PROTOPORPHYRIN-IX, AN ENDOGENOUS LIGAND OF THE PERIPHERAL BENZODIAZEPINE RECEPTOR, POTENTIATES INDUCTION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION AND THE KILLING OF CULTURED-HEPATOCYTES BY ROTENONE

The peripheral benzodiazepine receptor (PBzR) is associated with the o uter mitochondrial membrane. Protoporphyrin IX (PPIX), an endogenous s ubstance with high affinity for the PBzR, induced the inner membrane p ermeability transition (MPT) in respiring liver mitochondria de-energi zed by carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Cyclosporin A (CyA), an inhibitor of the permeability transition, prevented this effect. In cultured hepatocytes, the MPT was measured as an increased [H-3]sucrose-accessible space sensitive to CyA. Nanomolar concentratio ns of PPIX potentiated the induction of the MPT and the extent of cell killing in hepatocyte cultures de-energized by rotenone. CyA prevente d the enhanced cell killing by PPIX. PPIX did not increase the rate or extent of ATP depletion, the loss of the mitochondrial membrane poten tial, or the accumulation of long chain acyl-CoA thioesters. The assoc iation of the PBzR with the voltage-dependent anion channel of the out er mitochondrial membrane and with the adenine nucleotide carrier of t he inner membrane suggests that this complex mediates the transport of PPIX across the mitochondrial membranes. In turn, this same complex p articipates in the MPT. Thus, the same structural complex (PBzR, volta ge-dependent anion channel, and adenine nucleotide carrier) can intera ct with the endogenous substrate PPIX to result in different functiona l consequences depending on the state of mitochondrial energization.