Lactate metabolism is essential in early-onset mitochondrial myopathy.
Lactate metabolism is essential in early-onset mitochondrial myopathy.
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DOI：
10.1126/sciadv.add3216
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发表时间：
2023-01-04
期刊：
影响因子：
13.6
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中科院分区：
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继发于线粒体电子传递链（ETC）功能障碍的肌病可导致毁灭性疾病。虽然ETC缺陷的后果已被广泛研究的文化，很少在体内数据。使用严重的早发性线粒体肌病小鼠模型，我们表征了疾病进展的蛋白质组学、转录组学和代谢特征。出乎意料的是，肌肉中的ETC功能障碍导致我们的动物模型和患者肌肉活检中糖酵解酶的表达减少。糖酵解的减少是由组成性Hif1α信号传导的丧失、嘌呤核苷酸循环酶AMPD 1的下调和AMPK的激活介导的。体内同位素示踪实验表明，肌病肌肉依赖乳酸盐输入来提供中心碳代谢物。抑制乳酸输入降低了三羧酸循环中间体的稳态水平，并损害了肌病小鼠的寿命。这些数据表明，在严重线粒体肌病中存在一种意想不到的代谢重编程模式，可调节疾病进展。严重线粒体肌病动物模型的代谢分析揭示了对乳酸盐使用的惊人依赖性。
Myopathies secondary to mitochondrial electron transport chain (ETC) dysfunction can result in devastating disease. While the consequences of ETC defects have been extensively studied in culture, little in vivo data are available. Using a mouse model of severe, early-onset mitochondrial myopathy, we characterized the proteomic, transcriptomic, and metabolic characteristics of disease progression. Unexpectedly, ETC dysfunction in muscle results in reduced expression of glycolytic enzymes in our animal model and patient muscle biopsies. The decrease in glycolysis was mediated by loss of constitutive Hif1α signaling, down-regulation of the purine nucleotide cycle enzyme AMPD1, and activation of AMPK. In vivo isotope tracing experiments indicated that myopathic muscle relies on lactate import to supply central carbon metabolites. Inhibition of lactate import reduced steady-state levels of tricarboxylic acid cycle intermediates and compromised the life span of myopathic mice. These data indicate an unexpected mode of metabolic reprogramming in severe mitochondrial myopathy that regulates disease progression. Metabolic analysis in an animal model of severe mitochondrial myopathy reveals a surprising dependence on lactate usage.