A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy

Abstract

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. image 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. In human patients and COX10 KO mice, increased glutamate oxidation and alanine release are adaptive responses to muscle OXPHOS defect. Muscle ISRmt activation and FGF21 release are early events in the COX10 KO mouse. Increased WAT lipolysis and impaired muscle fatty acid oxidation result in adipose store depletion and intramuscular lipid accumulation. Inter‐organ crosstalk through the hypothalamic–pituitary–adrenocortical axis, driven by low leptin, increases glucocorticoids, stimulates lipolysis, and triggers liver ketogenesis, gluconeogenesis, and ureagenesis. Glucocorticoid signaling inhibition by RU486 improves adipose stores in COX10 KO mice.