MICU1 imparts the mitochondrial uniporter with the ability to discriminate between Ca and Mn.

Proc Natl Acad Sci U S A
Authors
Keywords
Abstract

The mitochondrial uniporter is a Ca-activated Ca channel complex that displays exceptionally high conductance and selectivity. Here, we report cellular metal toxicity screens highlighting the uniporter's role in Mn toxicity. Cells lacking the pore-forming uniporter subunit, MCU, are more resistant to Mn toxicity, while cells lacking the Ca-sensing inhibitory subunit, MICU1, are more sensitive than the wild type. Consistent with these findings, lacking the uniporter's pore have increased resistance to Mn toxicity. The chemical-genetic interaction between uniporter machinery and Mn toxicity prompted us to hypothesize that Mn 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 Mn and Ca can pass through the uniporter, as evidenced by mitochondrial Mn uptake assays, mitochondrial membrane potential measurements, and mitoplast electrophysiology. We show that Mn does not elicit the conformational change in MICU1 that is physiologically elicited by Ca, preventing Mn 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.

Year of Publication
2018
Journal
Proc Natl Acad Sci U S A
Volume
115
Issue
34
Pages
E7960-E7969
Date Published
2018 08 21
ISSN
1091-6490
DOI
10.1073/pnas.1807811115
PubMed ID
30082385
PubMed Central ID
PMC6112746
Links
Grant list
R00 HL124070 / HL / NHLBI NIH HHS / United States
R01 HL130143 / HL / NHLBI NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States