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A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy

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 impairme...

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Detalles Bibliográficos
Autores principales: Southwell, Nneka, Primiano, Guido, Nadkarni, Viraj, Attarwala, Nabeel, Beattie, Emelie, Miller, Dawson, Alam, Sumaitaah, Liparulo, Irene, Shurubor, Yevgeniya I, Valentino, Maria Lucia, Carelli, Valerio, Servidei, Serenella, Gross, Steven S, Manfredi, Giovanni, Chen, Qiuying, D'Aurelio, Marilena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10331581/
https://www.ncbi.nlm.nih.gov/pubmed/37222423
http://dx.doi.org/10.15252/emmm.202216951
Descripción
Sumario: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.