In Canada and the United States, approximately 44% and 60% of adults, respectively, are afflicted by a chronic condition such as diabetes, cardiovascular disease, or asthma. (11)(42)

Chronic disease, which is often the result of poor lifestyle habits, involves mitochondrial dysfunction and oxidative stress. You’ve perhaps heard that the mitochondria are the powerhouses of the cell, meaning they’re responsible for creating our cellular energy, known as adenosine triphosphate (ATP). Mitochondria are also key regulators of both innate and adaptive immune function through metabolic and cell-signaling mechanisms. (33)(50) However, we often forget how mitochondria are negatively impacted by oxidative stress, the hypothalamus-pituitary-adrenal (HPA) axis, metabolic stressors, certain medications, and poor lifestyle habits. Given that the most metabolically active tissues in the body are the heart, brain, and liver, you can see how many diseases of those tissues need mitochondrial antioxidant support. (31)

 

Group of people exercising
Mitochondria are affected by various factors such as oxidative stress, certain medications, and poor lifestyle habits.

 

What is oxidative stress?

Oxidative stress occurs in the body when there is an imbalance between antioxidants and the production and/or accumulation of reactive free radicals, favoring free radicals. (40) Free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), are molecules with one or more unpaired electrons. (39) The production of free radicals itself is not problematic and is, in fact, part of normal physiology. (56) Free radicals are produced as a consequence of ATP production during a process called oxidative phosphorylation, which occurs in the mitochondria. (12)(35) As a defense mechanism, free radicals are also produced by immune cells as part of the innate and adaptive immune response. (8)(54)

In health, these reactive products are attenuated by our endogenous antioxidants (produced by the body) or by exogenous antioxidants consumed through our diet or supplementation. (39) Therefore, this balance between free radicals and antioxidants plays a significant role in the health status of an individual. If our antioxidant defenses are no longer able to overcome the reactive and damaging free radicals accumulated, harmful oxidative stress may occur. (56)

Oxidative stress is a contributing factor in the pathogenesis of numerous chronic diseases (e.g., cardiovascular disease, diabetes, neurodegenerative conditions) and can damage the mitochondria. (7)(27)(39)(44)(45) Therefore, it is important to maintain adequate antioxidant reserves to protect cells against reactive free radicals.

In addition to endogenous free radical production via metabolism and immune cell activity, we also encounter free radicals in our daily lives through environmental exposure, such as pollutants, radiation, processed foods, medications, and poor lifestyle habits. (6) Therefore, lifestyle is an important modifiable factor that can limit some forms of free radical exposure and increase our antioxidant reserves. For example, you can decrease free radical exposure by avoiding processed foods and cigarettes while boosting your antioxidant reserves by consuming a healthy diet rich in antioxidants. (6)

How does oxidative stress affect the mitochondria?

Oxidative stress can negatively affect mitochondria if the body does not have adequate antioxidant defenses against free radicals. Mechanisms by which oxidative stress affect the mitochondria include:

  • Alterations to mitochondrial membrane fluidity, permeability, and structure
  • Damage to mitochondrial respiratory chain
  • Decreased efficiency of electron transport
  • Disturbances to calcium homeostasis
  • Formation of mitochondrial DNA lesions which may lead to decreased transcription or mutations (16)

 

Woman talking to a practitioner
Your practitioner may recommend a label panel to identify mitochondrial dysfunction.

 

Measuring oxidative stress and mitochondrial dysfunction

Your practitioner may recommend a lab panel to determine if there is a dysfunction or interruption in the ATP production process. Basic lab markers may also serve as indicators of oxidative stress. For example, hemoglobin A1C or oxidized low-density lipoprotein (LDL) are tests commonly used to diagnose conditions such as diabetes or dyslipidemia. Elevated levels of these markers is also an indication of increased reactive oxygen species. (3)(21)(48) Since the Krebs cycle, a key metabolic pathway, supplies the body with its primary energy needs, when mitochondrial issues arise, individuals often present with symptoms like fatigue, pain, and accelerated aging. (15)(22)(46) The following lab tests may be used to measure oxidative stress and mitochondrial dysfunction.

