title: Divalent cation chelators citrate and EDTA unmask an intrinsic uncoupling pathway in isolated mitochondria.
abstract: We demonstrate a suppression of ROS production and uncoupling of mitochondria by exogenous citrate in Mg2+free medium. Exogenous citrate suppressed H2O2emission and depolarized mitochondria. The depolarization was paralleled by the stimulation of respiration of mitochondria. The uncoupling action of citrate was independent of the presence of sodium, potassium, or chlorine ions, and it was not mediated by the changes in permeability of the inner mitochondrial membrane to solutes. The citrate transporter was not involved in the citrate effect. Inhibitory analysis data indicated that several well described mitochondria carriers and channels (ATPase, IMAC, ADP/ATP translocase, mPTP, mKATP) were not involved in citrate's effect. Exogenous MgCl2strongly inhibited citrate-induced depolarization. The uncoupling effect of citrate was demonstrated in rat brain, mouse brain, mouse liver, and human melanoma cells mitochondria. We interpreted the data as an evidence to the existence of a hitherto undescribed putative inner mitochondrial membrane channel that is regulated by extramitochondrial Mg2+or other divalent cations.
authors.affiliation: The Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY, 10065, USA. ans2024@med.cornell.edu.
authors.forename: Anatoly A
authors.identifier: http://orcid.org/0000-0002-1334-4828
authors.initials: AA
authors.lastname: Starkov
authors.affiliation: Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.|MTA-SE Lendület Neurobiochemistry Research Group, Budapest, Hungary.
authors.forename: Christos
authors.initials: C
authors.lastname: Chinopoulos
authors.affiliation: Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Starkova
authors.affiliation: Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Konrad
authors.affiliation: Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Kiss
authors.affiliation: School of Biological Sciences, Medical Biology Centre, Queens University Belfast, Belfast, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Stepanova
authors.affiliation: Voronezh State University, Voronezh, Russia.
authors.forename: Vasily N
authors.initials: VN
authors.lastname: Popov
mesh_terms: D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000648:ultrastructure; D002413:Cations, Divalent / Q000494:pharmacology*; D019343:Citric Acid / Q000494:pharmacology*; D004492:Edetic Acid / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D015636:Magnesium Chloride / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002413:Cations, Divalent; D007473:Ion Channels; D017382:Reactive Oxygen Species; D015636:Magnesium Chloride; D019343:Citric Acid; D004492:Edetic Acid; D006861:Hydrogen Peroxide
keywords: Inner membrane; Membrane potential; Proton channel; Reactive oxygen species; Uncoupling