Oxidative Stress
Oxidative Stress
Inflammation,
Elevated Cytokines
IL-1β, IL-6, IL-10, TNF-a
Inflammation,...
Hepcidin
Increased
Hepcidin...
Low Iron
Low Iron
ssDNA Breakage, PARP ->
AP-1, MAPK,
NF-kB Increased
ssDNA Breakage, PARP...
L-DOPA Decreased
L-DOPA Decreased
Neurotransmitters, Blood Volume Impaired
Neurotransmitters, B...
Norepinephine, Epinephine Dysregulation
Norepinephine, Epine...
Fatty Acid Oxidation, Cori Cycle
Impaired
Fatty Acid Oxidation...
Postural Orthostatic Tachycardia Syndrome
Postural Orthostatic...
Histamine Increased
Histamine Increased
Backup Pathways to Succinyl-CoA, Succinate, Fumarate Overused
Backup Pathways to S...
Mast Cell Activation Syndrome
Mast Cell Activation...
Hypovolemia,
Electrolyte Losses
Hypovolemia,...
Post-Exertion
(Lactic) Acidemia,
pH Shift Down
Post-Exertion...
Oxidized
Riboflavin Metabolite
Insufficiency
Oxidized...
Folate Metabolism, BH4 Impaired
Nitric Oxide Decreased
Folate Metabolism, B...
Cholesterol Elevation,
BCAA Overuse,
Nitrogen Elevation
Cholesterol Elevatio...
Unproductive
Sleep
Unproductive...
Complex II /
Succinate Dehydrogenase Impaired
Complex II /...
TCA Cycle Impairments
TCA Cycle Impairments
Acetyl-CoA
Decreased
Acetyl-CoA...
Pyruvate Dehydrogenase
Decreased
Pyruvate Dehydrogena...
Hypoxia Inducible Factors (HIF) Promoted
Hypoxia Inducible Fa...
Renal Function
Dysregulated
Renal Function...
LDH Increased, Lactic Acid
Increased
LDH Increased, Lacti...
Prolyl Hydroxylases
Decreased
Prolyl Hydroxylases...
Collagen Synthesis
Impaired
Collagen Synthesis...
Energy Deficiency
Energy Deficiency
Intracellular
Pyridoxal-5'-Phosphate
Impaired
Intracellular...
Cell Membranes / Transporters Impaired, PEM,
Insulin Resistance
Cell Membranes / Tra...
Rouleaux, Thrombi,
Hypoxia, Metabolite Backlog
Rouleaux, Thrombi,...
Low
Copper
Low...
Thyroid Function
Decreased
Thyroid Function...
Low
Manganese
Low...
Low
Rubidium
Low...
Excess Lead, Mercury, Uranium, Cadmium, Bismuth
Excess Lead, Mercury...
Glucose Metabolism
Impaired
Glucose Metabolism...
Low
Selenium
Low...
Low
Lithium
Low...
Muscle Weakness,
Gastroparesis
Muscle Weakness,...
Low
Chromium
Low...
Low
Vanadium
Low...
Low
Phosphorus
Low...
Low
Iodine
Low...
Low
Boron
Low...
Low
Cobalt
Low...
Small Intestinal
Bowel Overgrowth, LPS
Small Intestinal...
Low
Zinc
Low...
Low
Germanium
Low...
Low
Zirconium
Low...
Urea Cycle Dysregulated
Urea Cycle Dysregula...
Choline Increased, Acetylcholine Decreased
Choline Increased, A...
Cognitive
 Impairment
Cognitive...
Complex V Impaired,
ATP Decreased
Complex V Impaired,...
Low
Bismuth
Low...
Figure 2.
Figure 2.
Pathway Diagram: (High-Level) Hypothetical Disease Model for ME/CFS, Long COVID / Long Vaccine.
Pathway Diagram: (High-Level) Hypothetical Disease Model for ME/CFS, Long COVID / Long Vaccine.
