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

作者：Julia Liu, Jie Liu, Kira M. Holmström, Sara Menazza, Randi J. Parks, Marı́a M. Fergusson, Zu-Xi Yu, Danielle Springer, Charles Halsey, Chengyu Liu, Elizabeth Murphy, Toren Finkel · 发表于：Cell Reports · 年份：2016 · DOI：10.1016/j.celrep.2016.07.011 · 被引用次数：231 · 研究领域：Mitochondrial Function and Pathology、ATP Synthase and ATPases Research、Metabolism and Genetic Disorders

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.