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 .mu.M Mn2+ to energized 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 [ethyleneglycol bis (.beta.-aminoethylether) N,N,N'',N''tetraacetic acid] or ruthenium red-induced release of Ca2+ from the mitochondria. 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.