A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.
A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.
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协调的多器官代谢反应有助于人类线粒体肌病。
DOI：
10.15252/emmm.202216951
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发表时间：
2023-07-10
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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线粒体疾病是由氧化磷酸化受损（OXPHOS）引起的一组异质性单基因疾病。由于神经肌肉组织是高度能量依赖性的，线粒体疾病通常会影响骨骼肌。虽然人类线粒体肌病中OXPHOS损伤的遗传和生物能量原因已经很好地建立，但对肌肉变性的代谢驱动因素的理解有限。这种知识差距导致缺乏对这些疾病的有效治疗。在这里，我们发现了线粒体疾病患者和线粒体肌病小鼠模型共享的基本肌肉代谢重塑机制。这种代谢重塑是由饥饿样反应引发的，通过截短的克雷布斯循环引起氨基酸的加速氧化。虽然最初是适应性的，这种反应演变成一个综合的多器官分解代谢信号，脂质储存动员，肌内脂质积累。我们发现，这种多器官前馈代谢反应涉及瘦素和糖皮质激素信号传导。本研究阐明了人类线粒体肌病的全身代谢平衡障碍机制，并确定了代谢干预的潜在新靶点。在受OXPHOS缺陷影响的患者和线粒体肌病的小鼠模型中，由线粒体整合应激反应（ISRmt）引发的代谢适应是由肌因子和激素信号传导协调的器官间串扰的一部分。
Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy‐dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation‐like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed‐forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention. In patients affected by OXPHOS defects and a mouse model of mitochondrial myopathy, metabolic adaptations initiated by mitochondrial integrated stress response (ISRmt) are part of inter‐organ crosstalk coordinated by myokines and hormonal signaling.