Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1853, Issue 1, Pages 183-191Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2014.10.016
Keywords
Mitochondria; Respiratory complex I; cAMP/PKA signaling; Soluble adenylyl cyclase; Mitochondrial proteases
Categories
Funding
- MIUR (Progetto FIRB futuro in ricerca) [RBFR0813Z5]
- MIUR (FIRB-MERIT 'Molecular basis in ageing-related degenerative syndrome') [RBNE08HWLZ]
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In mammalian cells the nuclear-encoded subunits of complex I are imported into mitochondria, where they are assembled with mt-DNA encoded subunits in the complex, or exchanged with pre-existing copies in the complex. The present work shows that in fibroblast cultures inhibition by KH7 of cAMP production in the mitochondrial matrix by soluble adenylyl cyclase (sAC) results in decreased amounts of free non-incorporated nuclear-encoded NDUFS4, NDUFV2 and NDUFA9 subunits of the catalytic moiety and inhibition of the activity of complex I. Addition of permeant 8-Br-cAMP prevents this effect of KH7. KH7 inhibits accumulation in isolated rat-liver mitochondria and incorporation in complex I of in vitro produced, radiolabeled NDUFS4 and NDUFV2 subunits. 8-Br-cAMP prevents also this effect of KH7. Use of protease inhibitors shows that intramitochondrial cAMP exerts this positive effect on complex I by preventing digestion of nuclear-encoded subunits by mitochondrial protease(s), whose activity is promoted by KH7 and KH89, an inhibitor of PICA. (C) 2014 Elsevier B.V. All rights reserved.
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