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

Federica Valsecchi, Csaba Konrad, Marilena D'Aurelio, Lavoisier S Ramos-Espiritu, Anna Stepanova, Suzanne R Burstein, Alexander Galkin, Jordi Magranè, Anatoly S. Starkov, Jochen Buck, Lonny R Levin, Giovanni Manfredi

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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 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 KO fibroblasts have a defect in OXPHOS activity and attempt to compensate for this defect by increasing OXPHOS proteins. Importantly, sAC KO cells also exhibit decreased probability of endoplasmic reticulum (ER) Ca(2+) release associated with diminished phosphorylation of the inositol 3-phosphate receptor. Restoring sAC expression exclusively in the mitochondrial matrix rescues OXPHOS activity and reduces its biogenesis, indicating that these phenotypes are regulated by intramitochondrial sAC. In contrast, ER Ca(2+) release 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(2+) signaling.

Original languageEnglish
JournalJournal of Cell Science
Early online date01 Sep 2017
DOIs
Publication statusEarly online date - 01 Sep 2017
Externally publishedYes

Keywords

  • Journal Article

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    Valsecchi, F., Konrad, C., D'Aurelio, M., Ramos-Espiritu, L. S., Stepanova, A., Burstein, S. R., Galkin, A., Magranè, J., Starkov, A. S., Buck, J., Levin, L. R., & Manfredi, G. (2017). Distinct intracellular sAC-cAMP domains regulate ER calcium signaling and OXPHOS function. Journal of Cell Science. https://doi.org/10.1242/jcs.206318