Integrative Reference Tables

The following tables synthesize the ten-step analysis into cross-step reference views: reactions (success and failure), therapeutic targets, yield accounting, and step interactions.

1 Key Reactions: Success and Failure Modes per Step

Primary biochemical reaction and documented or predicted failure-mode reactions at each step. Failure modes listed are those with ME/CFS-specific evidence or strong mechanistic prior.
Step Success reaction ME/CFS failure mode(s)
1: Substrate delivery Glucose \(\rightarrow\) cell via GLUT1/4; fatty acids via CD36/CPT1 Impaired GLUT4 trafficking (G1); reduced fatty acid oxidation with paradoxical lipid accumulation
2: Glycolysis Glucose \(\rightarrow\) 2 pyruvate + 2 ATP + 2 NADH Impaired AMPK-stimulated glycolytic activation (Brown et al. 2018); possible HK/PFK1/PKM2 deficits (G4, unstudied)
3: PDC Pyruvate + CoA + NAD+ \(\rightarrow^{\text{TPP, FAD, lipoate}}\) acetyl-CoA + CO2 + NADH PDK-mediated PDC phosphorylation (inactivation); cofactor depletion (thiamine, riboflavin, lipoate); SIRT4 lipoamidase E2 delipoylation
4: Beta-oxidation Fatty acyl-CoA \(\rightarrow^{\text{FAD, NAD+, CoA}}\) acetyl-CoA + FADH2 + NADH (per 2C removed) Reduced CPT1 activity or malonyl-CoA dysregulation; VLCAD/LCAD/MCAD deficits (G12, unstudied)
5: Krebs cycle Acetyl-CoA \(\rightarrow^{\text{NAD+, FAD, GDP}}\) 3 NADH + FADH2 + GTP + 2 CO2 Aconitase inactivation by superoxide (G16: protein up 1.9\(\\times\), activity unmeasured); KGDHC inhibition by H2O2 and HNE (G17)
6: Cofactors NAD+ \(\leftrightarrow\) NADH; FAD \(\leftrightarrow\) FADH2; CoQ10 shuttles electrons NAD+ depletion in energy-intensive tissues (G22, predicted); riboflavin/FAD insufficiency (G23); CoQ10 tissue deficit (G26)
7: ANT ATPmatrix + ADPcytosol \(\leftrightarrow^{\text{ANT}}\) ADPmatrix + ATPcytosol Anti-ANT1 autoantibodies trapping ATP in matrix (G28, unstudied)
8: PCr shuttle ATP + Cr \(\leftrightarrow^{\text{mi-CK}}\) ADP + PCr; PCr + ADP \(\leftrightarrow^{\text{cy-CK}}\) Cr + ATP Brain creatine depletion (Godlewska 2025, 7T MRS ); SLC6A8 dysfunction (G29, unstudied)
9: ROS scavenging O2β€’βˆ’ \(\rightarrow^{\text{MnSOD}}\) H2O2 \(\rightarrow^{\text{GPX, PRDX3}}\) H2O Decreased MnSOD protein ; GPX4-mediated lipid peroxidation; NRF2 unmeasured (G34)
10: Dynamics Fission \(\rightarrow\) mitophagy; PGC-1\(\alpha\) \(\rightarrow\) biogenesis PGC-1\(\alpha\) hyperacetylation (inferred: impaired AMPK/SIRT1 + elevated SIRT4 ); IgG-induced fragmentation (Liu et al. 2026)

