L-Lactate Protects Skin Fibroblasts against Aging-Associated Mitochondrial Dysfunction via Mitohormesis.

Jaroslav Zelenka,Lukáš Alán,Aleš Dvořák

doi:10.1155/2015/351698

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.

Highlights

Aging and associated pathologies represent the major global health problem of the 21st century [1]
This led to a suggestion of the “mitochondrial free radical theory of aging” (MFRTA) which states that aging results from accumulation of oxidative damage caused by mitochondrial reactive oxygen species (ROS)
The extended lifespan and the prevention of chronic diseases has been described in the group of genetic and pharmaceutical models ranging from yeasts to mice, which share a phenotype of mild inhibition of mitochondrial respiratory chain accompanied with a moderate elevation of mitochondrial ROS production

Summary

Introduction

Aging and associated pathologies represent the major global health problem of the 21st century [1]. The extended lifespan and the prevention of chronic diseases has been described in the group of genetic and pharmaceutical models ranging from yeasts to mice, which share a phenotype of mild inhibition of mitochondrial respiratory chain accompanied with a moderate elevation of mitochondrial ROS production This effect termed the mitochondrial hormesis or mitohormesis [4,5,6,7,8] has been linked to the activation of protective and quality control mechanisms including hypoxia-inducible factor 1α (HIF1α), the 5󸀠AMP-activated protein kinase (AMPK), and the unfolded protein response (UPR) signaling [7,8,9,10]. Little is known about signaling effects of the intermittent l-lactate elevation associated with the exercise

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Methods

Results