title: Lithocholic bile acid accumulated in yeast mitochondria orchestrates a development of an anti-aging cellular pattern by causing age-related changes in cellular proteome.
abstract: We have previously revealed that exogenously added lithocholic bile acid (LCA) extends the chronological lifespan of the yeast Saccharomyces cerevisiae, accumulates in mitochondria and alters mitochondrial membrane lipidome. Here, we use quantitative mass spectrometry to show that LCA alters the age-related dynamics of changes in levels of many mitochondrial proteins, as well as numerous proteins in cellular locations outside of mitochondria. These proteins belong to 2 regulons, each modulated by a different mitochondrial dysfunction; we call them a partial mitochondrial dysfunction regulon and an oxidative stress regulon. We found that proteins constituting these regulons (1) can be divided into several "clusters", each of which denotes a distinct type of partial mitochondrial dysfunction that elicits a different signaling pathway mediated by a discrete set of transcription factors; (2) exhibit 3 different patterns of the age-related dynamics of changes in their cellular levels; and (3) are encoded by genes whose expression is regulated by the transcription factors Rtg1p/Rtg2p/Rtg3p, Sfp1p, Aft1p, Yap1p, Msn2p/Msn4p, Skn7p and Hog1p, each of which is essential for longevity extension by LCA. Our findings suggest that LCA-driven changes in mitochondrial lipidome alter mitochondrial proteome and functionality, thereby enabling mitochondria to operate as signaling organelles that orchestrate an establishment of an anti-aging transcriptional program for many longevity-defining nuclear genes. Based on these findings, we propose a model for how such LCA-driven changes early and late in life of chronologically aging yeast cause a stepwise development of an anti-aging cellular pattern and its maintenance throughout lifespan.
authors.affiliation: a Department of Biology; Concordia University ; Montreal , QC , Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Beach
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Richard
authors.forename: Simon
authors.initials: S
authors.lastname: Bourque
authors.forename: Tatiana
authors.initials: T
authors.lastname: Boukh-Viner
authors.forename: Pavlo
authors.initials: P
authors.lastname: Kyryakov
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gomez-Perez
authors.forename: Anthony
authors.initials: A
authors.lastname: Arlia-Ciommo
authors.forename: Rachel
authors.initials: R
authors.lastname: Feldman
authors.forename: Anna
authors.initials: A
authors.lastname: Leonov
authors.forename: Amanda
authors.initials: A
authors.lastname: Piano
authors.forename: Veronika
authors.initials: V
authors.lastname: Svistkova
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Titorenko
mesh_terms: D005786:Gene Expression Regulation / Q000187:drug effects*; D008095:Lithocholic Acid / Q000493:pharmacokinetics / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects*; D013058:Mass Spectrometry; D008563:Membrane Lipids / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D018085:Regulon / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
chemical_list: D008563:Membrane Lipids; D024101:Mitochondrial Proteins; D008095:Lithocholic Acid
keywords: D, diauxic growth phase; DMSO, dimethyl sulfoxide; ER, endoplasmic reticulum; ETC, electron transport chain; ISC, iron-sulfur clusters; LCA, lithocholic acid; MAM, mitochondria-associated membrane; OS, oxidative stress; PD, post-diauxic growth phase; PMD, partial mitochondrial dysfunction; ROS, reactive oxygen species; ST, stationary growth phase; TCA, tricarboxylic acid; WT, wild type; anti-aging compounds; cell metabolism; cellular aging; lithocholic bile acid; longevity; mitochondria; mitochondrial proteome; mitochondrial signaling; signal transduction; yeast
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