DISRUPTION OF BRAIN MITOCHONDRIAL CALCIUM SEQUESTRATION BY METHYLMERCURY

  • 1 January 1991
    • journal article
    • research article
    • Vol. 256  (1) , 236-242
Abstract
In vitro effects of methylmercury (MeHg) on Ca2+ transport and respiratory control of mitochondria isolated from rat forebrain were examined to determine whether MeHg disrupted sequestration of Ca2+ by neuronal mitochondria. Uptake of Ca-45(2+) mitochondria and release of Ca-45(2+) from preloaded mitochondria were measured in the presence and absence of ATP. Release of Ca-45(2+) from preloaded mitochondria by MeHg was measured in the presence and absence of ruthenium red (RR), a putative inhibitor of the mitochondrial Ca2+ uptake uniporter. During incubation intervals ranging from 10 sec to 5 min, 10-mu-M MeHg reduced mitochondrial uptake of Ca-45(2+) by about 50% and 100 mu-M MeHg completely prevented Ca-45(2+) uptake. These effects of MeHg occurred in both the presence and absence of ATP. Exposure of mitochondria preloaded with Ca-45(2+) to either 10-mu-M or 100-mu-M MeHg for 10 sec resulted in increased efflux of Ca-45(2+) of 10% and 65%, respectively, in both the absence and presence of ATP. Loading mitochondria with Ca-45(2+) in the presence of 20-mu-M RR reduced total uptake of Ca-45(2+) and greatly attenuated MeHg-induced release of Ca-45(2+) from mitochondria. RR did not inhibit the effects of MeHg on Ca2+ release by merely preventing the binding of MeHg to mitochondria because RR did not alter mitochondrial binding of methyl[203Hg]. The ratio of state 3 to state 4 respiration (respiratory control ratio) was measured as a means of assessing functional integrity of isolated mitochondria in the absence and presence of MeHg. Control ratios of from 3 to 5 were only marginally reduced by 2-mu-M MeHg but were greatly reduced by 10 and 20-mu-M MeHg. The results of this study indicate that concentrations of MeHg that stimulate spontaneous release of transmitter impair mitochondrial respiration, thus impairing the functional integrity of the organelle. Consequently, the ability of mitochondria to sequester Ca2+ is disrupted, inducing efflux and inhibiting uptake of Ca2+. The MeHg-induced efflux of Ca2+ from mitochondria was prevented by block of the mitochondrial Ca2+ uniporter with RR. Thus, the mechanism by which MeHg increases spontaneous quantal release of transmitter may involve perturbation of mitochondrial Ca2+ sequestration perhaps by alterations of the Ca2+ uniporter.

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