Mitohormesis: How Mitochondria Protect Themselves from Oxidative Stress

Key Learning Objectives

• Learn about the benefits and harms of reactive oxygen species
• Discover the relevance of mitohormesis for healthy aging
• Find out how antioxidant defenses protect cells from damage
• Learn what compounds support antioxidant defenses 

Introduction to Mitohormesis

Mitohormesis is a type of biological response where mild mitochondrial stress leads to an enhancement of health, viability, and longevity of a cell, tissue, or organism. Crucial to the development of mitohormetic responses are reactive oxygen species (ROS).[1,2] 

Mitohormesis implies that, while high amounts of ROS cause damage and promote aging, low levels of ROS may be needed to promote healthy adaptation and to slow aging. In Mitochondria Functions for Healthy Aging: What Does the Mitochondria Do? we’ve learned that mitochondria generate ROS as byproducts of energy metabolism. At high levels, ROS can have toxic effects known as oxidative stress. But at just the right amount, ROS are fundamental for healthy cell function and homeostasis. 

In this article, we’re going to learn about mitohormesis, the activity of ROS as signaling molecules, and how and why ROS can be both beneficial and harmful. We will also discuss what leads to excessive ROS production and accumulation, how this associates with aging, and where antioxidants fit into the equation. Lastly, we’ll discuss nutritional strategies that can support the antioxidant defenses cells and mitochondria use to protect themselves against excessive ROS.

What Are Reactive Oxygen Species?

ROS are highly reactive compounds that contain oxygen. ROS are naturally produced in all cells, where they act as signaling molecules with important roles in cellular function and homeostasis.[3]  Mitochondria are the main site of ROS generation and one of their roles is to link mitochondrial metabolism and cell signaling pathways.[4] 

Left unchecked, ROS can damage mitochondria and accelerate aging, so they have historically been thought of as “bad.” This gave rise to the free radical theory of aging, which hypothesized that aging was caused by the accumulation of damage inflicted by ROS. This theory has been contradicted by research, leading to a more nuanced understanding of the role ROS play in aging and health.[5]

Mitohormesis means that, while high amounts of ROS cause damage and promote aging, low levels of ROS may be needed to promote healthy adaptation and to slow aging. This understanding implies that oxidative stress, similar to most types of stress, would follow a Goldilocks principle, where there’s a range that’s just right—amounts less than or greater than this just right range tend to be counter-productive.[1,2]

Reactive oxygen species (ROS) are byproducts of energy metabolism that can cause oxidative stress if there’s an imbalance between how much ROS are made and cellular antioxidant defenses that protect against them.

How Do Cells Protect Themselves from ROS?

Oxidative stress damages molecules and cell structures and eventually leads to cellular dysfunction and cell death.[3] Because this is one of the factors that drive the aging process and the development of age-related health challenges, it’s important that ROS levels are kept under control by cells. 

As mentioned in Mitochondria Functions for Healthy Aging: What Does the Mitochondria Do? cells have a set of antioxidant defenses that inactivate ROS. The enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and peroxiredoxins (Prx), along with the glutathione and thioredoxin redox systems act together as part of a ROS scavenging system that helps to calibrate the levels of ROS in mitochondria and throughout the cell.[6]

A characteristic of healthy cells is that the generation and elimination of ROS are balanced because these antioxidant defenses are sufficient to keep pace with the ROS being created. But as we age the balance is slowly lost. Therefore, it is important to help cells respond to the ROS they are generating by upregulating their own antioxidant defenses. 

Antioxidant enzymes—SOD, GPx, CAT, and Prx—can be supported by a wide range of dietary compounds. These include extracts from foods such as strawberries,[7–9] cocoa,[10–13], citrus,[14–17], and grape;[18–20] spices like cinnamon,[21–23] and herbs including rosemary [24–26], Kaempferia parviflora (called black ginger or black turmeric),[27] Withania somnifera (Ashwagandha),[28–33] and Gynostemma pentaphyllum.[34–37] 

Antioxidant defenses can also be supported by the flavonoid compounds apigenin [38–42] and rutin,[27–29] as well as the mitochondrial dietary supplements coenzyme Q10 (CoQ10; ubiquinone),[43–48] lipoic acid,[49–54] and pyrroloquinoline quinone (PQQ).[55–57]

Glutathione is a cellular antioxidant and detoxification molecule, which is used to protect cells and mitochondria against damage from ROS. Glutathione exists in both reduced (GSH) and oxidized (GSSG) states. In the GSH state, it’s able to donate a reducing equivalent (H⁺+ e⁻) to other molecules, such as ROS, to neutralize them. After this occurs, it reacts with another reactive glutathione to form GSSG. 

