Journal
EMBO MOLECULAR MEDICINE
Volume 1, Issue 8-9, Pages 392-406Publisher
WILEY
DOI: 10.1002/emmm.200900046
Keywords
mitochondria; sAC; cytochrome oxidase; mtDNA; ROS
Categories
Funding
- NIH
- Muscular Dystrophy Association
- United Mitochondrial Disease Foundation
- Milstein Foundation
- MSTP
- Marriot Foundation
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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 CO2 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 ROS 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.
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