Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2016-08, Vol.16 (6), p.1561-1573

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •The absence of MICU1 leads to impaired gatekeeping by the calcium uniporter•Surviving MICU1−/− mice manifest mitochondrial calcium overload•MICU1−/− mice improve as they age, correlating with decreased EMRE expression•Deleting one allele of EMRE helps rescue MICU1−/− mice 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.