Manganese stimulates calcium flux through the mitochondrial uniporter.
Mn2+ alters the balance between the simultaneous uptake and release of Ca2+ across the mitochondrial inner membrane toward a lower external level. Addition of as little as 0.5 microM Mn2+ to energised mitochondria from rat liver, rat heart or guinea-pig brain changed the level at which they buffered Ca2+ in the medium. That extramitochondrial Mn2+ was responsible was suggested by a partial decay in the shift in Ca2+ steady state at a rate similar to the rate at which Mn2+ was accumulated by the mitochondria. The alteration of transmembrane Ca2+ distribution by Mn2+ required that both Mg2+ and Pi be present, and was almost maximal at Mg2+ and Pi levels in the physiological range. Substitution of spermine or Ni2+ for Mg2+, or acetate for Pi, abolished the effect. In contrast to Sr2+, Mn2+ did not inhibit either EGTA- or Ruthenium red-induced release of Ca2+ from the mitochondria. However, when flux through the uniporter was rate-limiting, Mn2+ accelerated Ca2+ uptake. The stimulation showed hyperbolic kinetics, with an element of competition discernible in the Mn2+-Mg2+ interaction. Thus, extramitochondrial Mn2+ at levels occurring in vivo can alter the mitochondrial 'set-point' by stimulating Ca2+ influx through the uniporter.
D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008345:Manganese / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; C034703:mitochondrial calcium uniporter; D008345:Manganese; D008274:Magnesium; D002118:Calcium