Control of the pro-oxidant-dependent calcium release from intact liver mitochondria.

Abstract

The reduction of molecular oxygen to water provides most of the energy that enables higher organisms to exist. Oxygen reduction is a mixed blessing because incompletely reduced oxygen species are more reactive than molecular oxygen in the ground state and can, when out of control, damage biological molecules. However, incompletely reduced oxygen species may also serve useful functions, as exemplified by their control of mitochondrial Ca(2+) homeostasis, the understanding of which has improved greatly during the last few years. Hydrogen peroxide can stimulate a specific Ca(2+) release pathway from intact mitochondria by oxidizing mitochondrial pyridine nucleotides through the activities of glutathione peroxidase, glutathione reductase, and the energy-linked transhydrogenase. Other pro-oxidants such as menadione, alloxan, or divicine also stimulate the specific Ca(2+) release, because they furnish NAD(+). The specific Ca(2+) release requires for its activation the hydrolysis of intramitochondrial NAD(+) to ADPribose and nicotinamide, and is prevented by inhibitors of NAD(+) hydrolysis and protein monoADPribosylation. Recent experiments reveal that NAD(+) hydrolysis and therefore Ca(2+) release is regulated by vicinal thiols in mitochondria. When reduced or alkylated, the thiols prevent hydrolysis, but when they are cross-linked hydrolysis takes place. Cyclosporine A, which also prevents NAD(+) hydrolysis, acts distal of these vicinal thiols. Since mitochondrial Ca(2+) handling is physiologically relevant, its control by pro-oxidants must be added to the growing list of their useful functions.