2 Therapeutic Map: Interventions Targeting Each Step

Medications and supplements with mechanistic rationale at each step. Evidence: RCT = randomised controlled trial in ME/CFS or related condition; OL = open-label; Mech = mechanistic rationale only. All require physician review.
Step Intervention (target) Evidence
1 Metformin (AMPK \(\rightarrow\) GLUT4) (Brown et al. 2018) Mech
2 AMPK activators (glycolytic flux) (Brown et al. 2018) Mech
3 DCA (PDK inhibitor); caution: may worsen ROS Mech
3 Thiamine 300–600 mg/day (PDC E1) (Bager et al. 2021) RCT (IBD)
3 Riboflavin 400 mg/day (PDC E3) (Schoenen, Jacquy, and Lenaerts 1998) RCT (migraine)
4 L-carnitine 1–2 g/day (CPT1 substrate) OL
5 Alpha-lipoic acid 600 mg/day (KGDHC E2) Mech
6 CoQ10 200–400 mg/day ubiquinol RCT
6 NR/NMN 250–500 mg/day (NAD+) (Heng et al. 2025) Mech
7 Elamipretide (cardiolipin stabilizer) Mech
8 Creatine monohydrate 5 g/day (Godlewska et al. 2024) OL
9 Sulforaphane (NRF2); caution: may be futile if NRF2 overwhelmed Mech
9 NAC 600–1200 mg/day (glutathione precursor) Mech
10 Metformin (AMPK \(\rightarrow\) PGC-1\(\alpha\)) (Brown et al. 2018) Mech
10 Urolithin A (mitophagy; phase 1–2 in sarcopenia) Mech

3 Yield Accounting: Cumulative ATP Loss Under Failure Scenarios

Rough estimated ATP yield per glucose under isolated single-step failure; values are author estimates based on gated-yield logic from The Energy Chain: Ten Steps from Substrate to ATP, not derived from quantitative modeling or experimental data. Combined failures are worse than additive (Integrative Reference Tables). Steps 8–10 (\(dagger\)) do not change per-cycle yield but degrade performance over time.
Step Healthy Mild Severe Mechanism of loss
1: Substrate delivery ~30 ~25 ~5 Reduced substrate \(\rightarrow\) lower flux
2: Glycolysis ~30 ~28 ~20 Glycolytic ATP lost; downstream flux reduced
3: PDC ~30 ~20 ~7 ~25 gated ATP lost (83%); only glycolytic ATP remains
4: Beta-oxidation ~30 ~30 ~15 Glucose basis unaffected; fatty-acid tissues lose ~50%
5: Krebs cycle ~30 ~22 ~7 ~20 gated ATP (67%) at risk
6: Cofactors ~30 ~22 ~5 Multi-step gate: one deficit impairs multiple steps
7: ANT ~30 ~20 ~2 Matrix ATP trapped; 93% is matrix-produced
8\(dagger\): PCr shuttle ~30 ~30 ~30 Per-cycle yield unchanged; burst capacity degraded
9\(dagger\): ROS scavenging ~30 ~28 ~15 Progressive: ROS damages Steps 3, 5, 6, 7 over days–weeks
10\(dagger\): Dynamics ~30 ~28 ~10 Longitudinal: mito mass declines over weeks–months

4 Cross-Step Interaction Matrix

Failure at Step X (row) exacerbating Step Y (column), based on mechanistic reasoning from the step-by-step analysis. \(\Rightarrow\) = direct amplification with cited evidence; \(\rightarrow\) = indirect/delayed or inferred from general biochemistry; β€” = no significant interaction. Individual cell assignments reflect author judgment and have not been systematically validated.
↓X \ Yβ†’ 1 2 3 4 5 6 7 8 9 10
1 β€” \(\Rightarrow\) \(\Rightarrow\) \(\Rightarrow\) \(\Rightarrow\) β€” β€” β€” β€” β€”
2 β€” β€” \(\rightarrow\) β€” β€” β€” β€” β€” β€” β€”
3 β€” β€” β€” β€” \(\Rightarrow\) β€” β€” β€” \(\rightarrow\) β€”
4 β€” β€” β€” β€” \(\Rightarrow\) β€” β€” β€” β€” β€”
5 β€” β€” β€” β€” β€” \(\rightarrow\) β€” β€” \(\rightarrow\) β€”
6 β€” β€” \(\Rightarrow\) \(\rightarrow\) \(\Rightarrow\) β€” \(\rightarrow\) β€” \(\rightarrow\) \(\rightarrow\)
7 β€” β€” β€” β€” β€” β€” β€” \(\rightarrow\) β€” β€”
8 β€” β€” β€” β€” β€” β€” β€” β€” β€” β€”
9 β€” β€” \(\Rightarrow\) β€” \(\Rightarrow\) \(\Rightarrow\) \(\Rightarrow\) β€” β€” \(\Rightarrow\)
10 \(\rightarrow\) β€” \(\rightarrow\) \(\rightarrow\) \(\rightarrow\) \(\rightarrow\) \(\rightarrow\) \(\rightarrow\) \(\Rightarrow\) β€”

