Mitochondrial Impairment in Long COVID-19

Viral diseases, like SARS-CoV-2, are known for their ability to hijack and destabilize the intracellular environment, creating conditions that are favorable for their replication.¹ The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections.¹ Mitochondrial disorders are a complex group of diseases caused by impairment of the mitochondrial respiratory chain (or electron transport chain), which in some patients can lead to an unexplained post-viral illness, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).² In fact, the first analysis of a prospective observational study of patients who remained ill six months after mild or moderate acute SARS-CoV-2 found that about half met criteria for ME/CFS.³ What have researchers discovered about the possible link between post-acute sequelae of SARS-CoV-2 infection (PASC), mitochondrial dysfunction, and ME/CFS? How can clinicians support the mitochondrial health of patients with COVID-19?

Research on the long-term effects of SARS-CoV-2 continues to indicate that a substantial number of individuals experience lasting symptoms after the initial infection has been cleared,⁴ including psychiatric disorders and neurocognitive decline.^5,6 Autopsies of patients confirm the presence of the coronaviruses in the central nervous system (CNS), especially in the brain.⁷ Follow-ups conducted in Germany and the United Kingdom found PASC neuropsychiatric symptoms in 20-70% of patients, including young adults.^8,9 Multiple studies have shown that SARS-CoV-2 can directly or indirectly affect the CNS, and some patients experience a component of cognitive dysfunction, called “brain fog,” which includes psychological symptoms such as difficulty concentrating, forgetfulness, confusion, behavioral changes, depression, and fatigue.^5,10 Relapse or recurrence of these symptoms may be triggered by exercise, physical or mental activity, and stress.⁸

Scientists hypothesize that both direct and indirect mechanisms may contribute to the development of these symptoms, which are similar to those experienced by patients with ME/CFS and are often linked to mitochondrial dysfunction.⁶ Furthermore, some studies suggest that the neuropsychiatric manifestations of PASC may also lead to an increased additional long-term risk of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.⁵

Mitochondrial Involvement in COVID-19

ME/CFS is a chronic debilitating illness that causes a variety of symptoms, including extreme tiredness, sleep problems, and muscle pain.⁶ The cause is unknown; however, some scientists suspect that, in some individuals, these symptoms may be induced by a viral infection like Epstein-Barr or glandular fever, called postviral fatigue syndrome, which can develop as a result of a disruption to the mitochondrial metabolic pathway.⁶ Researchers hypothesize that the SARS-CoV-2 infection might lead to a redox imbalance, similar to what was observed in postviral fatigue syndrome, thus causing the symptoms observed in PASC.^2,6,11

Multiple examples of redox dysregulation have been reported in acute SARS-CoV-2.¹¹ SARS-CoV-2 induces redox imbalance, in part because it uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter cells. This leads to accumulation of O₂·^– as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS) by inducing mitochondrial dysfunction and production of proinflammatory cytokines, which leads to oxidative damage. In both PASC and ME/CFS, symptoms like fatigue and brain fog may also be generated by neuroinflammation, reduced cerebral perfusion due to autonomic dysfunction, and autoantibodies directed at neural targets.¹¹

A 2022 study on 50 patients provided the first evidence of mitochondrial dysfunction in PASC syndrome. During the test, the participants exercised to exhaustion (or near) on a bicycle.¹² This retrospective study found normal exercise capacity overall (but reduced exercise capacity in a third of the PASC patients), but more importantly, perhaps, it found increased lactate levels early in the exercise process and reduced fatty acid oxidation, indicating that mitochondrial dysfunction was present and “metabolic reprogramming” had occurred.¹²

Mechanisms of Action

The mechanisms by which SARS-CoV-2 may disrupt mitochondrial metabolism is unknown; however, researchers have developed several hypotheses. One possible mechanism used could be by altering the expression of genes encoded in the mitochondrial genome.⁶ SARS-CoV-2 may directly infect or “hijack” the mitochondria, leading to the integration of the viral genome into mitochondrial DNA, potentially directly impairing mitochondrial energy metabolism via targeted action on oxygen availability and utilization.⁵ By hijacking the cellular metabolic hub, the virus is able to activate inflammatory pathways, including inflammasomes, which may inadvertently suppress host innate and adaptive immune responses.⁵ Combined with its induced pro-inflammatory response, SARS-CoV-2 infection leads to neuronal dysfunction, resulting in ‘brain fog,’ as cognition requires a high and uninterrupted supply of oxygen.¹⁰