Authors: Joshua Leisk, Aline Noçon ©2023, [DRAFT / INCOMPLETE - may contain errors]
Authors: Joshua Leisk, Aline Noçon ©2023, [DRAFT / INCOMPLETE - may contain errors]
ME/CFS: Correcting Chronic Mitochondrial Dysfunction
ME/CFS: Correcting Chronic Mitochondrial Dysfunction
cAMP,
Protein Kinase A
Dysregulated
cAMP,...
Borrelia, Bartonella
Infection, Opioids
Borrelia, Bartonella...
Vitamin D,
Vitamin A
Sufficiency
Vitamin D,...
(Pathogenic) GDH Elevation, as Direct Competition Against a-KGDH
(Pathogenic) GDH Ele...
v0.95b
v0.95b
5-AR Inhibitors,
AR Antagonists
5-AR Inhibitors,...
Vitamin C
Insufficiency
Vitamin C...
Hyperoxaluria
Hyperoxaluria
Isocitrate Lyase Expressing Bacteria, 
Glyoxylate Shunt
Isocitrate Lyase Exp...
D-Lactate Producing Bacteria
D-Lactate Producing...
Tyrosinase
Decreased, Tyramine Increased
Tyrosinase...
Dopamine Beta Hydroxylase
 Insufficiency
Dopamine Beta Hydrox...
Clostridia1
Clostridia1
Adaptive Immune Deficiency,
T cell Exhaustion
Adaptive Immune Defi...
GABA
Decreased
GABA...
Free Testosterone
Decreased
Free Testosterone...
Cortisol
Dysregulated
Cortisol...
Peripheral Neuropathy
Peripheral Neuropathy
Estrogen
Decreased
Estrogen...
Pathogenic & Deficiency Based Pathway Promoters

Pathway Inhibitor
Pathogenic & Deficiency Base...
Lines intersecting at right
angles do not connect.
Lines intersecting at right...
Key:
ADP - Adenosine Diphosphate
AP-1 - Activator Protein-1
a-KGDH - alpha-Ketoglutarate Dehydrogenase
ATP - Adenosine Triphosphate
BH4 - Tetrahydrobiopterin
cAMP- Cyclic Adenosine Monophosphate
GABA - Gamma-Aminobutyric Acid
GDH - Glutamate Dehydrogenase
GI - Gastro-Intestinal
IDH - Isocitrate Dehydrogenase
HHV - Human Herpesviruses
HIV - Human Immunodeficiency virus
HYPDH - Hydroxyproline Dehydrogenase
IDO - Indoleamine 2,3-dioxygenase
KYAT - Kynurenine--oxoglutarate transaminase
LDH - Lactate Dehydrogenase
LPS - Lipopolysaccharides
MAPK - Mitogen Activated Protein Kinases
MDH - Malate Dehydrogenase
NF-kB - Nuclear Factor Kappa Beta
NO - Nitric Oxide
ODC - Ornithine Decarboxylase
PARP - Poly (ADP-ribose) Polymerase
PEM - Post Exertion Malaise
PRODH - Proline Dehydrogenase
RR-MADD - Riboflavin-Responding Multiple Acyl-CoA                        Dehydrogenase Deficiency
ssDNA - Single Stranded DNA
TCA - TriCitric Acid
Th[#] - T Helper
Key:...
Intracellular Mineral Decrease, GI Absorption Blocked
Intracellular Minera...
Ferroportin, DMT-1 Decreased
Ferroportin, DMT-1 D...
Clostria Species - C. sporogenes, C.botulinum, C. caloritolerans, C. mangenoti, C. ghoni, C.bifermentans, C. difficile, C. sordellii
1 Clostria Species - C. sporogenes, C.botulinum, C. caloritolerans, C. mangenoti, C. ghoni, C.bifermentans, C. difficile,...
