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Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects
Phosphorylation of respiratory chain components has emerged as a mode of regulation of mitochondrial energy metabolism, but its mechanisms are still largely unexplored. A recently discovered intramitochondrial signalling pathway links CO(2) generated by the Krebs cycle with the respiratory chain, th...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
WILEY-VCH Verlag
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814779/ https://www.ncbi.nlm.nih.gov/pubmed/20049744 http://dx.doi.org/10.1002/emmm.200900046 |
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author | Acin-Perez, Rebeca Salazar, Eric Brosel, Sonja Yang, Hua Schon, Eric A Manfredi, Giovanni |
author_facet | Acin-Perez, Rebeca Salazar, Eric Brosel, Sonja Yang, Hua Schon, Eric A Manfredi, Giovanni |
author_sort | Acin-Perez, Rebeca |
collection | PubMed |
description | Phosphorylation of respiratory chain components has emerged as a mode of regulation of mitochondrial energy metabolism, but its mechanisms are still largely unexplored. A recently discovered intramitochondrial signalling pathway links CO(2) generated by the Krebs cycle with the respiratory chain, through the action of a mitochondrial soluble adenylyl cyclase (mt-sAC). Cytochrome oxidase (COX), whose deficiency causes a number of fatal metabolic disorders, is a key mitochondrial enzyme activated by mt-sAC. We have now discovered that the mt-sAC pathway modulates mitochondrial biogenesis in a reactive oxygen species dependent manner, in cultured cells and in animals with COX deficiency. We show that upregulation of mt-sAC normalizes reactive oxygen species production and mitochondrial biogenesis, thereby restoring mitochondrial function. This is the first example of manipulation of a mitochondrial signalling pathway to achieve a direct positive modulation of COX, with clear implications for the development of novel approaches to treat mitochondrial diseases. |
format | Text |
id | pubmed-2814779 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | WILEY-VCH Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-28147792010-05-01 Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects Acin-Perez, Rebeca Salazar, Eric Brosel, Sonja Yang, Hua Schon, Eric A Manfredi, Giovanni EMBO Mol Med Research Articles Phosphorylation of respiratory chain components has emerged as a mode of regulation of mitochondrial energy metabolism, but its mechanisms are still largely unexplored. A recently discovered intramitochondrial signalling pathway links CO(2) generated by the Krebs cycle with the respiratory chain, through the action of a mitochondrial soluble adenylyl cyclase (mt-sAC). Cytochrome oxidase (COX), whose deficiency causes a number of fatal metabolic disorders, is a key mitochondrial enzyme activated by mt-sAC. We have now discovered that the mt-sAC pathway modulates mitochondrial biogenesis in a reactive oxygen species dependent manner, in cultured cells and in animals with COX deficiency. We show that upregulation of mt-sAC normalizes reactive oxygen species production and mitochondrial biogenesis, thereby restoring mitochondrial function. This is the first example of manipulation of a mitochondrial signalling pathway to achieve a direct positive modulation of COX, with clear implications for the development of novel approaches to treat mitochondrial diseases. WILEY-VCH Verlag 2009-11 /pmc/articles/PMC2814779/ /pubmed/20049744 http://dx.doi.org/10.1002/emmm.200900046 Text en Copyright © 2009 EMBO Molecular Medicine |
spellingShingle | Research Articles Acin-Perez, Rebeca Salazar, Eric Brosel, Sonja Yang, Hua Schon, Eric A Manfredi, Giovanni Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects |
title | Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects |
title_full | Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects |
title_fullStr | Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects |
title_full_unstemmed | Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects |
title_short | Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects |
title_sort | modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814779/ https://www.ncbi.nlm.nih.gov/pubmed/20049744 http://dx.doi.org/10.1002/emmm.200900046 |
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