In healthy cells and tissue, as much as 98% of the total glutathione pool is as GSH, which means that cellular health is characterized by a very high ratio of GSH to GSSG (GSH:GSSG).[58] A reduction in this ratio (i.e., GSH decreases and GSSG increases) is an indicator of oxidative stress.[59,60]

GSH levels can be supported by providing GSH substrates. While GSH is synthesized de novo from the amino acids glycine, cysteine and glutamic acid,[61] cysteine is rate-limiting.[62] N-acetyl-L-cysteine (NAC) is a form of L-cysteine used to support the production of GSH. Supplying NAC allows the body to restore intracellular glutathione levels when demand has been increased or under circumstances when it is lower (such as older age or increased toxin exposure) in tissues throughout the body (including the brain, liver, and muscles).[63–65] The combination of NAC and glycine is additive,[66] which makes sense since both are used in glutathione production.

Foods, spices, and compounds in the diet can also influence cellular GSH. Cocoa,[67,68] cinnamon,[22] and rosemary[25,69] can support GSH synthesis and/or increased GSH:GSSG ratios. Other supportive compounds include apigenin [40] and resveratrol.[70,71]

Promoting antioxidant defenses includes enhancing the cellular glutathione pool and supporting antioxidant enzymes.

How ROS Trigger Cellular Adaptation

Mitochondria are so vital to cells that any threat to their function is a cause of alarm. There are many situations that can cause mitochondrial stress, such as a sudden high demand for ATP or a low level of glucose, for example. Mitochondria need to inform the cell of their stress so that the cell can devise a response that allows it to adapt and survive. One of the most important ways they do so is by increasing the production of ROS as signaling molecules.[72]

ROS activate signaling pathways that change gene expression and strengthen endogenous (i.e., generated within the cell) stress defense pathways, including antioxidant defenses. This cellular stress response enables the detoxification of ROS.[2,73]

Most importantly, whereas the increase in ROS is transient, the increase in the cell’s stress defenses induced by ROS persists. This adaptive stress response allows cells to protect themselves more efficiently from increases in ROS levels in the future.[73] 

As signaling molecules, ROS can be beneficial. But it’s all a matter of dose: whereas high concentrations of ROS cause irreversible damage to cellular structures, mild increases in ROS can be protective.[74] This may seem odd, but it’s actually a common biological response: the hormetic response.

Mild stress-induced increases in ROS levels trigger cellular adaptations that improve cells capabilities to deal with stress now and in the future.

Why Mild Stress Can Be Beneficial

Hormesis (i.e., a hormetic response) is a biological response in which there’s benefit at a low dose and damage at a high dose.[75] In other words, hormesis is a non-linear dose-effect response that allows potentially damaging compounds or biological stressors to have a beneficial action at a milder dose.

Hormesis is a survival-enhancing mechanism: it activates cellular stress response pathways that repair damage and protect cells from the cause of stress.[75] Furthermore, hormesis leads to long-lasting changes that increase long-term stress resistance and enhance protection against future challenges.[76] Hormesis underlies the association between mild biological stress and increased longevity that has been repeatedly shown by scientific research.[77,78]

Hormesis is a biological response to a compound or stressor characterized by benefit at a low dose and damage at a high dose; it is the property that allows potentially damaging compounds to have a beneficial effects at a milder dose.

How Mitohormesis Strengthens Antioxidant Defenses

Mitohormesis (from mitochondria + hormesis) is a specific form of hormesis in which cellular protective responses are triggered by mitochondrial stress. Mitohormesis explains why ROS are beneficial at lower levels: Modest increases in ROS production are protective because they (1) trigger stress response mechanisms that prevent cellular damage, and (2) increase cellular defenses.[73,74] 

ROS are not the only signals of mitochondrial stress. For example, there are other molecules that sense metabolic imbalances in mitochondria and trigger adaptive responses. These include nutrient-sensing pathways like AMPK and sirtuins. But ROS assume a central role in mitohormesis because they are active means of communication between mitochondria and the cell.

And it’s not just antioxidant defenses that mitohormesis supports. Mitochondrial stress may regulate metabolism, growth, autophagy (i.e., the degradation and recycling of proteins and organelles), and mitochondrial biogenesis (i.e., the generation of new mitochondria). This set of cellular adaptations improve the chances of survival during times of stress and create long-lasting improvements in cellular function that better prepare organisms for future challenges.[2]

Through mitohormesis, mild increases in ROS production, caused by mitochondrial stress, results in long-lasting improvements in cellular defenses.

How Mitohormesis Supports Longevity

Mitochondrial dysfunction is one of the nine hallmarks of aging.[79] With age, the mitochondrial electron transport chain becomes less efficient in generating ATP and produces higher levels of ROS. As a consequence, oxidative damage accumulates, impacting cellular function, and leading to progressive cellular degeneration.[80–82]

During aging, there is also a loss of efficacy in the responses to ROS signaling and a decrease in antioxidant defenses. This affects cells’ ability to maintain ROS homeostasis and prevent oxidative stress. Furthermore, aging affects other mitochondrial quality control mechanisms that maintain mitochondrial fitness by repairing or eliminating damaged molecules and organelles and by creating new functional proteins and mitochondria.[82,83]

The good news is that supporting mitohormesis may lead to long-lasting metabolic and biochemical changes that delay these age-associated changes and support longevity.[2] Mitohormesis is believed to be one of the reasons why exercise and calorie restriction, both of which increase ROS, promote longevity.[84]

