Regulation of the permeability transition pore in skeletal muscle mitochondria modulation by electron flow through the respiratory chain complex I
J. Biol. Chem.. 1998-05-15; 273(20): 12662-12668
DOI: 10.1074/jbc.273.20.12662
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We have investigated the regulation of the permeability transition pore (PTP), a
cyclosporin A-sensitive channel, in rat skeletal muscle mitochondria. As is the
case with mitochondria isolated from a variety of sources, skeletal muscle
mitochondria can undergo a permeability transition following Ca2+ uptake in the
presence of Pi. We find that the PTP opening is dramatically affected by the
substrates used for energization, in that much lower Ca2+ loads are required when
electrons are provided to complex I rather than to complex II or IV. This
increased sensitivity of PTP opening does not depend on differences in membrane
potential, matrix pH, Ca2+ uptake, oxidation-reduction status of pyridine
nucleotides, or production of H2O2, but is directly related to the rate of
electron flow through complex I. Indeed, and with complex I substrates only, pore
opening can be observed when depolarization is induced with uncoupler (increased
electron flow) but not with cyanide (decreased electron flow). Consistent with
pore regulation by electron flow, we find that PTP opening is inhibited by
ubiquinone 0 at concentrations that partially inhibit respiration and do not
depolarize the inner membrane. These data allow identification of a novel site of
regulation of the PTP, suggest that complex I may be part of the pore complex,
and open new perspectives for its pharmacological modulation in living cells.