M.tuberculosis, C.albicans, P. indigofera, P. aeruginosa, A.calcoaceticus, S. Typhimurium, B. suis, Y. enterocolitica,
Y. pseudotuberculosis, Y. pestis, R. equi, E. coli., H. pylori strains P12, G27, 26, 695, Tx30a
2 M.tuberculosis, C.albicans, P. indigofera, P. aeruginosa, A.calcoaceticus, S. Typhimurium, B. suis, Y. enterocoli...
Complex III
Impaired
Complex III...
Complex I
Impaired, NAD+ Redox Impaired
Complex I...
Complex IV
Impaired
Complex IV...
ETF-QO Impaired
ETF-QO Impaired
NAD+ Insufficiency
NAD+ Insufficiency
 Increased
Peroxynitrites,
BH4 Oxidation
Increased...
Low
Molybdenum
Low...
Acyl-CoA Dehydrogenases
Decreased, Mito Lipid Accumulation
Acyl-CoA Dehydrogena...
PRODH, HYPDH
Excess Activity
PRODH, HYPDH...
Innate Immune Response
Innate Immune Respon...
Numerous
Pathogens -
eg. SARS-CoV-2,
Herpesviridae
Numerous...
Chronic Cranial Instability
Chronic Cranial Inst...
Lytic Reactivation
of Latent
HHV, HIV
Lytic Reactivation...
Riboflavin Kinase Decreased
Riboflavin Kinase De...
FAD Synthase Decreased
FAD Synthase Decreas...
Tinnitus, Myoclonus
Tinnitus, Myoclonus
Silicon
Sufficiency
Silicon...
SARS-CoV-2 Spike Protein, Fibrinogen
SARS-CoV-2 Spike Pro...
Necrosis
Necrosis
Decreased ODC, Spermidine
Decreased ODC, Sperm...
Low
Strontium
Low...
NADPH Oxidase Increased
NADPH Oxidase Increa...
Lymphatic Flow Impeded
Lymphatic Flow Imped...
KYAT1 Insufficiency
KYAT1 Insufficiency
IDO1 Promotion
IDO1 Promotion
Interferon-alpha
Elevation
Interferon-alpha...
Itaconate Pathway Activation
Itaconate Pathway Ac...
Interferon-gamma
Elevation
Interferon-gamma...
FAD Redox
Impaired
FAD Redox...
Viewer does not support full SVG 1.1
v0.77
v0.77
IFN-alpha: "Reactivates latent infections
and exposes them to T-cell surveillance.
Inhibits proliferation by impairing energy metabolism, via Complex II / SDH and
Methylmalonyl-CoA Mutase inhibition.
Negatively modulates IFN-gamma cascade."
IFN-alpha: "Reactivates latent infections...
IFN-gamma: "NAD+:NADH powered pathogen oxidation.
xanthine oxidase powered by NAD+ (at idle) and
NAD(P)H oxidase, uncoupled NOS powered by redirected NADH (from exertion), via Complex I inhibition and xanthine dehydrogenase activity.
Promoted by temperature, exhertion and primary sex hormones.
Negatively regulated by cortisol. "
IFN-gamma: "NAD+:NADH powered pathogen oxidation....
Connector Key:
Promoted

Inhibited
Connector Key:...
Best explored interactively at https://bornfree.life/diagrams/
Best explored interactively at https://bornfree.life/diagrams/
Figure 3.
Figure 3.
Pathway Diagram: The role of IFN- gamma in mitochondrial dysfunction.
Pathway Diagram: The role of IFN- gamma in mitochondrial dysfunction.
Authors: Joshua Leisk, Aline Noçon ©2023, [DRAFT / INCOMPLETE - may contain errors]
Authors: Joshua Leisk, Aline Noçon ©2023, [DRAFT / INCOMPLETE - may contain errors]
ME/CFS: Correcting Chronic Mitochondrial Dysfunction
ME/CFS: Correcting Chronic Mitochondrial Dysfunction
IFN-gamma (Promoted)
IFN-gamma (Promoted)
Complex I,
NADH:NAD+
Redox (Inhibited)
Complex I,...
Xanthine Oxidase (Promoted)
Xanthine Oxidase (Pr...
