Chronic Fatigue, Oxidative Stress, and the Mitochondria

One of the benefits that Covid has brought to the health care system is a dramatic increase in a desire to understand Chronic Fatigue symptoms. Many researchers, like Bruce Patterson, have poured countless hours to understand what is behind long haul covid, and what is driving it. Many of the theories being currently explored are linked to viral infections that become reactivated like Epstein Barr, Cytomegalovirus, etc. This article is going to focus on another aspect that has been researched over the years and has been linked to Chronic Fatigue - Oxidative Stress. Specifically, this article will focus on - oxidative stress inside the Mitochondria.

Before we get started into the details - its important to understand the basic front line anti oxidant systems in the body, Super Oxide Dismutase, Glutathione, and Catalase [1]. These 3 systems detoxify the oxidative radicals super oxide, hydrogen peroxide, and hydrogen peroxide (again) respectively. Two specific free radicals are thought to be the most damaging, Hydroxyl Radicals (formed from iron and hydrogen peroxide), and Peroxynitrite (formed from super oxide and nitric oxide). It becomes easy to see why excessive amounts of iron, nitric oxide, super oxide, and hydrogen peroxide can be problematic.

Most of the super oxide in the body is produced in the mitochondria [2]. The enzyme that is responsible for neutralizing super oxide inside the mitochondria is SOD2. The other two super oxide dismutase genes, SOD1 is mainly present in the kidneys, while SOD3 is more ubiquitous. The cofactor for SOD2 is manganese, while the cofactors for SOD3 is iron, and copper for SOD1 [1]. Knowing that mitochondria produce the majority of the super oxide, and turn it into hydrogen peroxide is helpful - there are known herbal remedies to upregulate SOD production in the body. However, there is one enzyme that also needs to be in concert with SOD2, and that is GPX4, it is the only glutathione peroxidase enzyme also located inside the mitochondria that takes the exhaust (hydrogen peroxide) from SOD2 and neutralizes it into water. So genetic weakness in one or both of SOD2 and GPX4 may cause oxidative stress inside the mitchondria, resulting in lipid peroxidation, and specifically the cardiolipins [2]. "Most forms of GPx are tetrameric in structure but GPx4 which is often regarded as phospholipid hydroperoxide is a monomer and differs in substrate specificity. This is because Gpx4 is the only GPx enzyme that breaks down phospholipid hydroperoxides. The enzyme also has a mitochondrial isoform that mediates the apoptotic response to oxidative stress and has a peroxidase independent structural role in sperm maturation" [1].

Catalase is also an enzyme that can break down hydrogen peroxide into water. "CAT is highly efficient; it can breaks down millions of hydrogen peroxide molecules in one second. The enzyme is located primarily in the peroxisomes but absent in mitochondria of mammalian cells. The only exception is the mitochondria present in the heart of rat. This implies that the breakdown of hydrogen peroxide to water and oxygen is carried out by another enzyme known as glutathione peroxidase in mammalian cell mitochondria." [2] The cofactor required for catalase is iron or manganese, so you can see how importance of the right balance of iron, copper, and manganese.

With this context we can see why that using mitchondrial energy boosters like magnesium, coq10, pqq, d-ribose, and various b vitamins can increase oxidative stress in the mitochondria. Perhaps this is one of the key reasons why some people who aggressively pursue this type of therapy feel worse rather than better. One must have adequately functioning SOD2 and GPX4 before embarking on that journey and not experience an increase in mitochondrial oxidative stress.

Robert Naviaux has long proposed his theory on 'Cell Danger Response', and has mostly linked it to bacterial and viral infections, but also references toxins and redox balance, that the mitochondriasense - and then down regulate a whole series of things to slow and stop bacterial/viral replication, inflammation, etc [3]. Although no research has pinpointed the same mechanism is in play for how the mitochondria may sense elevated oxidative stress and down regulate energy production - it certainly would not be surprising to see some discovery of that nature in the future. Even without that inherent intelligence, it is well accepted that increased oxidative stress is linked to fatigue.

As one would suspect studies around 'long haul covid' and ME/CFS, have both been linked to redox imbalance, or high levels of oxidative stress. This is exactly what Paul, et al, found in hhis paper, "Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome".

Back to the question of mitochondrial oxidative stress - how to investigate the genetic status of SOD2 and GPX4, and how to support their full functioning if they appear to be potentially compromised. SOD2 has well known supports available commercially along with its cofactor, manganese. GPX4 is not so well researched nor understood, its cofactor being selenium. However, Ighodaro, et al do provide us some clues that seem to be rather logical - that the ubiquitous GPX1 enzyme is also crucial, and thus perhaps exogenous supplementation of glutathione can be taken up by the mitochondria as support for GPX4 and GPX1. However, before exogenous glutathione can be used effectively, another enzyme, GSR, must be prepared to help recycle oxidized glutathione back to reduced glutathione (using its co-factor b2) and with support from NRF2 and Keap1. As a first step those enzymes must be supported, and perhaps exogenous catalase can be used to off load some of the work from GPX enzymes in the liver freeing up some capacity for GPX1 to share glutathione supplies across the mitochondrial membrane to support GPX4.

It is my observation that folks who have significant mutations in SOD2 and or GPX4 have higher levels of oxidative stress, and often are struggling the most. These are often the first enzymes i look at as i begin to investigate various genetic patterns. Markers for oxidative stress are available on Genova's Nutreval, The Chronic Inflammatory Test [5], and Doctors Data Oxidative Stress panel. It may be a worthwhile investigation into SOD2, manganese, GPX4, and selenium if you have chronic fatigue, and have not responded to traditional mitochondrial supports.

[1] First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid O.M. Ighodaro a,b, , O.A. Akinloye b. 2017.

[2] A mitochondrial superoxide theory for oxidative stress diseases and aging. Hiroko P. Indo, et al. (2014).

[3] Metabolic features of the cell danger response. Robert K. Naviaux

[4] Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome Bindu D. Paul, et al. 2021.


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