Since the initiation of work on mitochondrial Ca2+ transport in the early 1960s, the relationship between experimental observations and physiological function has often seemed enigmatic. Why, for example, should an organelle dedicated to the crucial task of producing approximately 95% of the cell's ATP sequester Ca2+, sometimes in preference to phosphorylating ADP? Why should there be two separate efflux mechanisms, the Na+ independent and the Na+ dependent, both thought until recently to be driven exclusively either directly or indirectly by the energy of the pH gradient? Does intramitochondrial free Ca2+ concentration control metabolism? Is there evidence for any separate function of the mitochondrial Ca2+ transport mechanisms under pathological conditions? What is the relationship between mitochondrial Ca2+ transport, the mitochondrial membrane permeability transition, and irreversible cell damage under pathological conditions? First, we review what is known about control of metabolism, evidence for a role for intramitochondrial Ca2+ in control of metabolism, the cellular conditions under which mitochondria are exposed to Ca2+, characteristics of the mitochondrial Ca2+ transport mechanisms including the permeability transition, and evidence for and against mitochondrial Ca2+ uptake in vivo. Then the questions listed above and others are addressed from the perspective of the characteristics of the mechanisms of mitochondrial Ca2+ transport.

Manganese shares the uniport mechanism of mitochondrial calcium influx, accumulates in mitochondria and is cleared only very slowly from brain. Using dual-label isotope techniques, we have investigated both Mn2+ and Ca2+ mitochondrial efflux kinetics. We report that (1) there is no significant Na(+)-dependent Mn2+ efflux from brain mitochondria; (2) Mn2+ inhibits both Na(+)-dependent and Na(+)-independent Ca2+ efflux in brain, in a mode that appears to be primarily competitive and with apparent Ki values of 5.1 and 7.9 nmol/mg respectively; and (3) Ca2+ does not appear to inhibit Mn2+ efflux from brain mitochondria. Findings (1) and (2) suggest the possibility of mitochondrial accumulation of both Mn2+ and Ca2+ in Mn2(+)-intoxicated brain.

Manganese (Mn) is an essential dietary nutrient but excess or accumulations can be toxic. Disease states, like manganism, are associated with overexposure or accumulation of Mn and are due to the production of reactive oxygen species, free radicals and toxic metabolites, alteration of mitochondrial function and ATP production and depletion of cellular antioxidant defense mechanisms. This review focuses on all of the preceding mechanisms and the scientific studies that support them as well as provides an overview of the absorption, distribution, and excretion of Mn and the stability and transport of Mn compounds in the body.

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