TDO / IDO1
(Promoted)
TDO / IDO1...
NAD+ Biosynthesis
(Impaired)
NAD+ Biosynthesis...
Pathogen, Responsive to IFN-gamma cascade
Pathogen, Responsive...
P5P (Insufficiency)
PMP (Elevated)
P5P (Insufficiency)...
NAD(P)H Oxidase (Promoted)
NAD(P)H Oxidase (Pro...
KYAT1
(Impaired)
KYAT1...
NAD+ (Insufficiency)
NADH (Elevated)
NADPH (Elevated)
NAD+ (Insufficiency)...
Riboflavin Kinase
(Impaired)
Riboflavin Kinase...
Reactive Oxygen Species (Promoted)
Reactive Oxygen Spec...
T3
(Insufficiency)
T3...
Magnesium
(Insufficiency)
Magnesium...
Pyridoxal Kinase
(Impaired)
Pyridoxal Kinase...
PNPO,
PMP->P5P 
(Impaired)
PNPO,...
Riboflavin
(Insufficiency)
Riboflavin...
TCA Cycle
(Impaired)
TCA Cycle...
11-HSDB1
(Promoted)
11-HSDB1...
11-HSDB2
(Impaired)
11-HSDB2...
Cortisol (Promoted),
Cortisone (Decreased)
Cortisol (Promoted),...
PNMT (Promoted)
PNMT (Promoted)
Gluconeogenesis (Promoted)
Gluconeogenesis (Pro...
Epinephrine (Promoted)
Epinephrine (Promote...
Serum Glucose Increased,
Glycogen Decreased
Serum Glucose Increa...
Pyridoxal
(Insufficiency)
(Rare - usually high)
Pyridoxal...
Pyridoxine / Pyridoxamine
(Insufficiency)
Pyridoxine / Pyridox...
Insomnia
Insomnia
Testosterone (Male)
Estradiol (Female)
(Insufficiency)
Testosterone (Male)...
Pseudo-Cushings
Pseudo-Cushings
Dopamine Beta Hydoxylase
(Impaired)
Dopamine Beta Hydoxy...
Copper
(Insufficiency)
Copper...
Vitamin C (Insufficiency)
Vitamin C (Insuffici...
CuZnSOD
(Impaired)
CuZnSOD...
GI and Renal (Re-)absorption (Insufficiency)
GI and Renal (Re-)ab...
Tryptophan
(Insufficiency)
Tryptophan...
Niacin
(Insufficiency)
Niacin...
(Re-)activated
HHV, HIV, HPV
(Re-)activated...
FMN
(Insufficiency)
FMN...
NAD+ (Insufficiency)
NADH->NADPH
(Insufficiency)
NAD+ (Insufficiency)...
Insufficient
Metabolic Activity, Exertion
Insufficient...
Manganese
(Insufficiency)
Manganese...
Selenium
(Insufficiency)
Selenium...
MnSOD
(Impaired)
MnSOD...
Glutathione Peroxidase
(Impaired)
Glutathione Peroxida...
BH4
(Insufficiency)
BH4...
Dopamine (Insufficiency)
Dopamine (Insufficie...
HIF-1a
Stabilised
HIF-1a...
CYP11B2
(Impaired)
CYP11B2...
Tachycardia,
Anxiety
Tachycardia,...
CYP21A2
(Impaired)
CYP21A2...
CYP11B1
(Impaired)
CYP11B1...
Aldosterone (Insufficiency)
Aldosterone (Insuffi...
Complex I
Glutamate catabolism (Inhibited)
Complex I...
NRF2
NRF2
Pathogen, Responsive to IFN-alpha cascade
Pathogen, Responsive...
Iodine
(Insufficiency)
Iodine...
IMMUNE ACTIVITY
IMMUNE ACTIVITY
OUTCOMES
OUTCOMES
NUTRIENT HOMEOSTASIS
NUTRIENT HOMEOSTASIS
IFN-alpha
(Promoted)
IFN-alpha...
