Mitochondrial Fission and Fusion Factors Reciprocally Orchestrate Mitophagic Culling in Mouse Hearts and Cultured Fibroblasts

被引：422

作者：

Song, Moshi ^{[1
]}

Mihara, Katsuyoshi ^{[2
]}

Chen, Yun ^{[1
]}

Scorrano, Luca ^{[3
,4
]}

Dorn, Gerald W., II ^{[1
]}

机构：

[1] Washington Univ, Sch Med, Dept Internal Med, Ctr Pharmacogen, St Louis, MO 63110 USA

[2] Kyushu Univ, Dept Mol Biol, Fukuoka 8128582, Japan

[3] Univ Padua, Venetian Inst Mol Med, Dulbecco Telethon Inst, I-35129 Padua, Italy

[4] Univ Padua, Dept Biol, I-35129 Padua, Italy

来源：

CELL METABOLISM | 2015年 / 21卷 / 02期

关键词：

CELL-DEATH; PERMEABILITY TRANSITION; EMBRYONIC-DEVELOPMENT; CYCLOPHILIN-D; PARKIN; AUTOPHAGY; CARDIOMYOPATHY; HYPERTROPHY; APOPTOSIS; MITOFUSIN;

D O I：

10.1016/j.cmet.2014.12.011

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

How mitochondrial dynamism (fission and fusion) affects mitochondrial quality control is unclear. We uncovered distinct effects on mitophagy of inhibiting Drp1-mediated mitochondrial fission versus mitofusin-mediated mitochondrial fusion. Conditional cardiomyocyte-specific Drp1 ablation evoked mitochondrial enlargement, lethal dilated cardiomyopathy, and cardiomyocyte necrosis. Conditionally ablating cardiomyocyte mitofusins (Mfn) caused mitochondrial fragmentation with eccentric remodeling and no cardiomyocyte dropout. Parallel studies in cultured murine embryonic fibroblasts (MEFs) and in vivo mouse hearts revealed that Mfn1/Mfn2 deletion provoked accumulation of defective mitochondria exhibiting an unfolded protein response, without appropriately increasing mitophagy. Conversely, interrupting mitochondrial fission by Drp1 ablation increased mitophagy and caused a generalized loss of mitochondria. Mitochondrial permeability transition pore (MPTP) opening in Drp1 null mitochondria was associated with mitophagy in MEFs and contributed to cardiomyocyte necrosis and dilated cardiomyopathy in mice. Drp1, MPTP, and cardiomyocyte mitophagy are functionally integrated. Mitochondrial fission and fusion have opposing roles during in vivo cardiac mitochondrial quality control.

引用

页码：273 / 285

页数：13

共 44 条

[1] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death [J].

Baines, CP ;

Kaiser, RA ;

Purcell, NH ;

Blair, NS ;

Osinska, H ;

Hambleton, MA ;

Brunskill, EW ;

Sayen, MR ;

Gottlieb, RA ;

Dorn, GW ;

Robbins, J ;

Molkentin, JD .

NATURE, 2005, 434 (7033) :658-662

[2] Calcium Elevation in Mitochondria Is the Main Ca2+ Requirement for Mitochondrial Permeability Transition Pore (mPTP) Opening [J].

Baumgartner, Heidi K. ;

Gerasimenko, Julia V. ;

Thorne, Christopher ;

Ferdek, Pawel ;

Pozzan, Tullio ;

Tepikin, Alexei V. ;

Petersen, Ole H. ;

Sutton, Robert ;

Watson, Alastair J. M. ;

Gerasimenko, Oleg V. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (31) :20796-20803

[3] Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and Its Containment by Suppressing Mitofusin [J].

Bhandari, Poonam ;

Song, Moshi ;

Chen, Yun ;

Burelle, Yan ;

Dorn, Gerald W., II .

CIRCULATION RESEARCH, 2014, 114 (02) :257-265

[4] Altered skeletal muscle mitochondrial biogenesis but improved endurance capacity in trained OPA1-deficient mice [J].

Caffin, F. ;

Prola, A. ;

Piquereau, J. ;

Novotova, M. ;

David, D. J. ;

Garnier, A. ;

Fortin, D. ;

Alavi, M. V. ;

Veksler, V. ;

Ventura-Clapier, R. ;

Joubert, F. .

JOURNAL OF PHYSIOLOGY-LONDON, 2013, 591 (23) :6017-6037

[5] Cyclophilin D is required for mitochondrial removal by autophagy in cardiac cells [J].

Carreira, Raquel S. ;

Lee, Youngil ;

Ghochani, Mariam ;

Gustafsson, Asa B. ;

Gottlieb, Roberta A. .

AUTOPHAGY, 2010, 6 (04) :462-472

[6] Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development [J].

Chen, HC ;

Detmer, SA ;

Ewald, AJ ;

Griffin, EE ;

Fraser, SE ;

Chan, DC .

JOURNAL OF CELL BIOLOGY, 2003, 160 (02) :189-200

[7] Mitochondrial fusion protects against neurodegeneration in the cerebellum [J].

Chen, Hsiuchen ;

McCaffery, J. Michael ;

Chan, David C. .

CELL, 2007, 130 (03) :548-562

[8] Mitochondrial Genome Linearization Is a Causative Factor for Cardiomyopathy in Mice and Drosophila [J].

Chen, Yun ;

Sparks, Megan ;

Bhandari, Poonam ;

Matkovich, Scot J. ;

Dorn, Gerald W. .

ANTIOXIDANTS & REDOX SIGNALING, 2014, 21 (14) :1949-1959

[9] PINK1-Phosphorylated Mitofusin 2 Is a Parkin Receptor for Culling Damaged Mitochondria [J].

Chen, Yun ;

Dorn, Gerald W., II .

SCIENCE, 2013, 340 (6131) :471-475

[10] Mitofusin 2-Containing Mitochondrial-Reticular Microdomains Direct Rapid Cardiomyocyte Bioenergetic Responses Via Interorganelle Ca2+ Crosstalk [J].

Chen, Yun ;

Csordas, Gyorgy ;

Jowdy, Casey ;

Schneider, Timothy G. ;

Csordas, Norbert ;

Wang, Wei ;

Liu, Yingqiu ;

Kohlhaas, Michael ;

Meiser, Maxie ;

Bergem, Stefanie ;

Nerbonne, Jeanne M. ;

Dom, Gerald W., II ;

Maack, Christoph .

CIRCULATION RESEARCH, 2012, 111 (07) :863-+

← 1 2 3 4 5 →