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

Abstract

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. Liu et al. describe the physiological effects of deleting MICU1, a key component of the mitochondrial calcium uniporter. MICU1-/- mice demonstrate in vivo calcium overload, mirroring what has been described recently for MICU1-deficient human patients. These animals can be rescued by reducing the expression of EMRE, another uniporter component.

Original languageEnglish (US)
JournalCell Reports
DOIs
StateAccepted/In press - Mar 3 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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