Renal Dysfunction
Renal Dysfunction
Histamine
Intolerance
Histamine...
Silicon
(Insufficiency)
Silicon...
Hypoxia
(Promoted)
Hypoxia...
Thrombosis, Rouleaux
(Promoted)
Thrombosis, Rouleaux...
SARS-CoV-2
Spike Protein
SARS-CoV-2...
Complex II / FADH2:FAD Redox
(Impaired)
Complex II / FADH2:F...
FADS
(FMN -> FAD)
(Promoted)
FADS...
FAD
(Insufficiency)
FAD...
ICL Expressing Pathogen, LPS Producing Pathogen 
ICL Expressing Patho...
Itaconate
(Promoted)
Itaconate...
Iron
(Insufficiency)
Iron...
MMUT
(Impaired)
MMUT...
Catabolic Pathways
(Impaired)
Catabolic Pathways...
H2O2
H2O2
Molybdenum
(Insufficiency)
Molybdenum...
Temperature
Increase, Exercise
Temperature...
GABA
(Insufficiency)
GABA...
Increased Cholesterols, LDH, GDH, CYP2D6, Reversed MTHFR ..
Increased Cholestero...
Dysregulated NOS, Blood Volume, Temperature
Dysregulated NOS, Bl...
TNF-a, IL-1b, IL-6,
IL-10, IL-22 ->
Hepcidin (Promoted)
TNF-a, IL-1b, IL-6,...
DMT-1, Ferroportin
(Impaired)
DMT-1, Ferroportin...
Arginase
(Impaired)
Arginase...
Uncoupled Nitric Oxide Synthase (Promoted)
Uncoupled Nitric Oxi...
Ethanol / Acetaldehyde,
ALDH inhibition
Ethanol / Acetaldehy...
Aspergillus, Candida, Yeast, E.coli, Klebsiella, Streptococcus, Staphylococcus [..]
Aspergillus, Candida, Yeast, E.coli, Klebsiella, Streptococcus, Staphylococ...
CYP2D6,
Renal Dopamine
CYP2D6,...
Sodium Excretion
Sodium Excretion
NLRP3
NLRP3
"Disulfiram-effect"
"Disulfiram-effect"
NADP Transhydrogenase (Promoted)
NADP Transhydrogenas...
Mucosal Tissue Damage (Promoted)
Mucosal Tissue Damag...
Phosphatidyserine (Insufficiency)
Phosphatidyserine (I...
PSAT1
(Impaired)
PSAT1...
PHGDH
(Impaired)
PHGDH...
TGF-β1, sIgA (Promoted)
TGF-β1, sIgA (Promote...
ATPase
Insufficiency, Post Exertional Malaise
ATPase...
Carbohydrates / Glucose / Glycogen
(Insufficiency)
Carbohydrates / Gluc...
Biotin
(Insufficiency)
Biotin...
hEDS Metabolism, Impaired Collagen Synthesis
hEDS Metabolism, Imp...
.
.
Viewer does not support full SVG 1.1
22(R)-OH
Cholesterol
22(R)-OH...
Pregnenolone
Pregnenolone
17-OH Pregnenolone
17-OH Pregnenolone
DHEA
DHEA
Androstenediol
Androstenediol
Progesterone
(Decreased)
Progesterone...
17-OH Progesterone
(Decreased)
17-OH Progesterone...
Androstenedione
(Decreased)
Androstenedione...
Testosterone
(Decreased)
Testosterone...
DHT
(Decreased)
DHT...
11-Deoxycorticosterone
(Decreased)
11-Deoxycorticostero...
11-Deoxycortisol
(Decreased)
11-Deoxycortisol...
Estrone
(Decreased)
Estrone...
Estradiol
(Promoted)
Estradiol...
Corticosterone
(Decreased)
Corticosterone...
Cortisol
(Promoted)
Cortisol...
Cortisone
(Decreased)
Cortisone...
STAR,
+ Mg2+
STAR,...
CYP17A1 + Heme
CYP17A...
