Disruption of brain mitochondrial calcium sequestration by methylmercury.
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 45Ca2+ by mitochondria and release of 45Ca2+ from preloaded mitochondria were measured in the presence and absence of ATP. Release of 45Ca2+ 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 microM MeHg reduced mitochondrial uptake of 45Ca2+ by about 50% and 100 microM MeHg completely prevented 45Ca2+ uptake. These effects of MeHg occurred in both the presence and absence of ATP. Exposure of mitochondria preloaded with 45Ca2+ to either 10 microM or 100 microM MeHg for 10 sec resulted in increased efflux of 45Ca2+ of 10% and 65%, respectively, in both the absence and presence of ATP. Loading mitochondria with 45Ca2+ in the presence of 20 microM RR reduced total uptake of 45Ca2+ and greatly attenuated MeHg-induced release of 45Ca2+ 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 microM MeHg but were greatly reduced by 10 and 20 microM MeHg.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Toxicology, Michigan State University, East Lansing.
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Levesque
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Atchison
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D002132:Calcium Radioisotopes; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012430:Ruthenium Red / Q000494:pharmacology
D002132:Calcium Radioisotopes; D008767:Methylmercury Compounds; D012430:Ruthenium Red; D002118:Calcium