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Research Article

Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production

Ming Fu, Weihua Zhang, Lingyun Wu, Guangdong Yang, Hongzhu Li, and Rui Wang
  1. aDepartment of Biology and
  2. dSchool of Kinesiology, Lakehead University, Thunder Bay, ON, Canada P7B 5E1;
  3. bDepartment of Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E5; and
  4. cDepartment of Pathophysiology, Harbin Medical University, Harbin 150086, China

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PNAS first published February 7, 2012; https://doi.org/10.1073/pnas.1115634109
Ming Fu
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Weihua Zhang
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Lingyun Wu
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Guangdong Yang
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Hongzhu Li
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Rui Wang
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  • For correspondence: rwang@lakeheadu.ca
  1. Edited* by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 10, 2012 (received for review September 22, 2011)

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Abstract

Although many types of ancient bacteria and archea rely on hydrogen sulfide (H2S) for their energy production, eukaryotes generate ATP in an oxygen-dependent fashion. We hypothesize that endogenous H2S remains a regulator of energy production in mammalian cells under stress conditions, which enables the body to cope with energy demand when oxygen supply is insufficient. Cystathionine γ-lyase (CSE) is a major H2S-producing enzyme in the cardiovascular system that uses cysteine as the main substrate. Here we show that CSE is localized only in the cytosol, not in mitochondria, of vascular smooth-muscle cells (SMCs) under resting conditions, revealed by Western blot analysis and confocal microscopy of SMCs transfected with GFP-tagged CSE plasmid. After SMCs were exposed to A23187, thapsigargin, or tunicamycin, intracellular calcium level was increased, and CSE translocated from the cytosol to mitochondria. CSE was coimmunoprecipitated with translocase of the outer membrane 20 (Tom20) in mitochondrial membrane. Tom20 siRNA significantly inhibited mitochondrial translocation of CSE and mitochondrial H2S production. The cysteine level inside mitochondria is approximately three times that in the cytosol. Translocation of CSE to mitochondria metabolized cysteine, produced H2S inside mitochondria, and increased ATP production. Inhibition of CSE activity reversed A23187-stimulated mitochondrial ATP production. H2S improved mitochondrial ATP production in SMCs with hypoxia, which alone decreased ATP production. These results suggest that translocation of CSE to mitochondria on specific stress stimulations is a unique mechanism to promote H2S production inside mitochondria, which subsequently sustains mitochondrial ATP production under hypoxic conditions.

  • mitochondrion
  • oxygen sensing
  • evolution
  • sulfur metabolism
  • phenylephrine

Footnotes

  • ↵1M.F. and W.Z. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. E-mail: rwang{at}lakeheadu.ca.
  • Author contributions: L.W., G.Y., and R.W. designed research; M.F., W.Z., and H.L. performed research; M.F., W.Z., L.W., G.Y., and R.W. analyzed data; and L.W. and R.W. wrote the paper.

  • The authors declare no conflict of interest.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1115634109/-/DCSupplemental.

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Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production
Ming Fu, Weihua Zhang, Lingyun Wu, Guangdong Yang, Hongzhu Li, Rui Wang
Proceedings of the National Academy of Sciences Feb 2012, 201115634; DOI: 10.1073/pnas.1115634109

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Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production
Ming Fu, Weihua Zhang, Lingyun Wu, Guangdong Yang, Hongzhu Li, Rui Wang
Proceedings of the National Academy of Sciences Feb 2012, 201115634; DOI: 10.1073/pnas.1115634109
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