HSD17B1 + B
HSD17B1 + B
HSD17B2,4 + B
HSD17B2,4 + B
HSD17B2 + B
HSD17B2 + B
HSD17B1,3 + B
HSD17B1,3 + B
HSD17B2,4 + B
HSD17B2,4 + B
HSD17B1 + B
HSD17B1 + B
HSD11B2
HSD11B2
HSD11B1
HSD11B1
HSD3B1,2
+ K+, Cl-, B
HSD3B1,2...
CYP21A1,2
CYP21A...
CYP21A1
CYP21A1
CYP19A1
CYP19A1
CYP19A1
CYP19A1
CYP11A1 + Heme
CYP11A1 +...
Adrenodoxin
(red.)
, O2
Adrenodoxin...
Pregnenolone
Sulfate
Pregnenolone...
5alpha
Dihydroprogesterone
(Decreased)
5alpha...
5a -Dehydro Deoxycorticosterone
(Decreased)
5a -Dehydro Deoxycor...
Allopregnanolone
(Decreased)
Allopregnanolone...
Tetrahydro Deoxycorticosterone
(Decreased)
Tetrahydro Deoxycort...
SRD5A1,2 + Zn2+
SRD5A1,2 + Zn2+
AKR1C2
AKR1C2
AKR1C4
AKR1C4
AKR1C3
AKR1C3
DHEA Sulfate
DHEA Sulfate
STS
STS
STS
STS
SULT2A1
SULT2B1
SULT2A...
SULT2A1
SULT2A1
Cholesterol
Cholesterol
20alpha,22(R)-Dihydroxycholesterol
20alpha,22(R)-Dihydr...
CYP11A1 + Heme
CYP11A1 +...
NADP, FADH2
NADP, FADH2
NADPH,
H+
NADPH,...
NADP
NADP
Adrenodoxin
Adrenodoxin
Adrenodoxin
(red.)
Adrenodoxin...
ADR
ADR
NADPH, H+, FAD
NADPH, H+, FAD
CYP11A1 + Heme
CYP11A1 +...
CYP11A1 + Heme
CYP11A1 +...
Adrenodoxin
(red.)
, O2
Adrenodoxin...
Adrenodoxin
(red.)
, O2
Adrenodoxin...
NADP
NADP
NADP
NADP
NADP
NADP
NADPH,
H+
NADPH,...
NADPH,
H+
NADPH,...
NADPH,
H+
NADPH,...
Aldosterone
(Decreased)
Aldosterone...
CYP11B2
+ Heme
CYP11B2...
NADPH,
H+
NADPH,...
NADP
NADP
CYP17A1 + Heme
CYP17A1 + H...
CYP17A1 + Heme
CYP17A1 +...
CYP17A1 + Heme
CYP17A1 +...
O2, 2[H+], 2e
O2, 2[H+], 2e
H2O
H2O
O2, 2[H+], 2e
O2, 2[H+], 2e
O2, 2[H+], 2e
O2, 2[H+], 2e
O2, 2[H+], 2e
O2, 2[H+], 2e
H2O
H2O
H2O
H2O
H2O
H2O
CYP11A1 + Heme
CYP11A1 +...
Adrenodoxin
(red.)
, O2
Adrenodoxin...
Adrenodoxin
(red.)
, O2
Adrenodoxin...
NADPH,
H+
NADPH,...
NADP
NADP
NAD+
NAD+
NADH
NADH
NADPH,
H+
NADPH,...
NADP
NADP
NADPH,
H+
NADPH,...
NADP
NADP
NADPH,
H+
NADPH,...
NADP
NADP
NADPH,
H+
NADPH,...
NADP
NADP
NADPH,
H+
NADPH,...
NADP
NADP
NADPH,
H+
NADPH,...
NADP
NADP
NAD+,
Mg2+, Zn2+
NAD+,...
NADH
NADH
HSD3B1,2
+ K+, Cl-, B
HSD3B1,2...
