体 DNA 含量正常。此外，从 Mfn2 肌肉中分离的线粒体在基础状态和复合物 I 呼吸时的 OCR 降低，与复合物 I 蛋白 NDUFB8（NADH 泛醌氧化还原酶亚基 B8）和 NDUFS3（NADH 泛醌氧化还原酶亚基 S3）水平降低有关。然而，Mfn2 对成肌细胞分化、肌肉发育和功能以及肌肉再生没有明显影响。这些结果表明 Mfn2 在调节肌源性祖细胞和肌纤维中线粒体复合物 I 蛋白丰度和呼吸功能方面具有新的作用。