Organic acids

Organic acid panels are somewhat similar to the emissions test for your vehicle.
Just like an emissions test provides an indication of how efficiently your engine is burning fuel, organic acids indicate how efficiently your mitochondria are producing ATP. (17)(18)

Oxidative stress panel

Oxidative stress panels evaluate your body’s availability of antioxidant reserves, the functionality of protective enzymes, and the presence or absence of tissue damage. (30)

8-Hydroxy-2’-deoxyguanosine

8-Hydroxy-2’-deoxyguanosine (8-OHdG) is a biomarker that can be measured to assess the effect of endogenous oxidative damage to DNA. (26)(51)(53) In nuclear and mitochondrial DNA, this is elevated due to free radical-induced lesions. (51)

Oxidized LDL

Oxidized LDL particles (oxLDL) are indicators of damaged fats and promote fatty plaques in the arteries. (37) They are readily accumulated by macrophages/foam cells, and elevation in this marker indicates excessive damage due to oxidation. (41)

Other indicators and symptoms of oxidative stress and mitochondrial dysfunction

Common signs of oxidative stress and mitochondrial dysfunction include extreme fatigue, pain, or weakness. Individuals with mitochondrial dysfunction may also have a prior or current chronic disease diagnosis such as autoimmunity, metabolic syndrome, chronic fatigue syndrome, or fibromyalgia. These diagnoses often indicate the need for mitochondrial support. (38)

If you’re currently taking certain medications with known mitochondrial toxicity (e.g., statins, metformin, steroids, valproic acid, antiretrovirals, aspirin, aminoglycoside antibiotics, beta-blockers, acetaminophen, aminoglycoside, platinum chemotherapeutics), your practitioner may recommend nutrients for mitochondrial support. (4)(9)(20)(34)(36)

Supplements to target oxidative stress and support mitochondrial function

There are specific nutrients that have been shown to drive ATP production while also quenching the reactive oxygen species produced as a byproduct. Three of the most powerful mitochondrial antioxidants are alpha-lipoic acid, N-acetyl cysteine, and acetyl L-carnitine.

Alpha-lipoic acid

Alpha lipoic acid (ALA) is a powerful antioxidant that is involved in energy metabolism. Importantly, ALA has been shown to minimize oxidative damage by scavenging both reactive oxygen species and reactive nitrogen species. (43)(47) Additionally, ALA is able to recharge other antioxidants (e.g., vitamin C, glutathione, and coenzyme Q10 ) and has shown the potential to activate the Nrf2-dependent antioxidant signaling pathway, which influences gene expression of proteins responsible for the detoxification and elimination of reactive oxidants. (14)(23)(25)

N-acetyl cysteine

N-acetyl cysteine (NAC) is a mucolytic agent (used to clear mucus from the lungs) with a number of important antioxidant functions. (1) NAC not only has direct antioxidant effects, but it also has indirect antioxidant action as a precursor to the intracellular antioxidant, glutathione. (1)(5)(29) Additionally, NAC has been shown in preclinical models to activate the Nrf2-dependent antioxidant signaling pathway. (10)(55) Preclinical studies also show NAC supports immune function by enhancing T-cells in models of immune compromise. (13)

Acetyl L-carnitine

Acetyl L-carnitine is an important molecule required for energy production. Its primary role involves the transport of fatty acids across the mitochondrial membrane—a crucial step in energy production. (28) L-carnitine is naturally found in high amounts in animal products (e.g., meat, poultry, fish) and can also be taken as a dietary supplement. A preclinical study found that co-supplementation of aged rats with acetyl L-carnitine and alpha lipoic acid led to improved metabolic function, reduced oxidative stress, and increased levels of the antioxidant ascorbate in hepatocytes (liver cells). (19)

Additional nutrients

Other nutrients to keep in mind when supporting mitochondrial function and reducing oxidative stress include phytonutrients such as broccoli seed extract, resveratrol, and green tea extract (EGCG). These nutrients support antioxidant function and have been shown to activate the Nrf2 antioxidant pathway in preclinical models. (32)(49)(52) Finally, it is essential to ensure that the foundational micronutrient needs of individuals are met to support cellular energy production with optimal levels of nutrients and cofactors for metabolism. (2)

To illustrate this point, a double-blind, randomized, controlled clinical trial found that administering a combination of foundational vitamins and minerals with the trio of mitochondrial antioxidants described above led to increased counts of CD4 cells, a type of white blood cell, by 24% in 40 human immunodeficiency virus (HIV)-infected subjects that had stabilized CD4 cells on standard antiviral medication. (24) This study suggests that the combination of mitochondrial antioxidants with foundational vitamins and minerals improved immune function in those with compromised immune systems.

