Endogenous hydrogen sulfide production is essential for dietary restriction benefits.

Abstract

Dietary restriction (DR) without malnutrition encompasses numerous regimens with overlapping benefits including longevity and stress resistance, but unifying nutritional and molecular mechanisms remain elusive. In a mouse model of DR-mediated stress resistance, we found that sulfur amino acid (SAA) restriction increased expression of the transsulfuration pathway (TSP) enzyme cystathionine γ-lyase (CGL), resulting in increased hydrogen sulfide (H2S) production and protection from hepatic ischemia reperfusion injury. SAA supplementation, mTORC1 activation, or chemical/genetic CGL inhibition reduced H2S production and blocked DR-mediated stress resistance. In vitro, the mitochondrial protein SQR was required for H2S-mediated protection during nutrient/oxygen deprivation. Finally, TSP-dependent H2S production was observed in yeast, worm, fruit fly, and rodent models of DR-mediated longevity. Together, these data are consistent with evolutionary conservation of TSP-mediated H2S as a mediator of DR benefits with broad implications for clinical translation. PAPERFLICK:

• Authors: Christopher Hine, Eylul Harputlugil, Yue Zhang, Christoph Ruckenstuhl, Byung Cheon Lee, Lear Brace, Alban Longchamp, Jose H Treviño-Villarreal, Pedro Mejia, C Keith Ozaki, Rui Wang, Vadim N Gladyshev, Frank Madeo, William B Mair, James R Mitchell
• Journal: Cell (Cell) Vol. 160 Issue 1-2 Pg. 132-44 (Jan 15 2015) ISSN: 1097-4172 [Electronic] United States
• PMID: 25542313 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Methionine
• Cystathionine gamma-Lyase
• Cysteine
• Hydrogen Sulfide

Topics

• Animals
• Biological Evolution
• Caenorhabditis elegans (physiology)
• Caloric Restriction
• Cystathionine gamma-Lyase (metabolism)
• Cysteine (metabolism)
• Diet
• Drosophila melanogaster (physiology)
• Female
• Hydrogen Sulfide (metabolism)
• Kidney (blood supply, injuries)
• Life Expectancy
• Liver (blood supply, injuries)
• Male
• Methionine (metabolism)
• Mice, Knockout
• NF-E2-Related Factor 2 (genetics, metabolism)
• Reperfusion Injury
• Signal Transduction
• Stress, Physiological
• Transcriptome
• Yeasts (physiology)