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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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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 |
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author | 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 |
author_facet | 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 |
author_sort | Southwell, Nneka |
collection | PubMed |
description | 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 | Online Article Text |
id | pubmed-10331581 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-103315812023-07-11 A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy 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 EMBO Mol Med Articles 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. John Wiley and Sons Inc. 2023-05-24 /pmc/articles/PMC10331581/ /pubmed/37222423 http://dx.doi.org/10.15252/emmm.202216951 Text en © 2023 The Authors. Published under the terms of the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles 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 A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy |
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 | Articles |
url | 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 |
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