Where microglia are involved, this may lead to impaired metabolic fitness, impaired autophagy, and metabolic support of basic function, including the clearance of pathologic plaques and deposits.⁵ Microglia represent a specialized population of macrophage-like cells in the CNS, considered immune sentinels, that are capable of orchestrating a potent inflammatory response.¹³ Ultimately, this could promote neurocognitive decline.⁵ Scientists speculate that this could promote the long-term symptoms of neurocognitive decline in some SARS-CoV-2 patients.⁵ However, whether these mechanisms are sufficient to induce or accelerate the premature occurrence of diseases like Alzheimer’s disease (AD) and Parkinson’s in a feed-forward cycle after the virus is gone warrants further research.⁵ Neuroinflammation, synaptic pruning, and neuron loss occurring in SARS-CoV-2 share commonalities with AD. Similar to SARS-CoV-2, patients with PD demonstrate impairment of cognitive and memory functions. And hyposmia and anosmia, which are early symptoms in SARS-CoV-2, are also precursor clinical symptoms of PD.⁵

Another suggestion is that one of the major sources of ROS that may be linked to cellular oxidative stress in SARS-CoV-2 is the mitochondria.⁷ The increased levels of mitochondrial ROS during viral infection are induced by excessive production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-6, and IL-10, which are found in SARS-CoV-2 patient serum. The entry of a virus induces mitochondria to release ROS, which stimulate proinflammatory cytokine production to help fight the virus. In healthy individuals, the acute hyperinflammatory phase is followed by an immune-tolerant phase to clear viral particles and cellular recovery. However, SARS-CoV-2 patients with dysfunctional mitochondria may exhibit a prolonged hyperinflammatory phase of sepsis, which may cause increased production of proinflammatory cytokines, resulting in increased cell death. The ROS-induced mitochondrial stress negatively affects mitochondrial metabolism and ATP synthesis and increases mitochondrial fragmentation.⁷

Researchers writing in the Journal of Leukocyte Biology suggest that a sustained decrease of the mitochondrial membrane potential ΔΨ_m may be related to PASC, as it is a parameter often used to determine mitochondrial function.¹⁴ The results of their study indicate that SARS-CoV-2–recovered subjects presented a loss of ΔΨ_m, even 11 months after infection. These results align with previous reports by other authors, who indicate that SARS-CoV-2 causes mitochondrial dysfunction, since the infection alters mitochondrial functionality, influencing its intracellular survival and/or evading host immunity. Furthermore, scientists speculate that ΔΨ_m could be an early indicator of multiple SARS-CoV-2–associated diseases, including neurodegenerative diseases.¹⁴

Supplements & Lifestyle-Based Interventions

Mitochondrial integrity is essential to maintain an adequate immune response against SARS-CoV-2 infection,¹⁴ and supporting mitochondria may help prevent neuronal complications.^7,15,16 IFM’s Mitochondrial Food Plan is an anti-inflammatory, low-glycemic, high-quality fat dietary approach that supports healthy mitochondria for improved energy production. The following nutritional supplements and lifestyle-based interventions have also been suggested for the treatment of PASC symptoms:

• Antioxidant supplementation: Vitamins C and E,⁷ as well as selenium, can counteract excess ROS production.¹⁷
• Plant-based diets: Diets high in plant defense compounds with pleiotropic actions that are known to modulate mitochondrial function and induce resolution of inflammation, as well as displaying anti-pathogen function.¹⁸
• CoQ10 supplementation: Strategies to target mitochondrial bioenergetics and antioxidant defense include supplemental therapy with CoQ10, an important antioxidant in the mitochondria.^2,17,19
• N-acetylcysteine (NAC) supplementation: In high doses (≥1,200 mg), NAC acts as an antioxidant through complex mechanisms that can improve situations of oxidative stress. For this reason, it has been proposed to have potential for early administration in patients at greater risk of severe COVID-19.^20,21
• Acetyl-L-carnitine (ALC): ALC is key to mitochondrial function, promoting the expression of nerve growth factors and peripheral nerve regeneration and conduction, and is considered an effective dietary supplement for diabetic neuropathy.²²
• α-Lipoic acid (ALA): ALA, also known as thioctic acid or simply as lipoic acid, is a powerful antioxidant, acting as a coenzyme in mitochondrial reactions in which glucose is converted into energy.²²
• Physical activity: Regular, moderate physical activity enhances immune function and mitochondrial fitness.²³ Moderate intensity training (MIT) is usually performed at around 50-75% of the maximal capacity, often in a continuous fashion (MICT).²³

With respect to interventions, the practice of functional medicine emphasizes the primacy of safety, validity, and effectiveness. Functional medicine practitioners are trained in providing personalized guidance to patients in the use of nutrition, nutraceuticals, and lifestyle to prevent, reverse, and decrease the burden of complex, chronic diseases like PASC. IFM has assembled a wealth of resources for functional medicine clinicians, including clinical recommendations and mechanisms of action; virus-specific nutraceuticals and botanical agents, nutrition, and lifestyle practices for strengthening host defense; practice considerations; testing; and vaccines. Gain additional evaluation insights and tools on promoting optimal mitochondrial function at the Immune Advanced Practice Module.