Mitochondrial Antioxidants
1) Coenzyme Q10 -Ubiquinone (CoQ10) Coenzyme Q10 (CoQ10) is considered the "mitochondrial specific antioxidant". It is an essential component of the mitochondrial electron transport chain. It is also an antioxidant in cellular membranes and lipoproteins. All cells produce CoQ10 by a specialized cytoplasmatic-mitochondrial pathway. CoQ10 deficiency can result from genetic failure or from simply ageing. Some drugs including statins, may inhibit endogenous CoQ10 synthesis. There are also chronic diseases with lower levels of CoQ10 in tissues and organs. High doses of CoQ10 may increase both circulating and intracellular levels, but there are conflicting results regarding bioavailability. Ubiquinone is the most biologically active form of CoQ10.
Below are links to two articles that review the current knowledge of CoQ10 biosynthesis, primary and acquired CoQ10 deficiency, and results from clinical trials based on CoQ10 supplementation. There are indications that supplementation positively affects mitochondrial deficiency syndrome and some of the symptoms of ageing. Cardiovascular disease and inflammation appear to be alleviated by the antioxidant effect of CoQ10.
Coenzyme Q10 supplementation – In ageing and disease
sciencedirect.com/science/a...
The following article also reviews the role of Resveratrol (in section 3) as well as CoQ10 (in section 4). This article is a worthwhile read on the topic.
CoQ10 and Resveratrol Effects to Ameliorate Aged-Related Mitochondrial Dysfunctions
pubmed.ncbi.nlm.nih.gov/362...
"Mitochondria participate in the maintenance of cellular homeostasis. Firstly, mitochondria regulate energy metabolism through oxidative phosphorylation. In addition, they are involved in cell fate decisions by activating the apoptotic intrinsic pathway. Finally, they work as intracellular signaling hubs as a result of their tight regulation of ion and metabolite concentrations and other critical signaling molecules such as ROS. Aging is a multifactorial process triggered by impairments in different cellular components. Among the various molecular pathways involved, mitochondria are key regulators of longevity. Indeed, mitochondrial deterioration is a critical signature of the aging process. In this scenario, we will focus specifically on the age-related decrease in CoQ levels, an essential component of the electron transport chain (ETC) and an antioxidant, and how CoQ supplementation could benefit the aging process. Generally, any treatment that improves and sustains mitochondrial functionality is a good candidate to counteract age-related mitochondrial dysfunctions. In recent years, heightened attention has been given to natural compounds that modulate mitochondrial function. One of the most famous is resveratrol due to its ability to increase mitochondrial biogenesis and work as an antioxidant agent. This review will discuss recent clinical trials and meta-analyses based on resveratrol and CoQ supplementation, focusing on how these compounds could improve mitochondrial functionality during aging."
2) Pyrroloquinoline quinone (PQQ)
PQQ is another natural phytonutrient. There are diverse food sources of PQQ with highest levels found in Nattokinase. Also found in green tea, parsley and green peppers. Supplements with 20mg are widely available. I do not supplement it directly, as I take Nattokinase daily for cancer related blood-clot risks, and it is the best natural source for it.
Pyrroloquinoline quinone (PQQ) protects mitochondrial function of HEI-OC1 cells under premature senescence
nature.com/articles/s41514-...
PQQ not only protects mitochondria from oxidative stress but also promotes mitochondrial biogenesis. Dietary supplementation of PQQ improves mitochondrial amounts and lipid metabolism in rats and has been shown to improve respiratory quotients by increasing the mitochondrial numbers and function in mice. PQQ prevents rotenone-induced neurotoxicity in Parkinson’s disease models by promoting mitochondrial function and regulating mitochondrial fission and fusion. In humans, dietary supplementation with PQQ recovers the antioxidant potential, attenuates the inflammatory response, and increases urinary metabolites related to mitochondrial functions.
