Redox imbalance and mitochondrial dysfunction lie at the root of the metabolic dysregulation that exacerbates cardiovascular disease progression. Mitochondria provide the critical energy required by the heart muscle for continuous contraction. However, mitochondria are also the most prevalent source of reactive oxygen species. These molecules execute important signaling functions when produced in an amount commensurate with antioxidant capacity. As the mitochondria age, accrue DNA damage, and lose efficiency, reactive oxygen species accumulate and overburden the body’s capacity to quench them. They subsequently wreak havoc on their local environment, including the mitochondria from which they originate. This cultivates a vicious cycle of oxidative stress that damages tissues, undermines mitochondrial performance, and sets off an inflammatory cascade.
Since reactive oxygen species are generated during the process of mitochondrial oxidation, hyperglycemia and dyslipidemia can amplify their production. Cardiometabolic disease is correlated with states of nutrient excess that drive oxidative stress and corresponding chronic inflammation. Moreover, reactive oxygen species trigger ferroptosis during which iron-driven phospholipid peroxidation initiates cell death. Iron is attracted to atherosclerotic lesions in the vasculature and interacts with polyunsaturated fatty acid-rich membranes. Circulating reactive oxygen species target LDL, and the resultant oxidized lipids injure vascular walls. Nitric oxide is impaired by oxidative stress, further compromising blood vessel reactivity and redox balance. Injury stimulates NF-kB, triggering immune cell invasion and macrophage foam cell formation. Foam cells show altered iron homeostasis which may destabilize plaque and cause ischemia. Once oxygen delivery is restored, mitochondria resume oxidative metabolism and spew out copious amounts of reactive oxygen species. Free iron combines with reactive oxygen species, precipitating lipid peroxidation and eventual ferroptotic cell death of cardiomyocytes.
Furthermore, metabolic dysfunction creates a self-reinforcing loop whereby impaired mitophagy fails to clear reactive oxygen species-generating mitochondria. Ineffective mitophagy perpetuates mitochondrial inefficiency, reactive oxygen species production, and makes cells especially vulnerable to ferroptosis and apoptosis. Nutritional redox reprogramming has been proposed as a novel strategy to restore redox balance through discriminate targeting of specific signaling cascades, lipid peroxidation pathways, antioxidant defense systems, mitochondrial turnover, and iron homeostasis. Alpha-lipoic acid (ALA), urolithin A, and ergothioneine have been elucidated as worthy candidates in the modulation of cardiometabolic disease and associated alterations in mitophagy, ferroptosis, and apoptosis.
ALA is a mitochondrial cofactor able to assist with antioxidant recycling. It also participates in the AMPK nutrient-sensing pathway, the Nrf2 antioxidant pathway, the NF-kB inflammatory pathway, and insulin signaling. It has been shown to augment the SOD, CAT, GPx, and GSH antioxidant systems and downregulate the pro-inflammatory cytokines TNF-a, IL-6, and IL-1B. ALA additionally improves lipid profile, prevents immune cell invasion, inhibits cell adhesion to vascular smooth muscle and endothelial cells, induces macrophage shift toward an anti-inflammatory M2 phenotype, and triggers autophagy. ALA subsequently ameliorates mitochondrial resilience in states of oxidative stress, protects mitochondrial membrane integrity, improves glucose regulation, and attenuates immune activation, inflammation, and apoptosis. Moreover, in comparison to other exogenous antioxidants, ALA uniquely attenuates iron-mediated oxidative damage, protecting against ferroptosis. ALA appears to control iron uptake and export, dampening DMT1 expression while simultaneously elevating ferroportin and ferritin expression. A subsequently smaller intracellular iron pool prevents lipid radicals generated by Fenton reactions that contribute to oxidative damage.
Urolithin A is a metabolite synthesized by the gut microbiota following ellagitannin intake. It exhibits less potent antioxidant potential, but acts as a powerful signal in the modulation of mitochondrial biogenesis and mitophagy. Urolithin A interacts with mitophagy-associated PINK1/Parkin signaling, as well as mitochondrial biogenesis regulators PGC-1a and NRF1. Additionally, urolithin A acts to elevate Nrf2 expression to bolster antioxidant defense and prompt autophagic flux. It also enhances nitric oxide synthesis and endothelial nitric oxide synthase activity, diminishing monocyte adhesion that promotes plaque build-up. Urolithin A has been found to reduce TNF-a, IL-6, IL-1b, and endothelin-1 levels and stimulate PPAR-y by inhibiting the ERK1/2 pathway. By improving mitochondrial performance, quality control, and metabolic flexibility, and supporting redox balance, urolithin A alleviates reactive oxygen species generation in cardiometabolic disease.
Ergothioneine from the diet concentrates in areas of the mitochondria subject to oxidative injury and, similar to ALA, behaves as a redox cycler. It is a robust protector of mitochondrial performance, resilience, and stability with profound redox buffering potential. Ergothioneine displays remarkable stability, enabling it to maintain long-lasting antioxidant activity. Ergothioneine appears to mitigate iron-induced lipid peroxidation and oxidative damage in part owing to its metal-chelation properties, positioning it as a therapeutic intervention in ferroptosis. It exhibits the capacity to inhibit NF-kB, subsequently diminishing inflammation, fibrosis, and apoptosis of cardiomyocytes. Through the preservation of mitochondrial redox equilibrium, ergothioneine stabilizes mitochondrial iron by fortifying iron-sulfur cluster integrity and averts lipid peroxidation.
In early preclinical studies, ALA, urolithin A, and ergothioneine have exhibited compelling effects on mitochondrial dysfunction in cardiometabolic disease. However, the greatest limitation to their clinical application resides in their poor bioavailability. ALA is rapidly metabolized and displays a very brief half-life, impairing its potency. Urolithin A is dependent on the composition of the gut microbiome and is thereby vulnerable to substantial inter-individual variability. Ergothioneine incorporation is reliant upon the OCTN1 transporter for tissue accumulation. Considerable exploration is thus required before arriving at a personalized implementation strategy. Well-designed clinical trials will be illustrative in identifying optimal dose, confirming efficacy, and determining long term impact of ALA, urolithin A, and ergothioneine in the prevention or management of cardiometabolic disease.
Yang W, Jian W. Nutritional redox reprogramming in cardiometabolic diseases: alpha-lipoic acid, urolithin A, and ergothioneine as modulators of the ferroptosis-mitophagy axis and mitochondrial metabolic remodeling. Front Nutr. 2026;13:1819082. Published 2026 May 15. doi:10.3389/fnut.2026.1819082