TY - JOUR
T1 - In S. cerevisiae hydroxycitric acid antagonizes chronological aging and apoptosis regardless of citrate lyase
AU - Baroni, Maurizio D.
AU - Colombo, Sonia
AU - Libens, Olivier
AU - Pallavi, Rani
AU - Giorgio, Marco
AU - Martegani, Enzo
N1 - Funding Information:
Open access funding provided by Universit? degli Studi di Padova within the CRUI-CARE Agreement. We thank J. Winderickx, University of Leuven, Belgium for kind gift of snf1? , sch9? and cyr1?msn2?msn4?pde2? strains, P. van DijcK, University of Leuven, Belgium for the gift of strain tps1? , Stefania Citterio, University of Milano-Bicocca, for technical support and N. Tosetto for technical help.
Funding Information:
This work was supported by the Biology Department of the University of Padua (PRID-SEED Grant 2018–19) to M.D.B. and by the University of Milano-Bicocca (Fondo di Ateneo Grant) to S.C. and E.M. Acknowledgements
Funding Information:
Open access funding provided by Universitá degli Studi di Padova within the CRUI-CARE Agreement. We thank J. Winderickx, University of Leuven, Belgium for kind gift of snf1Δ, sch9Δ and cyr1Δmsn2Δmsn4Δpde2Δ strains, P. van DijcK, University of Leuven, Belgium for the gift of strain tps1Δ, Stefania Citterio, University of Milano-Bicocca, for technical support and N. Tosetto for technical help.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Caloric restriction mimetics (CRMs) are promising molecules to prevent age-related diseases as they activate pathways driven by a true caloric restriction. Hydroxycitric acid (HCA) is considered a bona fide CRM since it depletes acetyl-CoA pools by acting as a competitive inhibitor of ATP citrate lyase (ACLY), ultimately repressing protein acetylation and promoting autophagy. Importantly, it can reduce inflammation and tumour development. In order to identify phenotypically relevant new HCA targets we have investigated HCA effects in Saccharomyces cerevisiae, where ACLY is lacking. Strikingly, the drug revealed a powerful anti-aging effect, another property proposed to mark bona fide CRMs. Chronological life span (CLS) extension but also resistance to acetic acid of HCA treated cells were associated to repression of cell apoptosis and necrosis. HCA also largely prevented cell deaths caused by a severe oxidative stress. The molecule could act widely by negatively modulating cell metabolism, similarly to citrate. Indeed, it inhibited both growth reactivation and the oxygen consumption rate of yeast cells in stationary phase. Genetic analyses on yeast CLS mutants indicated that part of the HCA effects can be sensed by Sch9 and Ras2, two conserved key regulators of nutritional and stress signal pathways of primary importance. Our data together with published biochemical analyses indicate that HCA may act with multiple mechanisms together with ACLY repression and allowed us to propose an integrated mechanistic model as a basis for future investigations.
AB - Caloric restriction mimetics (CRMs) are promising molecules to prevent age-related diseases as they activate pathways driven by a true caloric restriction. Hydroxycitric acid (HCA) is considered a bona fide CRM since it depletes acetyl-CoA pools by acting as a competitive inhibitor of ATP citrate lyase (ACLY), ultimately repressing protein acetylation and promoting autophagy. Importantly, it can reduce inflammation and tumour development. In order to identify phenotypically relevant new HCA targets we have investigated HCA effects in Saccharomyces cerevisiae, where ACLY is lacking. Strikingly, the drug revealed a powerful anti-aging effect, another property proposed to mark bona fide CRMs. Chronological life span (CLS) extension but also resistance to acetic acid of HCA treated cells were associated to repression of cell apoptosis and necrosis. HCA also largely prevented cell deaths caused by a severe oxidative stress. The molecule could act widely by negatively modulating cell metabolism, similarly to citrate. Indeed, it inhibited both growth reactivation and the oxygen consumption rate of yeast cells in stationary phase. Genetic analyses on yeast CLS mutants indicated that part of the HCA effects can be sensed by Sch9 and Ras2, two conserved key regulators of nutritional and stress signal pathways of primary importance. Our data together with published biochemical analyses indicate that HCA may act with multiple mechanisms together with ACLY repression and allowed us to propose an integrated mechanistic model as a basis for future investigations.
KW - Aging
KW - Apoptosis/necrosis
KW - Caloric restriction mimetics
KW - Hydroxycitric acid
KW - Oxidative stress
KW - Sch9 and Ras2 pathways
UR - http://www.scopus.com/inward/record.url?scp=85087918726&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087918726&partnerID=8YFLogxK
U2 - 10.1007/s10495-020-01625-1
DO - 10.1007/s10495-020-01625-1
M3 - Article
C2 - 32666259
AN - SCOPUS:85087918726
VL - 25
SP - 686
EP - 696
JO - Apoptosis : an international journal on programmed cell death
JF - Apoptosis : an international journal on programmed cell death
SN - 1360-8185
IS - 9-10
ER -