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

Julia Liu | Zendy; Jie Liu | Zendy; Kira M. Holmström | Zendy; Sara Menazza | Zendy; Randi J. Parks | Zendy; Marı́a M. Fergusson | Zendy; Zu-Xi Yu | Zendy; Danielle A. Springer | Zendy; Charles Halsey | Zendy; Chengyu Liu | Zendy; Elizabeth Murphy | Zendy; Toren Finkel | Zendy

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

Author(s) -

Julia Liu,

Jie Liu,

Kira M. Holmström,

Sara Menazza,

Randi J. Parks,

Marı́a M. Fergusson,

Zu-Xi Yu,

Danielle A. Springer,

Charles Halsey,

Chengyu Liu,

Elizabeth Murphy,

Toren Finkel

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.07.011

Subject(s) - uniporter , calcium , mitochondrion , microbiology and biotechnology , calcium binding protein , calcium signaling , biology , ataxia , mitochondrial disease , chemistry , neuroscience , biochemistry , medicine , signal transduction , mitochondrial dna , gene , cytosol , enzyme

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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