3) Alpha-Lipoic acid (ALA)
Although lipoic acid is produced naturally in the body, researchers were virtually unaware of its existence until the 1930s. When pure samples were isolated in the 1950s, ALA was first believed to be a new vitamin. Later, researchers discovered that ALA is, in fact, an essential coenzyme with a vital role in mitochondrial electron transport reactions involved in converting glucose into ATP to produce energy. By 1988 researchers had also learned that ALA is a powerful biological antioxidant, although one with some very unique health properties. What most impressed researchers was the discovery that ALA functions as both a fat and water-soluble antioxidant that can easily cross cell membranes. Thus, ALA can confer free radical protection to both interior and exterior cellular structures. alpha-lipoic acid (α-LA) is a well-known fatty acid used as a supplement in several health conditions and diseases, such as periphery neuropathies and neurodegenerative disorders. It is produced in several cell types, eukaryotes, and prokaryotes, showing antioxidant and anti-inflammatory properties. α-LA acts as an enzymatic cofactor able to regulate metabolism, energy production, and mitochondrial biogenesis. In addition, the antioxidant capacity of α-LA is associated with two thiol groups that can be oxidised or reduced, prevent excess free radical formation, and act on improvement of mitochondrial performance. Moreover, α-LA has mechanisms of epigenetic regulation in genes related to the expression of various inflammatory mediators, such PGE2, COX-2, iNOS, TNF-α, IL-1β, and IL-6. Regarding the pharmacokinetic profile, α-LA has rapid uptake and low bioavailability and the metabolism is primarily hepatic. However, α-LA has low risk in prolonged use, although its therapeutic potential, interactions with other substances, and adverse reactions have not been well established in clinical trials with populations at higher risk for diseases of aging.
Redox Active α-Lipoic Acid Differentially Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer and Its Control Cells
ncbi.nlm.nih.gov/pmc/articl...
"Alpha lipoic acid (ALA) is a sulphur-containing organic compound, derived from octanoic acid, and an important cofactor for mitochondrial respiratory enzymes. It has strong antioxidant properties that improve mitochondrial function.. . ROS levels were significantly lower in both cell lines treated with ALA. Conclusions: ALA increased the activity of the different complexes of the respiratory chain, and consequently enhanced the MMP, leading to increased ATP levels indicating improved mitochondrial function."
4) L-Carnitine
(L-Carnitine is a key transporter of fatty acids into mitochondria. Since A-Lipoic acid is a fatty acid, the combination of the two was proposed as a possible positive synergy by Nick Lane on Oxygen.)
The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation
ncbi.nlm.nih.gov/pmc/articl...
"Mitochondria control cellular fate by various mechanisms and are key drivers of cellular metabolism. Although the main function of mitochondria is energy production, they are also involved in cellular detoxification, cellular stabilization, as well as control of ketogenesis and glucogenesis. Conditions like neurodegenerative disease, insulin resistance, endocrine imbalances, liver and kidney disease are intimately linked to metabolic disorders or inflexibility and to mitochondrial dysfunction. Mitochondrial dysfunction due to a relative lack of micronutrients and substrates is implicated in the development of many chronic diseases. l-carnitine is one of the key nutrients for proper mitochondrial function and is notable for its role in fatty acid oxidation. l-carnitine also plays a major part in protecting cellular membranes, preventing fatty acid accumulation, modulating ketogenesis and glucogenesis and in the elimination of toxic metabolites. l-carnitine deficiency has been observed in many diseases including organic acidurias, inborn errors of metabolism, endocrine imbalances, liver and kidney disease. The protective effects of micronutrients targeting mitochondria hold considerable promise for the management of age and metabolic related diseases.
Preventing nutrient deficiencies like l-carnitine can be beneficial in maintaining metabolic flexibility via the optimization of mitochondrial function. This paper reviews the critical role of l-carnitine in mitochondrial function, metabolic flexibility and in other pathophysiological cellular mechanisms. l-carnitine is a vital molecule that is found in all living cells. It is a quaternary amine (3-hydroxy-4-N-trimethylaminobutyrate) whose main function in mammalian cells is the transfer of long chain fatty acids across the inner mitochondrial membrane for β- oxidation and generation of ATP energy. This process requires specific enzymes and transporters and any defects in these can cause disorders of the carnitine cycle. Once fatty acids are inside mitochondria, they undergo the process of β-oxidation through a series of acyl-CoA dehydrogenase enzymes that mediate the shortening of long-chain fats used to produce ATP. Deficiency of any of these enzymes can cause symptoms similar to those encountered in disorders of the carnitine cycle.
l-carnitine is also involved in the excretion of unwanted products of intermediary metabolism and in balancing the Coenzyme A (CoA) pool within mitochondria. Its unique properties enable other functions in cell metabolism such as buffering excess acyl residues and removal of xenobiotics from cells. These actions give l-carnitine a role in protecting cellular membranes, preventing fatty acid accumulation, modulating ketogenesis and glucogenesis and elimination of toxic metabolites."