HSD3B1,2
+ K+, Cl-, B
HSD3B1,2...
HSD3B1,2
+ K+, Cl-. B
HSD3B1,2...
NAD+,
Mg2+, Zn2+
NAD+,...
NAD+,
Mg2+, Zn2+
NAD+,...
NAD+,
Mg2+, Zn2+
NAD+,...
NADH
NADH
NADH
NADH
NADH
NADH
NADPH, H+, O2
NADPH,...
NADP, H2O
NADP,...
NADPH, H+, O2
NADPH,...
NADP, H2O
NADP,...
NADP, 2 [H2O]
NADP, 2...
NADP, 2 [H2O]
NADP, 2...
NADPH, 3 [O2], H+
NADPH,...
NADPH, 3 [O2], H+
NADPH,...
TSPO
TSPO
Cholesterol
Cholesterol
ATP, Mg2+
ATP, Mg2+
ADP, Pi
ADP, Pi
Figure 4.
Figure 4.
Pathway Diagram: The role of IFN-gamma in hormonal dysregulation.
Pathway Diagram: The role of IFN-gamma in hormonal dysregulation.
Author: Joshua Leisk, [DRAFT / INCOMPLETE - may contain errors]
Author: Joshua Leisk, [DRAFT / INCOMPLETE - may contain errors]
ME/CFS: Correcting Chronic Mitochondrial Dysfunction
ME/CFS: Correcting Chronic Mitochondrial Dysfunction
v0.41
v0.41
GnRH
(Downregulated)
GnRH...
LH
(Downregulated)
LH...
Connector Key:
Promoted

Inhibited
Connector Key:...
Gonadal Synthesis
Gonada...
Isocapro-
aldehyde
Isocapro-...
Females
Females
Males
Males
Females
Females
With insufficient NAD+ / elevated NADH and / or insufficiency of Mg2+ / Zn2+ / K+ / Cl-,
HSD3B1,2 reactions have decreased activity.


Low activity / NADPH insufficiency downregulates the entire pathway, reverses HSD17B1,2,3,4 and AKR1C2,3,4. Exercise / r
esistance training promotes IFN-gamma. IFN-gamma promotes NADPH elevation.

Cortisol:cortisone senses low NAD+:elevated NADH, with elevated NADPH:low NADP. Cortisol release is triggered by limbic system response and/or low phosphatidylserine -  sensing [low glucose / glycogen, low NAD+:elevated NADH | low P5P].
Cortisol promotes catabolic pathways and inhibits IFN-gamma, glycogen synthase, negatively regulating the IFN-gamma alterations.

The primary sex hormone (PSH) senses elevated NAD+:low NADH, with elevated NADPH:low NADP.

PSH inhibits cortisol, promoting IFN-gamma and glycogen synthase. PSH promotes anaplerosis to the TCA cycle at α-KG and promotes creatine synthesis via AGAT. Creatine promotes GLUT4 and glucose uptake. 

These combined alterations increase flux through the TCA cycle, eventually converting nitrogen metabolites such as glutamate and glutamine into glycogen, enhancing glycogen storage and IFN-gamma activity.

Dietary input and exertion insufficiency dysregulates hormones, glycogen levels and IFN-gamma activity.     
With insufficient NAD+ / elevated NADH and / or insufficiency of Mg2+ / Zn2+ / K+ / Cl-,...
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
ACTH
Corticotropin-Releasing Hormone
Corticotropin-Releas...
Adrenocorticotropic Hormone (ACTH)
Adrenocorticotropic...
Phosphatidylserine
Phosphatidylserine
Low
Blood
Voume
Low...
Angiotensin I
Angiotensin I
Angiotensin II
Angiotensin II
Renin
(Kidneys)
Renin...
Angiotensinogen
(Liver)
Angiotensinogen...
ACE
(Lungs)
ACE...
ACTH
ACTH
Anxiety / Stress (Limbic System)
Anxiety / Stress (Li...
