TY - JOUR
T1 - Endogenous hydrogen sulfide production is essential for dietary restriction benefits
AU - Hine, Christopher
AU - Harputlugil, Eylul
AU - Zhang, Yue
AU - Ruckenstuhl, Christoph
AU - Lee, Byung Cheon
AU - Brace, Lear
AU - Longchamp, Alban
AU - Treviño-Villarreal, Jose H.
AU - Mejia, Pedro
AU - Ozaki, C. Keith
AU - Wang, Rui
AU - Gladyshev, Vadim N.
AU - Madeo, Frank
AU - Mair, William B.
AU - Mitchell, James R.
N1 - Funding Information:
We thank Bruce Kristal and Jaan-Olle Andressoo for critical reading of the manuscript; Silvia Dichtinger, Manmeet Gujral, and Jason Li for technical assistance; and Paul Ney for sharing the NRF2KO mice. This work was supported by grants from NIH (RO1DK090629, R01AG036712) and the Glenn Foundation to J.R.M.; C.H. was supported by T32CA0093823; F.M. was supported by the Austrian Science Fund FWF (LIPOTOX, I1000, P23490-B12, and P24381-B20); W.B.M. was supported by 1R01AG044346; V.N.G. was supported by R01AG021518; C.K.O. was supported by American Heart Association 12GRNT9510001 and 12GRNT1207025; and R.W. was supported by an operating grant from the Canadian Institutes of Health Research.
PY - 2015/1/15
Y1 - 2015/1/15
N2 - 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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=84920995923&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84920995923&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2014.11.048
DO - 10.1016/j.cell.2014.11.048
M3 - Article
C2 - 25542313
AN - SCOPUS:84920995923
VL - 160
SP - 132
EP - 144
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1-2
ER -
