Comparative kinetic analysis reveals that inducer-specific ion release precedes the mitochondrial permeability transition.
Relationships among the multiple events that precede the mitochondrial membrane permeability transition (MPT) are not yet clearly understood. A combination of newly developed instrumental and computational approaches to this problem is described. The instrumental innovation is a high-resolution digital apparatus for the simultaneous, real-time measurement of four mitochondrial parameters as indicators of the respiration rate, membrane potential, calcium ion transport, and mitochondrial swelling. A computational approach is introduced that tracks the fraction of mitochondria that has undergone pore opening. This approach allows multiple comparisons on a single time scale. The validity of the computational approach for studying complex mitochondrial phenomena was evaluated with mitochondria undergoing an MPT induced by Ca(2+), phenylarsine oxide or alamethicin. Selective ion leaks were observed that precede the permeability transition and that are inducer specific. These results illustrate the occurrence of inducer-specific sequential changes associated with the induction of the permeability transition. Analysis of the temporal relationship among the multiple mitochondrial parameters of isolated mitochondria should provide insights into the mechanisms underlying these responses.
Krasnikov
Boris F
BF
Dementia Research Service, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA. bkrasnik@burke.org
Zorov
Dmitry B
DB
Antonenko
Yuri N
YN
Zaspa
Andrey A
AA
Kulikov
Igor V
IV
Kristal
Bruce S
BS
Cooper
Arthur J L
AJ
Brown
Abraham M
AM
D000408:Alamethicin / Q000494:pharmacology; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D001703:Biophysics / Q000295:instrumentation / Q000379:methods; D002118:Calcium / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D017736:Ion-Selective Electrodes; D007501:Iron / Q000378:metabolism*; D007700:Kinetics; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D009861:Onium Compounds / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000737:chemistry; D010101:Oxygen Consumption; D010539:Permeability; D051381:Rats; D011914:Rats, Inbred BN; D012815:Signal Processing, Computer-Assisted
D001152:Arsenicals; D009861:Onium Compounds; D009943:Organophosphorus Compounds; C029341:oxophenylarsine; D000408:Alamethicin; D007501:Iron; D002118:Calcium; C013289:tetraphenylphosphonium