Glucose / Glycogen
->
3-Phosphoglycerate
Glucose / Glycogen...
3-PHP
3-PHP
3-Pser
3-Pser
NAD+
NAD+
NADH
NADH
PHGDH
PHGDH
PSAT1
PSAT1
PSS
PSS
Glut, P5P
Glut, P5P
α-KG, PMP
α-KG, PMP
CTP
CTP
CDP
CDP
TGF-β1
TGF-β1
Tissue
Damage
Tissue...
Serum
Glucose
Serum...
GLUT4
GLUT4
Creatine
Creatine
PSH
PSH
TNF-α
TNF-α
IFN-gamma
(Inhibited)
IFN-gamma...
SRD5A1,2 + Zn2+
SRD5A1,2 + Zn2+
SRD5A2 + Zn2+
SRD5A2 + Zn2+
B
B
B
B
B
B
F
F
F
F
F
F
F
F
F
F
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[Gut | Oral | Other] Microbiome
Dysbiosis,
Biofilm Formation
[Gut | Oral | Other]...
Acetaldehyde
Excess
Acetaldehyde...
Epithelial
Damage and 
Inflammation
Epithelial...
Invasive
Microbiome
Dysbiosis
Invasive...
(Dysregulated)
IFN-gamma
Innate Immune
Response
(Dysregulated)...
"ME/CFS"
Metabolism / Symptoms
"ME/CFS"...
Antibiotics, (Vertical) Microbiome
Diversity Loss
Antibiotics, (Vertic...
Industrialised
Food Production.
Cooking. Hygiene.
Industrialised...
Mycotoxins,
Endotoxins
Mycotoxins,...
Silicon Depletion
as Si-Acetaldehyde
Adduct
Silicon Depletion...
Magnesium
Insufficiency
Magnesium...
Collagen
Synthesis
Impairment
Collagen...
Dietary
Restrictions
Dietary...
Hepcidin Increase
DMT-1, Ferroportin
Blockade
Hepcidin Increase...
Lytic Reactivation
of Latent HHV
via HIF-1α
Lytic Reactivation...
Postural Decline
Thoracic Duct Blockage
Postural Decline...
Lymphatic
Flow
Insufficiency
Lymphatic...
IFN-alpha Triggering Antigens
IFN-alpha Triggering...
Figure 5.
Figure 5.
Pathway Diagram: Simplified overview of the pathophysiology for ME/CFS, etc.
Pathway Diagram: Simplified overview of the pathophysiology for ME/CFS, etc.
Authors: Joshua Leisk, Aline Noçon ©2023, [DRAFT / INCOMPLETE - may contain errors]
Authors: Joshua Leisk, Aline Noçon ©2023, [DRAFT / INCOMPLETE - may contain errors]
ME/CFS: Correcting Chronic Mitochondrial Dysfunction
ME/CFS: Correcting Chronic Mitochondrial Dysfunction
v0.6
v0.6
Reduced
Activity Levels
Reduced...
Low NAD+, ALDH inhibition
Low NAD+, ALDH inhibition
Connector Key:
Promoted

Inhibited
Connector Key:...
ALDH inhibition
ALDH inhibition
Low Bifido, Lacto.
High Candida, Strep,
Staph, Aspergillus  [..]
Low Bifido, Lacto....
Low Fe
Low Fe
Low C, O2
Low C, O2
"Other Catalyst" -
SSRIs,
Finasteride, etc
"Other Catalyst" -...
"Other Catalyst" -
Accutane
"Other Catalyst" -...
ALDH inhibition
ALDH inhibition
Cortisol↑
Cortisol↑
TGF-β1↑ → P5P↓ → Cortisol↑
TGF-β1↑ → P5P↓ → Cortisol↑
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Click my yellow
circle, also.
Now I'm visible!...
Now those two boxes are highlighted and
I'm visible. Click me!
Now those two boxes...
Click my
yellow circle!
Click my...
Last one, lets complete the loop.
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Last one, lets compl...
Instructions / Demo
Instructions / Demo
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