PRECISION NUTRITION
TO RESET
Altered Bioenergetic Systems
Precision Nutrition to Reset Altered Bioenergetic Systems
Reset of Mitochondrial Dysfunction (m-Dys)
Mitochondrial dysfunction (m-Dys) is characterized by a loss of efficiency in oxidative phosphorylation (OXPHOS) and reductions in the ATP synthesis, a causative mechanism for several metabolic syndromes including the viral-induced HMR/D. m-Dys leads to fatigue (with reduced tolerance to exercise), a common persistent symptomatic feature amongst COVID-19 survivors. Nutritional strategies to resolve m-Dys should comprise specific bioactives and cofactors essential for mitochondrial bioenergetic pathways, as well as provide effective free radical (ROS) scavengers to prevent OxS, maintain Fe-RH, and reset virus-induced HMR/D.
Nicotinamide adenine dinucleotide: Nicotinamide adenine dinucleotide (NAD+) is a vital cofactor in mitochondrial bioenergetic pathways, including glycolysis, fatty acid β-oxidation, and the tricarboxylic acid (TCA) or Kreb’s cycle. It exists in both oxidized (NAD+) and reduced (NADH) forms, the latter is generated by NAD+ accepting high-energy electrons from glycolytic and TCA intermediates and acts as a primary electron donor in ATP synthesis to drive mitochondrial OXPHOS. NAD+ also regulates non-redox NAD+ -dependent enzymes such as poly-ADP-ribose-polymerases (PARPs) and sirtuins. Both NAD+ and NAD+ -consuming enzymes are critical for immune responses, cellular bioenergetics, and to design nutritional strategies to reset viral-induced HMR/D.
Furthermore, NAD+ plays a key role in several essential cellular processes including DNA repair, immune cell function, senescence, and chromatin remodeling. A decline in NAD+ metabolism among the elderly population and low tissue levels of NAD+ is a common trait in m-Dys, a predisposing risk factor in viral-induced HMR/D. SARS-CoV-2 infection dysregulates NAD+ metabolism, which could manifest m-Dys and lead to chronic fatigue syndrome (CFS) in HMR/D. Therefore, nutritional reset of m-Dys with NAD+ or its natural dietary precursors could be effective in improving myocardial bioenergetics and function in such patients. Dietary NAD+ could partially resolve SARS-CoV-2-induced dysregulated gene expression and mitochondrial metabolism. NAD supplement could also alleviate intestinal barrier injury by protecting mitochondrial function in gut epithelia. Also, NAD+ supplement could directly inhibit PARP-1, prevent pro-inflammatory cytokines and resolve hyper-activated immune system in viral-induced HMR/D.
Coenzyme Q10: Coenzyme Q10 (CoQ10) or ubiquinone is a lipophilic cofactor in the mitochondrial electron transport chain (ETC) of the OXPHOS system that exerts powerful antioxidant, anti-apoptotic, immuno-modulatory and anti-inflammatory effects in cellular metabolism. CoQ10 is also a potent anti-inflammatory agent that effectively down-regulates cytokines (i.e., TNF-α, IL- 6, CRP) and could optimize viral-disrupted ACE2/RAAS system, by exerting anti-angiotensin II effects and decreasing OxS in COVID-19 patients. Excess release of cytotoxic reactive oxygen species (ROS) during m-Dys leads to OxS, which may hyper-activate platelet function and pose risk of thrombosis in COVID-19 patients. As a potent mitochondrial redox regulator, CoQ10 could prevent thrombotic events in viral-induced HMR/D by resolving ROS-induced platelet aggregation. CoQ10 is expressed in all tissues; however, its biosynthesis drops down with ageing and sharply declines during OxS in COVID-19. Therefore, CoQ10 as an adjuvant combined with other mitochondrial nutrients could provide potential therapeutic options to resolve hyper-inflammation and reset HMR/D.
Creatine: Creatine could replenish mitochondrial viability and restore cognitive function(s) by down- regulating toll-like receptors (TLRs) involved in neuroinflammation and neurodegeneration. The potent antioxidant activity of creatine could also protect mitochondrial DNA from ROS-mediated oxidative damage, revitalize cellular bioenergetics, neuro-metabolism, and immune function, thereby may exert a multi-functional benefit to resolve myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) complications in HMR/D patients.
Reset of Oxidative Stress (OxS)
Viral-induced OxS with excess levels of ROS i.e., superoxide anion (O₂˙⁻), hydroxyl radical (˙OH), singlet oxygen (¹O₂), and hydrogen peroxide (H₂O₂), could trigger severe clinical manifestations including hyper inflammation, tissue damage, thrombosis, and MODS in COVID-19, which may continue in PASC. In the body, O₂˙⁻ anions are intended products of redox signaling enzyme cascade and byproducts of several metabolic processes including mitochondrial respiration. Superoxide (O₂˙⁻) anions are scavenged by redox enzyme superoxide dismutase (SOD), whereas H₂O₂ by catalase (CAT), glutathione (GSH), GSH-peroxidase (GPx), thioredoxin peroxidase (Trx), and peroxiredoxins (Prdx). Any decline in redox enzymes may increase free radical generation with subsequent induction of lipid peroxidation, protein oxidation, and DNA/RNA degradation.
