title: Cardiac mitochondria in heart failure: normal cardiolipin profile and increased threonine phosphorylation of complex IV.
abstract: Mitochondrial dysfunction is a major contributor in heart failure (HF). We investigated whether the decrease in respirasome organization reported by us previously in cardiac mitochondria in HF is due to changes in the phospholipids of the mitochondrial inner membrane or modifications of the subunits of the electron transport chain (ETC) complexes. The contents of the main phospholipid species, including cardiolipin, as well as the molecular species of cardiolipin were unchanged in cardiac mitochondria in HF. Oxidized cardiolipin molecular species were not observed. In heart mitochondria isolated from HF, complex IV not incorporated into respirasomes exhibits increased threonine phosphorylation. Since HF is associated with increased adrenergic drive to cardiomyocytes, this increased protein phosphorylation might be explained by the involvement of cAMP-activated protein kinase. Does the preservation of cAMP-induced phosphorylation changes of mitochondrial proteins or the addition of exogenous cAMP have similar effects on oxidative phosphorylation? The usage of phosphatase inhibitors revealed a specific decrease in complex I-supported respiration with glutamate. In saponin-permeabilized cardiac fibers, pre-incubation with cAMP decreases oxidative phosphorylation due to a defect localized at complex IV of the ETC inter alia. We propose that phosphorylation of specific complex IV subunits decreases oxidative phosphorylation either by limiting the incorporation of complex IV in supercomplexes or by decreasing supercomplex stability.
authors.affiliation: Center for Mitochondrial Diseases; Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Rosca
authors.forename: Paul
authors.initials: P
authors.lastname: Minkler
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000737:chemistry / Q000378:metabolism*; D019069:Cell Respiration / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008929:Mitochondria, Heart / Q000737:chemistry* / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013912:Threonine / Q000378:metabolism*
chemical_list: D002308:Cardiolipins; D010743:Phospholipids; D013912:Threonine; D000242:Cyclic AMP; D003576:Electron Transport Complex IV; D010100:Oxygen