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...
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| Language: | English |
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Springer Nature
2023-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202216951 |
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| author | Nneka Southwell Guido Primiano Viraj Nadkarni Nabeel Attarwala Emelie Beattie Dawson Miller Sumaitaah Alam Irene Liparulo Yevgeniya I Shurubor Maria Lucia Valentino Valerio Carelli Serenella Servidei Steven S Gross Giovanni Manfredi Qiuying Chen Marilena D'Aurelio |
| author_facet | Nneka Southwell Guido Primiano Viraj Nadkarni Nabeel Attarwala Emelie Beattie Dawson Miller Sumaitaah Alam Irene Liparulo Yevgeniya I Shurubor Maria Lucia Valentino Valerio Carelli Serenella Servidei Steven S Gross Giovanni Manfredi Qiuying Chen Marilena D'Aurelio |
| author_sort | Nneka Southwell |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3ac8c9834e7f48439c744d6d9391fd6b |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-3ac8c9834e7f48439c744d6d9391fd6b2025-08-20T03:43:26ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-05-0115712610.15252/emmm.202216951A coordinated multiorgan metabolic response contributes to human mitochondrial myopathyNneka Southwell0Guido Primiano1Viraj Nadkarni2Nabeel Attarwala3Emelie Beattie4Dawson Miller5Sumaitaah Alam6Irene Liparulo7Yevgeniya I Shurubor8Maria Lucia Valentino9Valerio Carelli10Serenella Servidei11Steven S Gross12Giovanni Manfredi13Qiuying Chen14Marilena D'Aurelio15Brain and Mind Research Institute, Weill Cornell MedicineFondazione Policlinico Universitario Agostino Gemelli IRCCSBrain and Mind Research Institute, Weill Cornell MedicineDepartment of Pharmacology, Weill Cornell MedicineBrain and Mind Research Institute, Weill Cornell MedicineDepartment of Pharmacology, Weill Cornell MedicineDepartment of Pharmacology, Weill Cornell MedicineBrain and Mind Research Institute, Weill Cornell MedicineBrain and Mind Research Institute, Weill Cornell MedicineIRCCS, Institute of Neurological Sciences of Bologna, Bellaria HospitalIRCCS, Institute of Neurological Sciences of Bologna, Bellaria HospitalFondazione Policlinico Universitario Agostino Gemelli IRCCSDepartment of Pharmacology, Weill Cornell MedicineBrain and Mind Research Institute, Weill Cornell MedicineDepartment of Pharmacology, Weill Cornell MedicineBrain and Mind Research Institute, Weill Cornell MedicineAbstract 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.https://doi.org/10.15252/emmm.202216951amino acid metabolismglucocorticoidsleptinmitochondrial myopathymuscle wasting |
| spellingShingle | Nneka Southwell Guido Primiano Viraj Nadkarni Nabeel Attarwala Emelie Beattie Dawson Miller Sumaitaah Alam Irene Liparulo Yevgeniya I Shurubor Maria Lucia Valentino Valerio Carelli Serenella Servidei Steven S Gross Giovanni Manfredi Qiuying Chen Marilena D'Aurelio A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy EMBO Molecular Medicine amino acid metabolism glucocorticoids leptin mitochondrial myopathy muscle wasting |
| title | A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy |
| title_full | A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy |
| title_fullStr | A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy |
| title_full_unstemmed | A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy |
| title_short | A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy |
| title_sort | coordinated multiorgan metabolic response contributes to human mitochondrial myopathy |
| topic | amino acid metabolism glucocorticoids leptin mitochondrial myopathy muscle wasting |
| url | https://doi.org/10.15252/emmm.202216951 |
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