title: L-Lactate Protects Skin Fibroblasts against Aging-Associated Mitochondrial Dysfunction via Mitohormesis.
abstract: A moderate elevation of reactive oxygen species (ROS) production and a mild inhibition of mitochondrial respiratory chain have been associated with a health promotion and a lifespan extension in several animal models of aging. Here, we tested whether this phenomenon called mitohormesis could be mediated by L-lactate. The treatment with 5 mM L-lactate significantly increased H2O2 production and slightly inhibited the respiration in cultured skin fibroblasts and in isolated mitochondria. The L-lactate exposure was associated with oxidation of intracellular glutathione, phosphorylation of 5'AMP-activated protein kinase (AMPK), and induction of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) transcription. A replicative aging of fibroblasts (L0) with a constant (LC), or intermittent 5 mM L-lactate (LI) in media showed that the high-passage LI fibroblasts have higher respiration, lower H2O2 release, and lower secretion of L-lactate compared to L0 and LC. This protection against mitochondrial dysfunction in LI cells was associated with lower activity of mechanistic target of rapamycin complex 1 (mTORC1), less signs of cellular senescence, and increased autophagy compared to L0 and LC. In conclusion, we demonstrated that intermittent but not constant exposure to L-lactate triggers mitohormesis, prevents aging-associated mitochondrial dysfunction, and improves other markers of aging.
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic ; Department of Biochemistry and Microbiology, Institute of Chemical Technology Prague, Technická 5, 166 28 Prague, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Zelenka
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.
authors.forename: Aleš
authors.initials: A
authors.lastname: Dvořák
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Alán
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D019344:Lactic Acid / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D019344:Lactic Acid; D006861:Hydrogen Peroxide; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005978:Glutathione