Mitohormesis, an Antiaging Paradigm (original) (raw)

Abstract

Mitohormesis is a term used to define a biological response where the induction of a reduced amount of mitochondrial stress leads to an increment in health and viability within a cell, tissue, or organism. The mitochondrial stress response activated by a potentially damaging stimulus requires a coordinated dialogue with the cellular nucleus, known as mitonuclear communication. This interplay induced by the hormetic response in mitochondria relies in a variety of signals among which the most relevant ones are reactive oxygen species (ROS), mitochondrial metabolites, proteotoxic signals, the mitochondria–cytosol stress response, and the release of mitokines. The activation of the mitohormetic response increases lifespan in different animal models, from worms to mammals. Further, mitohormesis also enhances healthspan, particularly improving metabolism and immune system. Although multiple mediators and stress signals have been proposed to activate this protective mechanism, beneficial outcomes of mitohormesis are most probably due to an increase in mitochondrial ROS. Activation of other protective stress mechanisms as mitochondrial unfolded protein response or the increase in the expression of mitokines are also associated with the positive benefits exerted by mitohormesis. Herein, we review the different mitohormetic signals and pathways described from worms to mammals and their effects on health and survival. The identification and description of pathways and molecules implicated in the beneficial effects of mitohormesis will help understand the complex balance between death and survival in the face of mitochondrial damage and will allow to open a novel area of therapies aimed at improving health in humans.

Introduction

In the XVI century, the Swiss physician Paracelsus, known as the father of the toxicology, stated in his Third Defense the concept that “only the dose makes the poison” (from Latin: “_sola dosis facit venenum_”) (Paracelsus, 1564). This idea was used to defend that all chemical compounds can be toxic depending on the dose and not on the chemical properties themselves. Three centuries later the term “hormesis” was coined to define compounds or substances that show a “biphasic dose response,” i.e., a low-dose stimulation and high-dose inhibition (Fig. 1). Nowadays, in Biology, the idea of hormesis, or the concept of hormetic responses, is well defined to describe the situation where a low dose of stress stimuli can activate an adaptive response in cells and organisms to maintain homeostasis, promoting health and even longevity, whereas higher doses become harmful. The concept of hormesis was then expanded and studied based on the stimuli. The concept of “mitohormesis” appeared in 2006 as a theory to define the hormetic response that promotes health and vitality induced by sublethal mitochondrial stress (Tapia, 2006). This theoretical hypothesis was proposed to unify a series of hormetic responses carried out by mitochondrial reactive oxygen species (mtROS), such as those induced by caloric restriction (CR), intermittent fasting, exercise, and dietary phytonutrients. A year later, in 2007, the group led by Michael Ristow provided experimental support to this theory by showing that glucose restriction extended lifespan of worms by increasing reactive oxygen species (ROS) and mitochondrial respiration (Schulz et al., 2007). This ROS-mediated hormetic response was shown to activate catalase activity and, therefore, increase oxidative stress response. Importantly, the role of mtROS was described as essential because treatment with antioxidants abolished the lifespan extension (Schulz et al., 2007). This study, together with previous evidences on ROS signaling, began to question the widespread use of antioxidants as supplements or as treatment against diverse pathological conditions, including type 2 diabetes (Kawagishi and Finkel, 2014, Ristow, 2014).

The study of hormetic responses has gained considerable relevance since the discovery that mtROS and other mitochondrial stress pathways can promote lifespan in a hormetic-dependent manner. Thus, several groups have focused their research on the pursuit of mitohormesis inducers to improve healthspan and lifespan, especially by using lower organisms, such as Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster, where it was observed that some mitochondrial mutants or the treatment with mitochondrial toxins induced an unexpected increase in lifespan. In this review, we describe recent advances in mitohormesis, beginning with a description of the major signaling pathways governing this response, and finally discussing experimental evidence in different model organisms supporting the potential of mitohormesis as a prohealth and prolongevity strategy.

Section snippets

Mitonuclear Communication

Mitochondria are highly dynamic organelles derived from alphaproteobacteria that were engulfed by the precursor of the eukaryotic cell. During evolution within the eukaryotic cell there was an endosymbiosis process that triggered the loss in the mitochondrial DNA (mtDNA) of genes encoding mitochondrial proteins. Thus, among more than 1000 proteins present in mammalian mitochondria, only 13 are encoded in the mtDNA, which correspond to subunits of the oxidative phosphorylation (OXPHOS) system;

Mitohormesis Signaling

The different ways of mitonuclear communication, especially those activated under stress conditions, are aimed at resolving the stress at mitochondrial, cellular, or tissue level. However, all these signals and forms of mitonuclear communication can also mediate a mitohormetic response. Among all, the most important signals or processes are ROS, mitochondrial metabolites, proteotoxic signals, the mitochondria–cytosol stress response, and the release of mitokines (Fig. 2).

Mitohormesis and Lifespan

Mitochondrial function declines during aging, contributing to cellular senescence, inflammation and stem cell exhaustion (Lopez-Otin et al., 2013, Sun et al., 2016). However, and in concordance with the concept of hormesis, mild mitochondrial damage can be beneficial to cells and extend organismal lifespan, whereas a severe stress can cause an irreparable damage. Indeed, there is ample evidence that mitochondrial dysfunction can promote longevity in a hormetic-dependent fashion in different

Mitohormesis and Healthspan

Besides the positive effects of mitohormesis in lifespan, its activation can also have beneficial outcomes enhancing healthspan and improving metabolism (Fig. 3). Although the activation of mitohormesis has been reported to protect from different stress conditions in multiple model organisms, such as yeast and worms, we will focus mainly on healthspan improvements observed in mammals.

One of the most studied effectors that mediate the health benefits of mitochondrial hormesis is probably the

Concluding Remarks and Future Outlook

Mitochondrial dysfunction is one of the hallmarks of aging (Lopez-Otin et al., 2013), and its role during the aging process, as player and trigger, has been widely studied during many years (Sun et al., 2016). However, the identification of a mitochondrial hormetic response, defined as mitohormesis, has modified the initial ideas about the negative role of mitochondrial stress during the aging process (Yun and Finkel, 2014). Activation of mitohormesis signaling after mild mitochondrial or