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Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):11908-11913. doi: 10.1073/pnas.1704723114. Epub 2017 Oct 20.

Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3.

Hu H1, Nan J1, Sun Y1, Zhu D1, Xiao C1, Wang Y1, Zhu L1,2, Wu Y1,2, Zhao J1,2, Wu R1, Chen J1,3, Yu H1, Hu X1, Zhu W4, Wang J4.

Author information

1
Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.
2
Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
3
Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China.
4
Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China; wangjianan111@zju.edu.cn weizhu65@zju.edu.cn.

Abstract

The causative relationship between specific mitochondrial molecular structure and reactive oxygen species (ROS) generation has attracted much attention. NDUFA13 is a newly identified accessory subunit of mitochondria complex I with a unique molecular structure and a location that is very close to the subunits of complex I of low electrochemical potentials. It has been reported that down-regulated NDUFA13 rendered tumor cells more resistant to apoptosis. Thus, this molecule might provide an ideal opportunity for us to investigate the profile of ROS generation and its role in cell protection against apoptosis. In the present study, we generated cardiac-specific tamoxifen-inducible NDUFA13 knockout mice and demonstrated that cardiac-specific heterozygous knockout (cHet) mice exhibited normal cardiac morphology and function in the basal state but were more resistant to apoptosis when exposed to ischemia-reperfusion (I/R) injury. cHet mice showed a preserved capacity of oxygen consumption rate by complex I and II, which can match the oxygen consumption driven by electron donors of N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD)+ascorbate. Interestingly, at basal state, cHet mice exhibited a higher H2O2 level in the cytosol, but not in the mitochondria. Importantly, increased H2O2 served as a second messenger and led to the STAT3 dimerization and, hence, activation of antiapoptotic signaling, which eventually significantly suppressed the superoxide burst and decreased the infarct size during the I/R process in cHet mice.

KEYWORDS:

NDUFA13; STAT3; hydroxyl peroxide; mitochondria; reactive oxygen species

PMID:
29078279
PMCID:
PMC5692532
DOI:
10.1073/pnas.1704723114
[Indexed for MEDLINE]
Free PMC Article

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