Manganese and calcium efflux kinetics in brain mitochondria. Relevance to manganese toxicity

Abstract

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.

Uptake of MnCl2 and mangafodipir trisodium in the myocardium: A magnetic resonance imaging study in pigs

“…The myocardium can be divided into intravascular space, extracellular space, and intracellular compartments (cytosol, organelles). It has been shown earlier that manganese ions enter cells and rapidly pass into the mitochondria where they are accumulated (16). Therefore, a possible explanation is that the early peak represents distribution in all these compartments, while the persistent contrast effect represents trapping of manganese ions in the cytosol and/or mitochondria and increase in relaxivity because of binding to intracellular proteins.…”

“…The toxicity consists of two components: one acute, cardiotoxic component resulting in a decrease in heart rate, arterial blood pressure, and decreased contractility, and one chronic, neurotoxic component (15,16). Upon injection of manganese-based substances most of the free Mn 2ϩ -ions are bound by transporting proteins, mainly albumin (17).…”

Excitation-contraction coupling and mitochondrial energetics

“…Furthermore, Mn 2+ might quench mitochondrial indo-1 [222]. Finally, the mNCE is inhibited by Mn 2+ as well [69,76,77,137], which could affect Ca 2+ efflux kinetics. To avoid these undesired effects of MnCl 2 , Griffiths et al [73], who had previously used the Mn 2+ -quench method [74], developed the "heat treatment" protocol, in which incubation of indo-1/AM loaded cardiac myocytes at 25 °C for 2.5 h and 37 °C for 1.5 h promoted the loss of cytosolic indo-1 through probenecid-sensitive plasma membrane anion pumps [73].…”

“…Mn 2+ enters the cell, presumably via L-type Ca 2+ -channels, binds to cytosolic indo-1 with ∼20-fold higher affinity than Ca 2+ and quenches its fluorescence [123,137,222]. Although Mn 2+ competes with Ca 2+ for the mCU [69,123], and thus can be taken up into mitochondria as well [26,222], it was proposed that at the concentrations used, cytosolic free Mn 2+ was too low to effectively compete with Ca 2+ for the mCU, since most cytosolic Mn 2+ should be bound to indo-1 [222]. Indeed, MnCl 2 did not affect cell shortening, indicating that despite a potential inhibitory effect of Mn 2+ on I Ca,L [123], EC coupling was not hampered [137].…”

“…Mn 2+ competes with Ca 2+ for the mCU [76,77] (although patch-clamp studies suggest that the selectivity of the mCU for Ca 2+ vs Mn 2+ is > 15-fold [109]) and can be taken up into mitochondria as well [26,33,69,76,77,222], where it may inhibit oxidative phosphorylation [70]. Thus, Mn 2+ could potentially reduce the rate of the mCU, on the one hand by competing with Ca 2+ , on the other hand by reducing Δψ m .…”