Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Department of Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2200549119. doi: 10.1073/pnas.2200549119. Epub 2022 Apr 28.
Primary mitochondrial diseases (PMDs) are a heterogeneous group of metabolic disorders that can be caused by hundreds of mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Current therapeutic approaches are limited, although one approach has been exercise training. Endurance exercise is known to improve mitochondrial function in heathy subjects and reduce risk for secondary metabolic disorders such as diabetes or neurodegenerative disorders. However, in PMDs the benefit of endurance exercise is unclear, and exercise might be beneficial for some mitochondrial disorders but contraindicated in others. Here we investigate the effect of an endurance exercise regimen in mouse models for PMDs harboring distinct mitochondrial mutations. We show that while an mtDNA ND6 mutation in complex I demonstrated improvement in response to exercise, mice with a CO1 mutation affecting complex IV showed significantly fewer positive effects, and mice with an ND5 complex I mutation did not respond to exercise at all. For mice deficient in the nDNA adenine nucleotide translocase 1 (Ant1), endurance exercise actually worsened the dilated cardiomyopathy. Correlating the gene expression profile of skeletal muscle and heart with the physiologic exercise response identified oxidative phosphorylation, amino acid metabolism, matrisome (extracellular matrix [ECM]) structure, and cell cycle regulation as key pathways in the exercise response. This emphasizes the crucial role of mitochondria in determining the exercise capacity and exercise response. Consequently, the benefit of endurance exercise in PMDs strongly depends on the underlying mutation, although our results suggest a general beneficial effect.
原发性线粒体疾病（PMD）是一组代谢紊乱的异质性疾病，可由线粒体 DNA（mtDNA）和核 DNA（nDNA）基因的数百种突变引起。目前的治疗方法有限，尽管有一种方法是运动训练。众所周知，耐力运动可以改善健康受试者的线粒体功能，并降低糖尿病或神经退行性疾病等继发性代谢紊乱的风险。然而，在 PMD 中，耐力运动的益处尚不清楚，运动可能对某些线粒体疾病有益，但对其他疾病则禁忌。在这里，我们研究了耐力运动方案对携带不同线粒体突变的 PMD 小鼠模型的影响。我们表明，虽然在 I 复合物中的 mtDNA ND6 突变对运动有反应，但影响 IV 复合物的 CO1 突变的小鼠表现出明显较少的积极影响，而 I 复合物中的 ND5 突变的小鼠根本不响应运动。对于缺乏核 DNA 腺嘌呤核苷酸转运蛋白 1（Ant1）的小鼠，耐力运动实际上使扩张型心肌病恶化。将骨骼肌和心脏的基因表达谱与生理运动反应相关联，确定氧化磷酸化、氨基酸代谢、基质（细胞外基质 [ECM]）结构和细胞周期调节作为运动反应的关键途径。这强调了线粒体在决定运动能力和运动反应中的关键作用。因此，耐力运动在 PMD 中的益处强烈取决于潜在的突变，尽管我们的结果表明存在一般的有益效果。
