Quantitative evaluation of the effects of mitochondrial permeability transition pore modifiers on accumulation of calcium phosphate: comparison of rat liver and brain mitochondria.
Mitochondria play a critical role in some forms of apoptosis, and the Ca(2+)-dependent permeability transition (PT) is a key initiator of this process. We quantitatively examined major control mechanisms of PT in rat brain (RBM) and liver (RLM) mitochondria. Compared with RLM, RBM were less sensitive to cyclosporin A (CsA), but the combined action of CsA+ADP was much more pronounced in RBM. Carboxyatractyloside abrogated the effects of all mPTP inhibitors in RBM but not in RLM, where the effects of CsA were not reduced. Estimated H(+)/Ca(2+) ratios were 0.81+/-0.01 for RLM and 0.84-0.93 for RBM, suggesting that Ca(2+) and Pi were sequestered in the matrix as CaHPO(4) and Ca(3)(PO(4))(2) salts, and that RBM sequester more CaPi as the least soluble salt. We conclude that: (1) RBM and RLM differ in their baseline behavior of the PT and in their responses to PT modifiers, and (2) PT modifiers can be functionally divided into those which directly affect the mitochondrial PT pore and are not energy-dependent (CsA, free Ca(2+), ADP(ex), and Mg(2+)), and those which affect the energy-dependent calcium phosphate sequestration process (ADP(mt), CATR, local anesthetics). We also conclude that ANT affects PT by changing mitochondrial capacity for energization.
Panov
Alexander V
AV
Department of Neurology and the Center for Neurodegenerative Disease, Emory University, Whitehead Biomedical Research Building, Room 575, 615 Michael St., Atlanta, GA 30322, USA. apanov@emory.edu
Andreeva
Larisa
L
Greenamyre
J Timothy
JT
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000408:Alamethicin / Q000494:pharmacology; D000818:Animals; D001278:Atractyloside / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002130:Calcium Phosphates / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003992:Dibucaine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008027:Light; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009840:Oligomycins / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D012542:Scattering, Radiation; D017186:Titrimetry / Q000379:methods
D002130:Calcium Phosphates; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009840:Oligomycins; C485828:alpha-tricalcium phosphate; C485830:tetracalcium phosphate; D001278:Atractyloside; D000408:Alamethicin; D000244:Adenosine Diphosphate; C485838:calcium phosphate, monobasic, anhydrous; D016572:Cyclosporine; C020243:calcium phosphate; C485829:calcium phosphate, dibasic, anhydrous; D003992:Dibucaine; C003853:carboxyatractyloside