Serum levels of SOD, CAT, GSH, and GPx are significantly altered in viral-induced HMR/D. Reduced total antioxidant capacity (in blood) of SARS-CoV-2 infected individuals serves as a predictive marker for COVID-19 severity. Both OxS and hyper-inflammatory state during the acute phase of COVID-19, could also predict severity of chronic fatigue, depression, and anxiety symptoms even after 3 to 4 months in the virus-free PASC patients. Based on cluster analysis, a majority of PASC patients show severe abnormalities in SpO₂ , increased OxS and reduced antioxidant indices. Severe OxS with elevated blood levels of high sensitivity-C-reactive protein (hs-CRP) is a hallmark of hyper-inflammatory state in COVID-19 and PASC; therefore, antioxidant enzymes could be considered an effective nutritional strategy to resolve OxS and reset viral-induced HMR/D.
Superoxide dismutase(s): Superoxide dismutases (SODs) are metallo-enzymes that trigger endogenous antioxidant machinery, the first-line defense against cytotoxic ROS in the body. SOD catalyzes the conversion of superoxide (O₂˙⁻) into O₂ and H₂O₂ . The H₂O₂ is further hydrolyzed to water via CAT and GPX enzymes. Three isoforms of SOD exist in human body: the cytosolic Cu-, Zn-SOD (SOD1), the mitochondrial Mn-SOD (SOD2) and the extracellular Cu-, Zn-SOD (SOD3). OxS plays a critical role in COVID-19 and PASC; therefore, the therapeutic use of SOD and SOD-mimetics may prove beneficial in metabolic reset of viral-induced HMR/D.
Catalase: Catalase (CAT), a heme enzyme that catalyzes the decomposition of H₂O₂ to water + molecular O₂, provides a vital cellular antioxidant defense. Excessive production of H₂O₂ in mitochondria could damage lipids, proteins, mDNA, resulting in necrosis or apoptosis; where then CAT could protect such cells from H₂O₂-induced oxidative injury and help regulate the cellular redox-oxidative status. CAT-mediated decomposition of H₂O₂ to water minimizes the downstream flow of excessive ROS, which otherwise could trigger OxS and m-Dys during viral-induced HMR/D. CAT plays a crucial intermediary role in viral spike (S)-protein binding to hACE2 receptors, thereby affects the host susceptibility to SARS-CoV-2 infection. CAT could also regulate cytokine production in leukocytes, protect alveolar cells from oxidative injury, and block SARS-CoV-2 replication.
Glutathione: Glutathione (GSH) (γ-L-glutamyl-L-cysteinyl-glycine) is a tripeptide synthesized in the cytosol by two ATP-consuming enzymatic reactions. GSH reaches millimolar levels (1–10 mM) within cells, micromolar levels (10–30 μM) in plasma, and its low redox potential (E'₀ = −240 mV) makes GSH an ideal cellular redox buffer. GSH is commonly found in reduced GSSG form in cytosol, nucleus, mitochondria, and endoplasmic reticulum. The GSSG/GSH redox couple interacts with other antioxidant enzymes to maintain mitochondrial function and cellular redox homeostasis. GSH plays the role of ‘master antioxidant’ in tissues; where the high millimolar levels of GSSG in reduced form emphasizes its regulatory role in processes such as detoxification, protein folding, antiviral defense and immune response. Mitochondria are the main source of ROS, generated from the ETC/OXPHOS and any excess release of toxic free radicals could trigger OxS and m-Dys. GSH is the main cellular antioxidant to reduce H₂O₂ and lipid hydroperoxides (LOOH) catalyzed by GPXs.
The SARS-CoV-2-induced FeRD, its ensuing OxS could deplete cellular antioxidant reserves and increase severity of viral-induced HMR/D. Decreased expression of GSH synthesis leads to low free GSH levels, resulting in elevated ROS, immune dysfunction, and increased disease severity. Furthermore, comorbidities such as hypertension (56.6%), obesity (41.7%), and diabetes (33.8%) are frequently linked to OxS and chronic inflammation in hospitalized COVID-19 patients. In obese patients, OxS is associated with diminished GSH levels and decreased GSH/GSSG ratio. Low GSH levels could also increase viral replication, pro-inflammatory cytokine release, endothelial damage, and immune-thrombosis, which is a hyper-coagulative clinical condition that could exacerbate morbidity and mortality in viral-induced HMR/D. Since m-Dys and OxS jointly contribute to patho-physiology, nutritional to replenish optimal GSH levels could be a promising strategy to reset viral-induced HMR/D and support patient recovery.
N-Acetyl-L-Cysteine: N-Acetyl-L-Cysteine (NAC) is a sulfur-containing amino acid that breaks disulfide bonds, increases viscosity of mucoproteins and serves as an antioxidant in pulmonary mucous secretions of the respiratory tract. NAC is widely used as a mucolytic agent to improve airway clearance in chronic respiratory diseases. As a precursor for GSH synthesis, adjuvant therapy with NAC could resolve viral-induced OxS via GSH release and help restore cellular redox homeostasis in HMR/D. NAC, as a precursor for reduced GSH, demonstrates antioxidant, anti-inflammatory and immunomodulatory effects, which may prove beneficial in modulating any excess inflammatory activation during COVID-19. Therefore, nutritional supplementation with NAC could effectively resolve OxS and target pathophysiological pathways and persistent pulmonary fibrotic sequelae in viral-induced HMR/D.