MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload

Julia C. Liu, Jie Liu, Kira M. Holmström, Sara Menazza, Randi J. Parks, Maria M. Fergusson, Zu Xi Yu, Danielle A. Springer, Charles Halsey, Chengyu Liu, Elizabeth Murphy, Toren Finkel

Research output: Contribution to journalArticlepeer-review

157 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1561-1573
Number of pages13
JournalCell reports
Issue number6
StatePublished - Aug 9 2016
Externally publishedYes

Bibliographical note

Funding Information:
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.).

Publisher Copyright:
© 2016


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