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

  1. Jian’an Wanga,2
  1. aCardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China;
  2. bClinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
  3. cInstitute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
  1. Edited by J. G. Seidman, Harvard Medical School, Boston, MA, and approved September 1, 2017 (received for review March 23, 2017)

Significance

Reactive oxygen species (ROS) generation due to electron leak from the mitochondria may be involved in physiological or pathological processes. NDUFA13 is an accessory subunit of mitochondria complex I with a unique molecular structure and is located close to FeS clusters with low electrochemical potentials. Here, we generated cardiac-specific conditional NDUFA13 heterozygous knockout mice. At the basal state, a moderate down-regulation of NDUFA13 created a leak within complex I, resulting in a mild increase in cytoplasm localized H2O2, but not superoxide. The resultant ROS served as a second messenger and was responsible for the STAT3 dimerization and, hence, the activation of antiapoptotic signaling, which eventually significantly suppressed the superoxide burst and decreased the infarct size during the ischemia-reperfusion process.

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.

Footnotes

  • ?1H.H., J.N., and Y.S. contributed equally to this work.

  • ?2To whom correspondence may be addressed. Email: wangjianan111{at}zju.edu.cn or weizhu65{at}zju.edu.cn.
  • Author contributions: H.H., J.N., Y.S., D.Z., Y. Wang, Y. Wu, R.W., J.C., H.Y., X.H., W.Z., and J.W. designed research; H.H., D.Z., C.X., L.Z., Y. Wu, and J.Z. performed research; J.N., Y.S., C.X., Y. Wang, L.Z., R.W., X.H., and W.Z. contributed new reagents/analytic tools; H.H., J.N., Y. Wang, L.Z., Y. Wu, J.Z., J.C., H.Y., X.H., and W.Z. analyzed data; and H.H., Y.S., D.Z., W.Z., and J.W. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1704723114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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