Research Program of Molecular Neurology, Biomedicum-Helsinki, 00290 Helsinki, Finland.
Hum Mol Genet. 2010 Oct 15;19(20):3948-58. doi: 10.1093/hmg/ddq310. Epub 2010 Jul 23.
Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.
线粒体呼吸链（RC）缺陷是最常见的遗传性代谢疾病的原因之一，但它的生理后果还没有很好地描述。我们研究了患有迟发性线粒体肌病的小鼠的骨骼肌基因表达谱。这些动物表达一种显性的线粒体复制解旋酶 Twinkle 的患者突变，导致多种 mtDNA 缺失的积累和骨骼肌中 RC 逐渐轻微缺陷。小鼠骨骼肌的整体基因表达模式显示参与氨基酸饥饿反应的途径和 Akt 信号的激活诱导。此外，肌肉还诱导了一种与禁食相关的激素，成纤维细胞生长因子 21（Fgf21）。这种分泌的脂质代谢调节剂在小鼠血清中也升高，并且动物表现出广泛的脂质代谢变化：小脂肪细胞大小、肝脏脂肪含量低以及对高脂肪饮食的抗性。我们提出，RC 缺陷在正常营养状态下诱导一种线粒体应激反应，具有局部和整体的饥饿样变化。这些结果可能对理解线粒体肌病的代谢后果具有重要意义。