The increased energy demand associated with exercise causes a transient decrease in ATP levels, leading to an increase in mitochondrial metabolism and oxygen consumption in muscles to meet the ATP demand. This acts as a physiological stressor that increases the generation of ROS in muscles, sending a stress signal to the cell. The cell responds by increasing antioxidant defenses and damage repair mechanisms, and by implementing metabolic adaptations that ultimately improve energy metabolism and mitochondrial function. Accordingly, ROS have been shown to be required for the health-promoting effects of physical activity.[2,85]

Likewise, nutrient scarcity associated with caloric restriction acts as a physiological stressor that increases mitochondrial production of ROS as signaling molecules, triggering stress defense responses and repair pathways, and promoting metabolic shifts that improve cell energy generation and mitochondrial function through mitohormetic mechanisms.[86,87]

The set of changes induced by mitohormesis within cells can promote a systemic (generalized, at the whole-body level) coordinated response via the endocrine system that increases the stress resistance of cells and tissues throughout the body, thereby prolonging healthspan and lifespan.[88,89]

Mitohormesis is believed to be one of the reasons why exercise and calorie restriction, both of which increase ROS, promote longevity.

Why High Doses of Antioxidant Vitamins Aren’t The Answer

The awareness of the role of ROS accumulation in aging gave rise to the free-radical theory of aging. This theory (1) proposed that aging was caused by the accumulation of damage inflicted by ROS, and (2) spiked the interest in antioxidant therapies. At the time, the rationale was that seizing ROS with ROS-scavenging antioxidant supplements (e.g., vitamins A, C, E) would allow their inactivation, stop their damaging actions, slow aging, and delay the onset of age-related health challenges. If ROS were the cause, it made sense that neutralizing them with antioxidants would be the solution. Providing antioxidants was also a fit with the research linking diets rich in antioxidant-loaded fruits and vegetables with improved health and longevity.

Yet, these antioxidant therapies never really delivered on the promise. Clinical trials where high doses of antioxidant vitamins were given consistently failed to validate this hypothesis. Meta-analyses of clinical studies showed that more than failing to improve health, antioxidants might even, in some circumstances, worsen health.[90] We now know that mitohormesis is the most likely reason why antioxidants failed to deliver the expected results.

Antioxidants do indeed scavenge excessive ROS, and an adequate intake of vitamins A, C, and E is important to prevent vitamin deficiencies and support antioxidant defenses. But excessive intake of antioxidants can inhibit the mitohormetic response, and thereby block its cytoprotective effects. This is supported by the fact that antioxidant supplementation has been shown to inhibit the benefits of exercise on endogenous antioxidant defenses, mitochondrial biogenesis, and consequently, health promotion.[91,92]

Furthermore, by decreasing ROS levels below a desirable threshold, antioxidants may actually cause damage by inhibiting ROS signaling, blocking the protective effects of ROS, and decreasing endogenous ROS defenses, possibly even leading to a long-term net result of increased ROS levels and oxidative stress.

Rather than trying to quench ROS with large amounts of antioxidants (this strategy hasn’t worked in scientific studies), a better approach might be to help mitochondria help themselves.

Supporting Endogenous Antioxidants Is the Best Defense

High doses of antioxidant vitamins failed to live up to the expectations. But diets supplying large amounts of antioxidant-rich plant foods have been health protective. How do we make sense of these seemingly conflicting pieces of information?

First off, fruit and vegetable-rich diets help to prevent deficiencies in antioxidant vitamins. They make sure we are getting a sufficient amount of these vitamins, but they don’t supply mega doses of them.

The second reason they help might be because of mitohormesis. Fruit and vegetable-rich diets are unquestionably associated with better health outcomes, but not necessarily because of their ROS-scavenging antioxidants. In fact, it’s becoming increasingly clear that the health benefits of plants are not due to their direct antioxidant actions, but rather to the ability of phytochemicals to upregulate our antioxidant stress response pathways—an effect known as xenohormesis.[93] So, instead of directly eliminating ROS, plants may actually help us indirectly by upregulating our endogenous defenses against oxidative stress.[74]

Phytochemicals from plants can keep us healthier by upregulating our endogenous stress response pathways and antioxidant defenses.

Because of mitohormesis, the goal isn’t to prevent mitochondria from producing ROS. Instead, rather than relying on high doses of antioxidant vitamins, a better approach is to (1) allow mitochondria to produce modest amounts of ROS, and (2) help them respond to the ROS they are generating by upregulating their own antioxidant defenses. Promoting antioxidant defenses, as we’ve seen, includes enhancing the cellular glutathione pool and supporting antioxidant enzymes.

Increasing our antioxidant defenses can contribute to the prevention of mitochondrial dysfunctions, thereby supporting the processes of cell energy generation while also delaying the accumulation of oxidative damage. By doing so, we can potentially delay the development of age-related disorders and thereby extend our healthspan. 

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