5) NMN: Nucotinamide Mononucleotide
Nicotinamide mononucleotide (NMN) as an anti-aging health product – Promises and safety concerns
ncbi.nlm.nih.gov/pmc/articl...
"NMN is a precursor of NAD+ and an intermediate of NAD+biosynthesis, which is achieved through three pathways. NMN isan intermediate by-product in two of them. NAD+ levels in thebody are depleted with aging as a result of activities of NAD+ consumingenzymes. Depletion of NAD+ level is associated with downregulation of energy production in mitochondria, increasing oxidative stress, DNA damage, cognitive impairments and inflammatory diseases. NMN, as the precursor of NAD+, has been seen to likely reverse these age-related complications and slow down the rate of aging by enhancing NAD+ levels in the body. Many studies have been done to explore NMN’s anti-aging effects in various cells and tissues. Most of the works have been done in vitro or in animal models. However, published reports about NMN’s long-term safety and clinical efficacy of anti-aging effects in humans are scarce."
6) Quercetin
(There is much overlap of functions across several phytochemicals that keep showing up. I will just highlight Quercetin with regards to mitochondrial benefits, that may well apply to others such as sulforaphane, ECGC etc.)
Quercetin and the mitochondria: A mechanistic view
sciencedirect.com/science/a...
"Quercetin is an important flavonoid that is ubiquitously present in the diet in a variety of fruits and vegetables. It has been traditionally viewed as a potent antioxidant and anti-inflammatory molecule. However, recent studies have suggested that quercetin may exert its beneficial effects independent of its free radical-scavenging properties. Attention has been placed on the effect of quercetin on an array of mitochondrial processes. Quercetin is now recognized as a phytochemical that can modulate pathways associated with mitochondrial biogenesis, mitochondrial membrane potential, oxidative respiration and ATP anabolism, intra-mitochondrial redox status, and subsequently, mitochondria-induced apoptosis. The present review evaluates recent evidence on the ability of quercetin to interact with the abovementioned pathways, and critically analyses how, such interactions can exert protection against mitochondrial damage in response to toxicity induced by several exogenously and endogenously-produced cellular stressors, and oxidative stress in particular."
7) Resveratrol
Much has been posted and discussed regarding resveratrol. I resumed supplementing it in light of the benefits and potentiation or resveratrol metabolytes by a healthy gut microbiome. So I take it along with my probiotic. See the article and abstract above on CoQ10. It has a very good summary on Resveratrol in Section 3.
CoQ10 and Resveratrol Effects to Ameliorate Aged-Related Mitochondrial Dysfunctions
pubmed.ncbi.nlm.nih.gov/362...
"As mentioned above, resveratrol has multiple healthful behaviors, such as antioxidation, anti-inflammation, and the modulation of gut microbiota. Therefore, this molecule is considered a promising target to ameliorate several pathological conditions such as diabetes, cardiovascular pathologies, and neurodegenerative diseases. Mitochondria can be the target of its beneficial effect, given that resveratrol enhances mitochondrial function in diverse ways. Firstly, it induces the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. In particular, mice treated with resveratrol show increased running capacity and OCR in muscle fibers. This phenomenon is due to the upregulation of oxphos genes and mitochondrial biogenesis. The mechanism of action is through SIRT1 activation, which, in turn, deacetylates PGC1, thus activating it. " Beyond the fundamental role of resveratrol as an oxidative phosphorylation enhancer, it is known as one of the principal antioxidant compounds, as demonstrated in different cell types, including microglia, cancer cells, and endothelial cells. Resveratrol regulates the cellular redox balance using two distinct mechanisms. It acts directly as a potent scavenger of hydrogen peroxide, superoxide anion, and hydroxyl radicals. Moreover, it can work indirectly, it stimulates endogenous systems that act against ROS." -MB
