Family 2: Redox and Oxidative Balance
Family overview. All aerobic cells produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) as metabolic byproducts. Antioxidant systems — glutathione, superoxide dismutase, catalase, peroxiredoxins — normally maintain redox homeostasis. When production exceeds scavenging capacity, oxidative and nitrosative stress damage lipids, proteins, and DNA.
Concrete mechanisms and ME/CFS evidence:
ROS overproduction. Elevated ROS in PBMCs and RBCs; RBC ROS ~30% higher than healthy controls; correlates with symptom severity and membrane stiffness (Marshall-Gradisnik et al. 2018).
Glutathione depletion and compensatory upregulation. Paradoxically elevated total glutathione levels alongside glutathione peroxidase 4 (GPx4)-mediated lipid oxidative damage in memory lymphocytes, suggesting compensatory upregulation under chronic oxidative load that nonetheless fails to contain damage (Shankar et al. 2025).
Mitochondrial SOD2 downregulation. Decreased mitochondrial superoxide dismutase protein in ME/CFS immune cells, reducing the first line of mitochondrial ROS defence.
Nitrosative stress. Elevated inducible nitric oxide synthase (iNOS), excess nitric oxide, peroxynitrite (ONOO⁻), and nitrate — particularly post-exercise; peroxynitrite damages proteins, lipids, and DNA simultaneously (Maes, Mihaylova, and Leunis 2014).
Lipid peroxidation. Elevated markers of oxidised fatty acids and lipid peroxidation products; immune responses to oxidised lipids elevated versus controls.
Oxidative DNA damage. Elevated 8-hydroxydeoxyguanosine (8-OHdG) as a marker of oxidative DNA damage; DNA repair pathway capacity has not been directly measured in ME/CFS (Maes et al. 2012).
Redox-immune-mitochondrial vicious cycle. ROS drive immune activation (NF-κB, NLRP3), which amplifies ROS production; mitochondrial dysfunction simultaneously increases ROS output and reduces antioxidant precursor (NADPH) availability. This forms a self-reinforcing loop linking Families 1, 2, 4, and 18.
Full discussion: Energy Metabolism and Mitochondrial Function.
Evidence status: Established (replicated across multiple cohorts; shared signature with Long COVID (Shankar et al. 2025)).