Key interactions: Step 9 (ROS scavenging) failure amplifies nearly every other step β€” superoxide inactivates aconitase (Step 5), oxidizes cardiolipin (Step 7), damages PDC E2 lipoyl groups (Step 3), depletes cofactors (Step 6), and accelerates mitochondrial damage requiring biogenesis (Step 10). Step 10 (biogenesis) failure is a slow amplifier: over weeks the declining mitochondrial population reduces capacity at Steps 3–9. Step 6 (cofactors) has the widest direct amplification because a single cofactor gates multiple enzymatic steps simultaneously. Step 7 (ANT) failure reduces cytosolic ATP availability, secondarily depleting the PCr pool as creatine kinase cannot regenerate PCr without ATP substrate.

References

Bager, Palle, Christian Lodberg Hvas, Charlotte Lock Rud, and Jens Frederik Dahlerup. 2021. β€œRandomised Clinical Trial: High-Dose Oral Thiamine Versus Placebo for Chronic Fatigue in Patients with Quiescent Inflammatory Bowel Disease.” Alimentary Pharmacology & Therapeutics 53 (1): 79–86. https://doi.org/10.1111/apt.16166.
Brown, Audrey E., Beth Dibnah, Elizabeth Fisher, Julia L. Newton, and Mark Walker. 2018. β€œPharmacological Activation of AMPK and Glucose Uptake in Cultured Human Skeletal Muscle Cells from Patients with ME/CFS.” Bioscience Reports 38 (3): BSR20180242. https://doi.org/10.1042/BSR20180242.
Godlewska, Beata R., Amy L. Sylvester, Uzay E. Emir, Ann L. Sharpley, William T. Clarke, Marieke A. G. Martens, and Philip J. Cowen. 2024. β€œSix-Week Supplementation with Creatine in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Magnetic Resonance Spectroscopy Feasibility Study at 3 Tesla.” Nutrients 16 (19): 3308. https://doi.org/10.3390/nu16193308.
Heng, Ruiwen Benjamin, Bavani Gunasegaran, Shivani Krishnamurthy, Sonia Bustamante, Ananda Staats, Sharron Chow, Seong Beom Ahn, et al. 2025. β€œMapping the Complexity of ME/CFS: Evidence for Abnormal Energy Metabolism, Altered Immune Profile, and Vascular Dysfunction.” Cell Reports Medicine 6 (12): 102514. https://doi.org/10.1016/j.xcrm.2025.102514.
Liu, Zhihang, Claudia Hollmann, Shreya Kalanidhi, Aeneas Grothey, Jan Lamerding, Ritika Bhargava, Hannah Graßhoff, et al. 2026. β€œImmunoglobulin G Complexes from Post-Infectious ME/CFS, Including Post-COVID ME/CFS Disrupt Cellular Energetics and Alter Inflammatory Marker Secretion.” Brain, Behavior, and Immunity – Health 52: 101187. https://doi.org/10.1016/j.bbih.2026.101187.
Schoenen, J, J Jacquy, and M Lenaerts. 1998. β€œEffectiveness of High-Dose Riboflavin in Migraine Prophylaxis: A Randomized Controlled Trial.” Neurology 50 (2): 466–70. https://doi.org/10.1212/WNL.50.2.466.