[Aging-related increase of sensitivity of the mitochondrial permeability transition pore to inductors in the rat heart].
An age-related increase in the sensitivity of the mitochondrial permeability transition pore (MPTP) to inductors of it's opening, Ca2+ ions and phenylarsineoxide (PAO) was studied in experiments in vitro on isolated heart mitochondria of adult and old rats. Two indices were measured spectrophotometrically (lambda = 520 nm) by a decrease in an optical density (OD), resulting from mitochondrial swelling and a release of mitochondrial unidentified substances (mitochondrial factor, MF) registered also spectrophotometrically in a range of waves lambda = 230-260 nm. Dose-dependent effect of Ca2+ (10(-7)-10(-4) mol/l) and PAO (10(-8)-10(-4) mol/l) on swelling of the mitochondria were observed in samples from both adult and old rats. Swelling of the mitochondria from the heart of old rats induced by application of the above inductors was more intensive than the respective effect in samples from adult rats. In samples from the heart of both adult and old rats Ca2+ ions within the tested concentration range (10(-7)-10(-4) mol/l) evoked the release of MF in a dose-dependent manner. Mitochondria from the heart of old rats were found to be capable of releasing some amounts of MF in the absence of the MPTP inductors PAO. When this inductor was applied in a 10(-9) to 10(-4) mol/l concentration range, isolated mitochondria from the heart of old rats released unidentified substances with the absorption peaks at two wavelength, lambda = 230 nm and lambda = 240-245 nm. The former peak was found to be Cyclosporin A-insensitive, while the latter peak could be practically completely inhibited by this antibiotic. The concentrations of tested solutions (10(-7) mol/l CaCl2 and 10(-9) mol/l PAO), at which the release of the factor from the mitochondria of the old rat heart was observed, were significantly lower than those in adult rats. Our experimental data show that mitochondria isolated from the heart tissue of old rats demonstrate significantly higher sensitivity to inductors of MPTP-opening, Ca(2+)-overload and PAO as compared to that typical of adult animals. A higher sensitivity of MPTP-opening in the heart of old rats was accompanied by a higher basal level of expression of mRNA of the bax gene, as compared to that found in adult animals. The expression of the bcl-2 gene showed no age group-related differences. It can be supposed that a proapoptotic agent, the Bax protein, is related to an increase in the sensitivity of the MPTP (in particular to that manifested in the processes of pore formation) in the course of aging. Antioxidants, melathonin and trolox, when applied in 10(-5) mol/l concentration, presented to a certain extent opening of the MPTP-induced by 10(-5) mol/l PAO in samples from adult and old rats. These findings can be used for correction of increased sensitivity of the MPTP to different inductors, which is typical of old rats. We conclude that physiological aging is accompanied by the mitochondrial dysfunction. The MF-released capability of the mitochondria from heart tissue of old rats observed both in the presence and absence of MPTP-opening inductors (probably related to a higher sensitivity of MPTP-opening) is one of the manifestation of such dysfunction.
Sahach
V F
VF
A.A. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kiev.
Vavilova
H L
HL
Strutyns'ka
N A
NA
Rudyk
O V
OV
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D002122:Calcium Chloride / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D051028:bcl-2-Associated X Protein
D001152:Arsenicals; C494828:Bax protein, rat; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C029341:oxophenylarsine; D002122:Calcium Chloride