FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

被引：46

作者：

Nguyen-Dien, Giang Thanh ^{[1
,2
]}

Kozul, Keri-Lyn ^{[1
]}

Cui, Yi ^{[1
]}

Townsend, Brendan ^{[1
]}

Kulkarni, Prajakta Gosavi ^{[1
]}

Ooi, Soo Siang ^{[1
]}

Marzio, Antonio ^{[3
,4
,5
]}

Carrodus, Nissa ^{[1
]}

Zuryn, Steven ^{[6
]}

Pagano, Michele ^{[3
,4
]}

Parton, Robert G. ^{[7
,8
]}

Lazarou, Michael ^{[9
,10
,11
]}

Millard, S. Sean ^{[1
]}

Taylor, Robert W. ^{[12
,13
]}

Collins, Brett M. ^{[7
]}

Jones, Mathew J. K. ^{[14
,15
]}

Pagan, Julia K. ^{[1
,7
,14
]}

机构：

[1] Univ Queensland, Sch Biomed Sci, Fac Med, Brisbane, Qld, Australia

[2] Viet Nam Natl Univ Int Univ, Sch Biotechnol, Dept Biotechnol, Ho Chi Minh City, Vietnam

[3] New York Univ, Grossman Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USA

[4] New York Univ, Grossman Sch Med, Perlmutter Canc Ctr, New York, NY USA

[5] Weill Cornell Med, Meyer Canc Ctr, Dept Pathol & Lab Med, New York, NY USA

[6] Univ Queensland, Queensland Brain Inst, Clem Jones Ctr Ageing Dementia Res, Brisbane, Qld, Australia

[7] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[8] Univ Queensland, Ctr Microscopy & Microanal, Brisbane, Qld, Australia

[9] Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia

[10] Monash Univ, Biomed Discovery Inst, Dept Biochem & Mol Biol, Melbourne, Vic, Australia

[11] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia

[12] Newcastle Univ, Translat & Clin Res Inst, Fac Med Sci, Wellcome Ctr Mitochondrial Res, Newcastle Upon Tyne, England

[13] Newcastle Tyne Hosp NHS Fdn Trust, NHS Highly Specialised Serv Rare Mitochondrial Dis, Newcastle Upon Tyne, England

[14] Univ Queensland, Diamantina Inst, Fac Med, Brisbane, Qld, Australia

[15] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld, Australia

来源：

EMBO JOURNAL | 2023年 / 42卷 / 13期

基金：

英国医学研究理事会; 澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

BNIP3; FBXL4; mitochondria; mitophagy; NIX; BNIP3L; UBIQUITIN LIGASES; HIF-ALPHA; PROTEIN; MITOCHONDRIA; AUTOPHAGY; PINK1; DNA; MECHANISMS; INHIBITOR; MUTATIONS;

D O I：

10.15252/embj.2022112767

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F-box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4-associated mtDNA depletion syndrome.

引用

页数：15