MICU1 imparts the mitochondrial uniporter with the ability to discriminate between Ca2+ and Mn2+

被引:58
|
作者
Kamer, Kimberli J. [1 ,2 ,3 ]
Sancak, Yasemin [2 ,3 ,7 ]
Fomina, Yevgenia [2 ,3 ]
Meisel, Joshua D. [2 ,3 ]
Chaudhuri, Dipayan [4 ]
Grabarek, Zenon [2 ,3 ]
Mootha, Vamsi K. [2 ,3 ,5 ,6 ]
机构
[1] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA
[2] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA
[3] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA
[4] Univ Utah, Dept Internal Med, Nora Eccles Harrison Cardiovasc Res & Training In, Div Cardiol, Salt Lake City, UT 84112 USA
[5] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA
[6] Broad Inst, Cambridge, MA 02142 USA
[7] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA
基金
美国国家卫生研究院;
关键词
neurodegeneration; calcium; manganese; EF hand; selectivity; RAT-LIVER MITOCHONDRIA; CALCIUM UNIPORTER; EF-HAND; CAENORHABDITIS-ELEGANS; MANGANESE TOXICITY; CRYSTAL-STRUCTURE; ION; CHANNEL; TRANSPORT; MEMBRANE;
D O I
10.1073/pnas.1807811115
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The mitochondrial uniporter is a Ca2+-activated Ca2+ channel complex that displays exceptionally high conductance and selectivity. Here, we report cellular metal toxicity screens highlighting the uniporter's role in Mn2+ toxicity. Cells lacking the pore-forming uniporter subunit, MCU, are more resistant to Mn2+ toxicity, while cells lacking the Ca2+-sensing inhibitory subunit, MICU1, are more sensitive than the wild type. Consistent with these findings, Caenorhabditis elegans lacking the uniporter's pore have increased resistance to Mn2+ toxicity. The chemical-genetic interaction between uniporter machinery and Mn2+ toxicity prompted us to hypothesize that Mn2+ can indeed be transported by the uniporter's pore, but this transport is prevented by MICU1. To this end, we demonstrate that, in the absence of MICU1, both Mn2+ and Ca2+ can pass through the uniporter, as evidenced by mitochondrial Mn2+ uptake assays, mitochondrial membrane potential measurements, and mitoplast electrophysiology. We show that Mn2+ does not elicit the conformational change in MICU1 that is physiologically elicited by Ca2+, preventing Mn2+ from inducing the pore opening. Our work showcases a mechanism by which a channel's auxiliary subunit can contribute to its apparent selectivity and, furthermore, may have implications for understanding how manganese contributes to neurodegenerative disease.
引用
收藏
页码:E7960 / E7969
页数:10
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