Abstract
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 mito- chondrial 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 forthe development of novel approaches to treat mitochondrial diseases.
Original language | English (US) |
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Pages (from-to) | 392-406 |
Number of pages | 15 |
Journal | EMBO Molecular Medicine |
Volume | 1 |
Issue number | 8-9 |
DOIs | |
State | Published - Nov 2009 |
Keywords
- Cytochrome oxidase
- Mitochondria
- ROS
- mtDNA
- sAC
ASJC Scopus subject areas
- Molecular Medicine