Family 1: Energy and Metabolic Regulation
Family overview. Cellular energy production — oxidative phosphorylation, glycolysis, fatty acid oxidation, and amino acid catabolism — must be continuously matched to demand. Pathological disruption can occur at any node: substrate supply, enzymatic capacity, electron transport chain integrity, or ATP sensing.
Concrete mechanisms and ME/CFS evidence:
Mitochondrial OXPHOS failure. Reduced Complex I and Complex II activity, impaired electron transport, decreased maximal oxidative capacity. Electron microscopy confirms structural mitochondrial damage in skeletal muscle biopsies, preferentially subsarcolemmal (Scheibenbogen and Wirth 2025). Established across multiple cohorts.
WASF3-mediated respiratory complex disruption. WASF3 protein overexpression in ME/CFS skeletal muscle disrupts assembly of respiratory supercomplexes, simultaneously inhibiting OXPHOS and promoting actin-driven glycolysis (Hwang et al. 2023). Single-group finding; replication pending.
Pyruvate dehydrogenase kinase (PDK) upregulation. PDK1, PDK2, and PDK4 are upregulated in circulating cells of ME/CFS patients, blocking pyruvate entry into the TCA cycle and diverting it to lactate even under aerobic conditions — a functional block rather than substrate shortage (Fluge et al. 2017). Replicated.
Glycolytic shift and lactate accumulation. Excess reliance on anaerobic glycolysis produces lactate at workloads where healthy individuals sustain OXPHOS; brain MRS shows elevated ventricular lactate, and a controlled-hypoxia MRI study reported elevated resting thalamic lactate with a blunted rise under hypoxia in patients (Bader et al. 2026). Consistent with PDK upregulation and reduced OXPHOS capacity.
Pathogen-driven glycolytic reprogramming (subset). Beyond the host’s intrinsic glycolytic shift, the pathogens that trigger post-infectious ME/CFS may impose one: neurotropic viruses reprogram glia toward glycolysis (Rodrigues et al. 2025), and the non-viral tick-borne pathogens do so too — Borrelia via LDHA induction and trained-immunity macrophage memory with mitochondrial downregulation (Barriales et al. 2021), Bartonella via HIF-1\(\alpha\) stabilisation and host ATP depletion (Kempf et al. 2005). In a tick-borne-triggered subset this may compound the host’s own glycolytic deficit (Chapter Immune System Dysfunction, Tick-Borne Pathogen-Driven Glycolytic Reprogramming as a Compounding Immunometabolic Insult in a Post-Infectious ME/CFS Subset). Mechanistic parallel only; not yet measured in ME/CFS.
NAD⁺ metabolism dysregulation. Elevated AMP and reduced ATP/ADP ratio in PBMCs indicate impaired ATP generation; kynurenine pathway disruption (Family 11) reduces NAD⁺ biosynthesis (Naviaux et al. 2016).
TCA cycle constraint. Metabolomics studies show reduced TCA intermediates, consistent with impaired cycle flux secondary to PDH inhibition and substrate limitation.
Lipid metabolism dysregulation. Abnormal fatty acid oxidation and altered lipid profiles; elevated immune responses to oxidised fatty acids.
IgG-mediated mitochondrial fragmentation. Patient-derived IgG induces mitochondrial fragmentation in endothelial cells, altering energetics — bridging autoimmunity (Family 5) and metabolic dysfunction (Cox et al. 2023).
Full discussion: Energy Metabolism and Mitochondrial Function. Functional CPET correlates: Causal Hierarchy: Root Causes, Amplifiers, and Consequences.
Evidence status: Established (multiple independent replication studies; functional correlates demonstrated).