MICU1 regulation of mitochondrial Ca2+ uptake dictates survival and tissue regeneration

被引：174

作者：

Antony, Anil Noronha ^{[1
]}

Paillard, Melanie ^{[1
]}

Moffat, Cynthia ^{[1
]}

Juskeyiciute, Egle ^{[1
]}

Correnti, Jason ^{[1
]}

Bolon, Brad ^{[2
]}

Rubin, Emanuel ^{[1
]}

Csordas, Gyoergy ^{[1
]}

Seifert, Erin L. ^{[1
]}

Hoek, Jan B. ^{[1
]}

Hajnoczky, Gyoergy ^{[1
]}

机构：

[1] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, MitoCare Ctr, Philadelphia, PA 19107 USA

[2] Ohio State Univ, Coll Vet Med, Comparat Pathol & Mouse Phenotyping Shared Resour, Columbus, OH 43210 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

LIVER-REGENERATION; CALCIUM UNIPORTER; PERMEABILITY TRANSITION; MCU; GATEKEEPER; ACTIVATION; PROTEIN; STRESS; SYSTEM;

D O I：

10.1038/ncomms10955

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Mitochondrial Ca2+ uptake through the recently discovered Mitochondrial Calcium Uniporter (MCU) is controlled by its gatekeeper Mitochondrial Calcium Uptake 1 (MICU1). However, the physiological and pathological role of MICU1 remains unclear. Here we show that MICU1 is vital for adaptation to postnatal life and for tissue repair after injury. MICU1 knockout is perinatally lethal in mice without causing gross anatomical defects. We used liver regeneration after partial hepatectomy as a physiological stress response model. Upon MICU1 loss, early priming is unaffected, but the pro-inflammatory phase does not resolve and liver regeneration fails, with impaired cell cycle entry and extensive necrosis. Ca2+ overload-induced mitochondrial permeability transition pore (PTP) opening is accelerated in MICU1-deficient hepatocytes. PTP inhibition prevents necrosis and rescues regeneration. Thus, our study identifies an unanticipated dependence of liver regeneration on MICU1 and highlights the importance of regulating MCU under stress conditions when the risk of Ca2+ overload is elevated.

引用

页数：10

共 42 条

[1]

Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter [J].