An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages

被引：67

作者：

Carneiro, Flavia R. G. ^{[1
,3
]}

Lepelley, Alice ^{[1
]}

Seeley, John J. ^{[1
]}

Hayden, Matthew S. ^{[1
,2
]}

Ghosh, Sankar ^{[1
]}

机构：

[1] Columbia Univ, Dept Microbiol & Immunol, Vagelos Coll Phys & Surg, New York, NY 10032 USA

[2] Dartmouth Hitchcock Med Ctr, Dermatol Sect, Dept Surg, Lebanon, NH 03756 USA

[3] Fiocruz MS, Ctr Technol Dev Hlth CDTS, Rio De Janeiro, Brazil

来源：

CELL REPORTS | 2018年 / 22卷 / 10期

关键词：

ALPHA-KETOGLUTARATE DEHYDROGENASE; ROS PRODUCTION; BACTERICIDAL ACTIVITY; PROTEIN-DEGRADATION; LACTIC-ACIDOSIS; INNER MEMBRANE; HOST-DEFENSE; DEFICIENCY; MUTATIONS; INDUCTION;

D O I：

10.1016/j.celrep.2018.02.051

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

ECSIT is a mitochondrial complex I (CI)-associated protein that has been shown to regulate the production of mitochondrial reactive oxygen species (mROS) following engagement of Toll-like receptors (TLRs). We have generated an Ecsit conditional knockout (CKO) mouse strain to study the in vivo role of ECSIT. ECSIT deletion results in profound alteration of macrophage metabolism, leading to a striking shift to reliance on glycolysis, complete disruption of CI activity, and loss of the CI holoenzyme and multiple subassemblies. An increase in constitutive mROS production in ECSIT-deleted macrophages prevents further TLR-induced mROS production. Surprisingly, ECSIT-deleted cells accumulate damaged mitochondria because of defective mitophagy. ECSIT associates with the mitophagy regulator PINK1 and exhibits Parkin-dependent ubiquitination. However, upon ECSIT deletion, we observed increased mitochondrial Parkin without the expected increase in mitophagy. Taken together, these results demonstrate a key role of ECSIT in CI function, mROS production, and mitophagy-dependent mitochondrial quality control.

引用

页码：2654 / 2666

页数：13

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