The bottom line

Since oxidation is a part of our daily lives through metabolism and the environment, it is essential to ensure adequate antioxidant status to mitigate free radical damage that contributes to aging, mitochondrial dysfunction, and chronic disease. If your practitioner is treating you for a chronic disease, they may assess your need for mitochondrial antioxidant support and implement support protocols if necessary. Supplements shown to improve antioxidant status include the trio of mitochondrial antioxidants (i.e., ALA, NAC, L-carnitine), phytonutrients (e.g., broccoli extract, green tea extract, resveratrol, etc.), and baseline micronutrients. If you’re a patient, speak to your practitioner for recommendations specific to your needs.

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Disclosure: This article was written in partnership with Ortho Molecular. All supplier partnerships have been approved by doctors on our Integrative Medical Advisory team, and this content adheres to all guidelines outlined in our content philosophy. Fullscript has not been compensated financially for the publication of this article.

  1. Aldini, G., Altomare, A., Baron, G., et al. (2018). N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 52(7):751-762.
  2. Ames, B.N. (2010). Optimal micronutrients delay mitochondrial decay and age-associated diseases. Mech Ageing Dev. 131(7-8):473-479.
  3. Aouacheri, O., Saka, S., Krim, M., Messaadia, A., Maidi, I. (2015). The investigation of the oxidative stress-related parameters in type 2 diabetes mellitus. 39(1):44-9.
  4. Apostolopoulou, M., Corsini. A., Roden, M. (2015). The role of mitochondria in statin-induced myopathy. Eur J Clin Invest. 45(7):745-754.
  5. Arfsten, D., Johnson, E., Thitoff, A., et al. (2004). Impact of 30-day oral dosing with N-acetyl-L-cysteine on Sprague-Dawley rat physiology. Int J Toxicol. 23(4):239-247.
  6. Aseervatham, G.S., Sivasudha, T., Jeyadevi, R., Arul Ananth, D. (2013). Environmental factors and unhealthy lifestyle influence oxidative stress in humans–an overview. Environ Sci Pollut Res Int. 20(7):4356-4369.
  7. Asmat, U., Abad, K., Ismail, K. (2016). Diabetes mellitus and oxidative stress-A concise review. Saudi Pharm J. 24(5):547-553.
  8. Belikov, A.V., Schraven, B., Simeoni, L. (2015). T cells and reactive oxygen species. J Biomed Sci. 22:85.
  9. Broniarek, I., Jarmuszkiewicz, W. (2016). Statins and mitochondria. Postepy Biochem. 62:77-84.
  10. Cai, Z., Lou, Q., Wang, F., et al. (2015). N-acetylcysteine protects against liver injure induced by carbon tetrachloride via activation of the Nrf2/HO-1 pathway. Int J Clin Exp Pathol. 8(7):8655-8662.
  11. Centers for Disease Control and Prevention. (n.d.). Chronic diseases in America. https://www.cdc.gov/chronicdisease/resources/infographic/chronic-diseases.htm
  12. Dan Dunn, J., Alvarez, L.A., Zhang, X., Soldati, T. (2015). Reactive oxygen species and mitochondria: A nexus of cellular homeostasis. Redox biology. 6:472-485.
  13. Eylar, E., Rivera-Quinones, C., Molina, C., Báez, I., Molina, F., Mercado, C.M. (1993). N-acetylcysteine enhances T cell functions and T cell growth in culture. Int Immunol. 5(1):97-101.
  14. Fayez, A.M., Zakaria, S., Moustafa, D. (2018). Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats. Biomed Pharmacother. 105:428-433.
