MICU1 is a component of the mitochondrial calcium uniporter, a multiprotein complex that also includes MICU2, MCU, and EMRE. Here, we describe a mouse model of MICU1 deficiency. MICU1−/− mitochondria demonstrate altered calcium uptake, and deletion of MICU1 results in significant, but not complete, perinatal mortality. Similar to afflicted patients, viable MICU1−/− mice manifest marked ataxia and muscle weakness. Early in life, these animals display a range of biochemical abnormalities, including increased resting mitochondrial calcium levels, altered mitochondrial morphology, and reduced ATP. Older MICU1−/− mice show marked, spontaneous improvement coincident with improved mitochondrial calcium handling and an age-dependent reduction in EMRE expression. Remarkably, deleting one allele of EMRE helps normalize calcium uptake while simultaneously rescuing the high perinatal mortality observed in young MICU1−/− mice. Together, these results demonstrate that MICU1 serves as a molecular gatekeeper preventing calcium overload and suggests that modulating the calcium uniporter could have widespread therapeutic benefits.
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We are grateful to Michele Allen for help with mouse phenotyping; Erin Stempinski, Camron Keshavarz, and Christopher Bleck for help with electron microscopic analysis; and Jeffrey Culver at the Sanford-Burnham Orlando Metabolomics Core for skeletal muscle lactate measurements. This work was supported by Intramural NIH funds, a Leducq Transatlantic Network grant (to T.F.), and a PRAT postdoctoral fellowship from NIGMS (to J.C.L.).