Mitochondrial Dysfunction Models
1 Reactive Oxygen Species Production and Damage
Reactive oxygen species (ROS) are an unavoidable byproduct of electron transport. Superoxide (\(\text{O}_2^{\bullet-}\)) is generated primarily at Complexes I and III when electrons “leak” to molecular oxygen instead of following the normal transfer chain. The ROS production rate increases when electron flow is impeded:
\[ J_{\text{ROS}} = k_{\text{ROS}} \cdot [\text{NADH}] \cdot (1 - \frac{J_{\text{CI}}}{J_{\text{CI,max}}}) + k_{\text{ROS,CIII}} \cdot [\text{UQH}_2] \cdot (1 - \frac{J_{\text{CIII}}}{J_{\text{CIII,max}}}) \tag{1}\]
where the terms \((1 - J / J_{max})\) capture the principle that reduced electron flow (due to impaired complexes) leads to increased electron residence time on carriers, increasing the probability of electron leak to oxygen. This creates a positive feedback loop: ETC damage \(->\) reduced flux \(->\) increased ROS \(->\) further ETC damage. The ROS balance includes antioxidant scavenging:
\[ \frac{d[\text{ROS}]}{d t} = J_{\text{ROS}} - k_{\text{SOD}} \cdot [\text{SOD}] \cdot [\text{ROS}] - k_{\text{GPx}} \cdot [\text{GPx}] \cdot [\text{ROS}] \tag{2}\]
where SOD (superoxide dismutase) and GPx (glutathione peroxidase) are the primary antioxidant enzymes. Oxidative damage accumulates as a function of cumulative ROS exposure, reducing enzyme activities over time and establishing the vicious cycle described qualitatively in Energy Metabolism and Mitochondrial Function.
2 Impaired Energy Production in ME/CFS
The ME/CFS disease state is modeled by modifying healthy-state parameters at specific points supported by experimental evidence:
- Reduced Complex I activity: \(V_{max, \text{CI}}^{\text{ME/CFS}} = \alpha_{\text{CI}} \cdot V_{max, \text{CI}}^{\text{healthy}}\) with \(\alpha_{\text{CI}} \in [0.5, 0.8]\), consistent with findings of impaired Complex I function in ME/CFS lymphocytes (Tomas et al. 2017)
- Increased proton leak: \(J_{\text{leak}}^{\text{ME/CFS}} = \beta \cdot J_{\text{leak}}^{\text{healthy}}\) with \(\beta \in [1.5, 3.0]\), reducing the fraction of proton-motive force available for ATP synthesis
- Reduced \(\text{NAD}^\text{+}\) pool: \([\text{NAD}^+]_{\text{total}}^{\text{ME/CFS}} = \gamma \cdot [\text{NAD}^+]_{\text{total}}^{\text{healthy}}\) with \(\gamma \in [0.6, 0.9]\), consistent with abnormal NAD+ metabolism documented in ME/CFS white blood cells (Heng et al. 2025) (note: Heng 2025 found NAD+ elevated in PBMCs, suggesting substrate backup; the \(\gamma < 1\) assumption applies to energy-intensive tissues where depletion is predicted but not yet measured)
- Elevated baseline ROS: \([\text{ROS}]_0^{\text{ME/CFS}} > [\text{ROS}]_0^{\text{healthy}}\), consistent with oxidative stress biomarkers
The model predicts that these parameter changes produce a new steady state with reduced ATP production, elevated lactate, and increased sensitivity to metabolic perturbation—qualitatively matching the ME/CFS metabolic phenotype described by Naviaux (Naviaux et al. 2016) and Germain et al. (Germain et al. 2020).
The impairment factors (\(\alpha_{\text{CI}}\), \(\beta\), \(\gamma\)) are constrained by in vitro studies on isolated cells, primarily lymphocytes and muscle biopsy samples. Whether these values accurately represent in vivo mitochondrial function across tissues remains uncertain. Patient-level variation in these parameters likely contributes to the clinical heterogeneity of ME/CFS.