  15. Gorman, G.S., Elson, J.L., Newman, J., et al. (2015). Perceived fatigue is highly prevalent and debilitating in patients with mitochondrial disease. Neuromuscul Disord. 25(7):563-566.
  16. Guo, C., Sun, L., Chen, X., Zhang, D. (2013). Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 8(21):2003-2014.
  17. Haas, J.D., Brownlie, T. (2001). Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J Nutr. 131(2s-2):676S-688S; discussion 688S-690S.
  18. Haas, R.H., Parikh, S., Falk, M.J., et al. (2008). The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab. 94(1):16-37.
  19. Hagen, T., Liu, J., Lykkesfeldt, J., et al. (2002). Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A. 99:1870-1875.
  20. Hargreaves, I.P., Al Shahrani, M., Wainwright, L., Heales, S.J. (2016). Drug-induced mitochondrial toxicity. Drug Saf. 2016;39(7):661-674.
  21. Itabe, H. (2012). Oxidized low-density lipoprotein as a biomarker of in vivo oxidative stress: from atherosclerosis to periodontitis. J Clin Biochem Nutr. 51(1):1-8.
  22. Jang, J.Y., Blum, A., Liu, J., Finkel, T. (2018). The role of mitochondria in aging. J Clin Invest. 128(9):3662-3670.
  23. Jones, W., Li, X., Qu, Z.C., Perriott, L., Whitesell, R.R., May, J.M. (2002). Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic Biol Med. 33(1):83-93.
  24. Kaiser, J.D., Campa, A.M., Ondercin, J.P., Leoung, G.S., Pless, R.F., Baum, M.K. (2006). Micronutrient supplementation increases CD4 count in HIV-infected individuals on highly active antiretroviral therapy: a prospective, double-blinded, placebo-controlled trial. J Acquir Immune Defic Syndr. 42(5):523-528.
  25. Kozlov, A.V., Gille, L., Staniek, K., Nohl, H. (1999). Dihydrolipoic acid maintains ubiquinone in the antioxidant active form by two-electron reduction of ubiquinone and one-electron reduction of ubisemiquinone. Arch Biochem Biophys. 363(1):148-154.
  26. Kroese, L.J., Scheffer, P.G. (2014). 8-hydroxy-2’-deoxyguanosine and cardiovascular disease: a systematic review. Current atherosclerosis reports. 2014;16(11):452.
  27. Lin, M.T., Beal, M.F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 443(7113):787-795.
  28. Longo, N., Frigeni, M., & Pasquali, M. (2016). Carnitine transport and fatty acid oxidation. Biochimica et biophysica acta, 1863(10), 2422–2435.
  29. Lu, Y., Qin, W., Shen, T., et al. (2011). The antioxidant N-acetylcysteine promotes atherosclerotic plaque stabilization through suppression of RAGE, MMPs and NF-κB in ApoE-deficient mice. Journal of atherosclerosis and thrombosis. 18(11):998-1008.
  30. Marrocco, I., Altieri, F., Peluso, I. (2017). Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans. Oxid Med Cell Longev. 2017:6501046.
  31. McClave, S.A., Snider, H.L. (2001). Dissecting the energy needs of the body. Curr Opin Clin Nutr Metab Care. 4(2):143-147.
  32. Mi, Y., Zhang, W., Tian, H., et al. (2018). EGCG evokes Nrf2 nuclear translocation and dampens PTP1B expression to ameliorate metabolic misalignment under insulin resistance condition. Food Funct. 9(3):1510-1523.
  33. Mills, E.L., Kelly, B., O’Neill, L.A.J. (2017) Mitochondria are the powerhouses of immunity. Nat Immunol. 18(5):488-498.
  34. Morén Núñez, C., Juarez, D., Cardellach, F., Garrabou, G. (2016). The role of therapeutic drugs on acquired mitochondrial toxicity. Curr Drug Metab. 17(7):648-62.
  35. Murphy, M.P. (2009). How mitochondria produce reactive oxygen species. Biochem J. 417(1):1-13.
