In S. cerevisiae hydroxycitric acid antagonizes chronological aging and apoptosis regardless of citrate lyase

Maurizio D. Baroni, Sonia Colombo, Olivier Libens, Rani Pallavi, Marco Giorgio, Enzo Martegani

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)686-696
Number of pages11
JournalApoptosis
Volume25
Issue number9-10
DOIs
Publication statusPublished - Oct 1 2020

Keywords

  • Aging
  • Apoptosis/necrosis
  • Caloric restriction mimetics
  • Hydroxycitric acid
  • Oxidative stress
  • Sch9 and Ras2 pathways

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

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