Reset of Mitochondrial Dysfunction (m-Dys)
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.