  36. Nadanaciva, S., Will, Y. (2011). Investigating mitochondrial dysfunction to increase drug safety in the pharmaceutical industry. Curr Drug Targets. 12(6):774-782.
  37. Parthasarathy, S., Raghavamenon, A., Garelnabi, M.O., Santanam, N. (2010). Oxidized low-density lipoprotein. Methods in molecular biology (Clifton, NJ). 610:403-417.
  38. Pieczenik, S.R., Neustadt, J. (2007). Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol. 83(1):84-92.
  39. Pisoschi, A,M., Pop, A. (2015). The role of antioxidants in the chemistry of oxidative stress: A review. Eur J Med Chem. 97:55-74.
  40. Pizzino, G., Irrera, N., Cucinotta, M., et al. (2017). Oxidative stress: Harms and benefits for human health. Oxid Med Cell Longev. 8416763-8416763.
  41. Poznyak, A.V., Nikiforov, N.G., Markin, A.M., et al. (2021). Overview of OxLDL and Its Impact on Cardiovascular Health: Focus on Atherosclerosis. Front Pharmacol. 11:613780.
  42. Public Health Agency of Canada. (n.d.). Prevalence of chronic diseases among Canadian adults. https://www.canada.ca/en/public-health/services/chronic-diseases/prevalence-canadian-adults-infographic-2019.html
  43. Scott, B.C., Aruoma, O.I., Evans, P.J., et al. (1994). Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic Res. 20(2):119-133.
  44. Singh, A., Kukreti, R., Saso, L., Kukreti, S. (2019). Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules. 24(8).
  45. Steven, S., Frenis, K., Oelze, M, et al. (2019). Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease. Oxid Med Cell Longev. 7092151-7092151.
  46. Sui, B., Xu, T.Q., Liu, J.W., et al. (2013). Understanding the role of mitochondria in the pathogenesis of chronic pain. Postgrad Med J. 89:709-714.
  47. Trujillo, M., Radi, R. (2002). Peroxynitrite reaction with the reduced and the oxidized forms of lipoic acid: new insights into the reaction of peroxynitrite with thiols. Arch Biochem Biophys. 397(1):91-98.
  48. Turpin, C., Catan, A., Guerin-Dubourg, A., et al. (2020). Enhanced oxidative stress and damage in glycated erythrocytes. PLoS One. 15(7):e0235335.
  49. Wang, G., Xie, X., Yuan, L., et al. (2020). Resveratrol ameliorates rheumatoid arthritis via activation of SIRT1-Nrf2 signaling pathway. Biofactors. 46(3):441-453.
  50. West, A.P., Shadel, G.S. (2017). Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol. 17(6):363-375.
  51. Wu, L.L., Chiou, C.C., Chang, P.Y., Wu, J.T. (2004). Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta. 339(1-2):1-9.
  52. Xu, L., Nagata, N., Ota, T. (2019). Impact of Glucoraphanin-Mediated Activation of Nrf2 on Non-Alcoholic Fatty Liver Disease with a Focus on Mitochondrial Dysfunction. Int J Mol Sci. 20(23):5920.
  53. Xu, G.W., Yao, Q.H., Weng, Q.F., Su, B.L., Zhang. X., Xiong, J.H. (2004). Study of urinary 8-hydroxydeoxyguanosine as a biomarker of oxidative DNA damage in diabetic nephropathy patients. J Pharm Biomed Anal. 36(1):101-104.
  54. Yang, Y., Bazhin, A.V., Werner, J., Karakhanova, S. (2013). Reactive oxygen species in the immune system. Int Rev Immunol. 32(3):249-270.
  55. Zhou, Y., Wang, H.D., Zhou, X.M., Fang, J., Zhu, L., Ding, K. (2018). N-acetylcysteine amide provides neuroprotection via Nrf2-ARE pathway in a mouse model of traumatic brain injury. Drug Des Devel Ther. 12:4117-4127.
  56. Zuo, L., Zhou, T., Pannell, B.K., Ziegler, A.C., Best, T,M. (2015). Biological and physiological role of reactive oxygen species–the good, the bad and the ugly. Acta Physiol (Oxf). 214(3):329-348.