Distinct intracellular sAC-cAMP domains regulate ER Ca signaling and OXPHOS function.

TitleDistinct intracellular sAC-cAMP domains regulate ER Ca signaling and OXPHOS function.
Publication TypeJournal Article
Year of Publication2017
AuthorsValsecchi F, Konrad C, D'Aurelio M, Ramos-Espiritu LS, Stepanova A, Burstein SR, Galkin A, Magranè J, Starkov A, Buck J, Levin LR, Manfredi G
JournalJ Cell Sci
Volume130
Issue21
Pagination3713-3727
Date Published2017 Nov 01
ISSN1477-9137
Abstract

cAMP regulates a wide variety of physiological functions in mammals. This single second messenger can regulate multiple, seemingly disparate functions within independently regulated cell compartments. We have previously identified one such compartment inside the matrix of the mitochondria, where soluble adenylyl cyclase (sAC) regulates oxidative phosphorylation (OXPHOS). We now show that sAC knockout fibroblasts have a defect in OXPHOS activity and attempt to compensate for this defect by increasing OXPHOS proteins. Importantly, sAC knockout cells also exhibit decreased probability of endoplasmic reticulum (ER) Ca release associated with diminished phosphorylation of the inositol 3-phosphate receptor. Restoring sAC expression exclusively in the mitochondrial matrix rescues OXPHOS activity and reduces mitochondrial biogenesis, indicating that these phenotypes are regulated by intramitochondrial sAC. In contrast, Ca release from the ER is only rescued when sAC expression is restored throughout the cell. Thus, we show that functionally distinct, sAC-defined, intracellular cAMP signaling domains regulate metabolism and Ca signaling.

DOI10.1242/jcs.206318
Alternate JournalJ. Cell. Sci.
PubMed ID28864766
PubMed Central IDPMC5702058
Grant ListMR/L007339/1 / / Medical Research Council / United Kingdom
R01 GM088999 / GM / NIGMS NIH HHS / United States
R01 GM107442 / GM / NIGMS NIH HHS / United States