Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain

被引：368

作者：

Kageyama, Yusuke ^{[1
]}

Hoshijima, Masahiko ^{[2
,3
]}

Seo, Kinya ^{[4
]}

Bedja, Djahida ^{[4
]}

Sysa-Shah, Polina ^{[5
]}

Andrabi, Shaida A. ^{[6
,7
,8
,9
]}

Chen, Weiran ^{[7
,8
]}

Hoeke, Ahmet ^{[7
,8
]}

Dawson, Valina L. ^{[6
,7
,8
,9
]}

Dawson, Ted M. ^{[6
,7
,8
,9
]}

Gabrielson, Kathleen ^{[5
]}

Kass, David A. ^{[4
]}

Iijima, Miho ^{[1
]}

Sesaki, Hiromi ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21218 USA

[2] Univ Calif San Diego, Ctr Res Biol Syst, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[4] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat & Stem Cell Programs, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[9] Adrienne Helis Malvin Med Res Fdn, New Orleans, LA USA

来源：

EMBO JOURNAL | 2014年 / 33卷 / 23期

关键词：

mice; mitochondria; organelle division; respiration; MITOCHONDRIAL DYNAMICS; ADULT CARDIOMYOCYTES; FISSION; CELLS; NEURONS; FUSION; YEAST;

D O I：

10.15252/embj.201488658

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：

Mitochondrial dynamics and mitophagy have been linked to cardiovascular and neurodegenerative diseases. Here, we demonstrate that the mitochondrial division dynamin Drp1 and the Parkinson's disease-associated E3 ubiquitin ligase parkin synergistically maintain the integrity of mitochondrial structure and function in mouse heart and brain. Mice lacking cardiac Drp1 exhibited lethal heart defects. In Drp1KO cardiomyocytes, mitochondria increased their connectivity, accumulated ubiquitinated proteins, and decreased their respiration. In contrast to the current views of the role of parkin in ubiquitination of mitochondrial proteins, mitochondrial ubiquitination was independent of parkin in Drp1KO hearts, and simultaneous loss of Drp1 and parkin worsened cardiac defects. Drp1 and parkin also play synergistic roles in neuronal mitochondrial homeostasis and survival. Mitochondrial degradation was further decreased by combination of Drp1 and parkin deficiency, compared with their single loss. Thus, the physiological importance of parkin in mitochondrial homeostasis is revealed in the absence of mitochondrial division in mammals.

引用

页码：2798 / 2813

页数：16

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