Amino Acid Neurotransmitter Dysfunction as a Central Driver of Mitochondrial Failure and Autonomic Instability in POTS, CFS/ME, Long COVID and Gulf War Syndrome

Dr Graham Exelby May 2025

Abstract

Amino acid neurotransmitter dysfunction—specifically involving glutamate, GABA, and aspartate—emerges as a central pathophysiological axis in POTS, ME/CFS, Long COVID, and Gulf War Syndrome.

This paper explores the convergence of excitotoxicity, mitochondrial failure, and autonomic instability as mediated by disruption of the glutamate-GABA-aspartate triad. Clinical observations and emerging biochemical profiles consistently reveal elevated extracellular glutamate, low GABA, and depleted aspartate across these syndromes, aligning with impaired baroreflex control, post-exertional malaise (PEM), and systemic energy failure.

Glutamate excess triggers NMDA receptor overactivation, mitochondrial calcium overload, and ROS generation. Aspartate depletion disrupts the malate-aspartate shuttle, impairing oxidative phosphorylation and ATP production in brainstem and autonomic centres. GABA deficits—exacerbated by mitochondrial dysfunction and gut dysbiosis—remove inhibitory control over sympathetic output, further destabilizing heart rate variability and vascular tone.

This triad sustains a bioenergetic and inflammatory feedback loop, intensifying central sensitization and fatigue.   The resulting metabolic bottleneck, particularly under exertional stress, explains the refractory nature of PEM and chronic dysautonomia.

We propose a therapeutic model targeting restoration of amino acid balance, including nicotinamide riboside (SIRT4 modulation), GABA supplementation, aspartate-magnesium co-therapy, and NMDA antagonists. These interventions aim to recalibrate the excitatory–inhibitory axis, enhance mitochondrial function, and reduce neuroinflammation.

By framing amino acid dysfunction as a core molecular driver of post-viral and neuroimmune dysautonomia, this work supports a paradigm shift toward mechanism-based intervention in these complex, overlapping conditions.

Introduction:

Glutamate, GABA, and Aspartate in Dysautonomia and Mitochondrial Dysfunction

Emerging evidence in post-viral syndromes such as POTS, CFS/ME, and Long COVID implicates dysregulation of key amino acid neurotransmitters as a central pathophysiological axis. Glutamate, GABA, and aspartate orchestrate a complex interplay between neuronal excitability, autonomic regulation, and mitochondrial bioenergetics. These neurotransmitters are deeply embedded in energy metabolism, neurovascular tone, and immune modulation. In dysautonomia, chronic excitotoxicity, mitochondrial failure, and neuroinflammation converge, producing the biochemical signature of elevated glutamate, reduced GABA, and depleted aspartate. This constellation perpetuates autonomic chaos, post-exertional malaise (PEM), and systemic energy collapse. This section explores the molecular and clinical implications of this amino acid triad, outlining its relevance to the pathogenesis and treatment of autonomic disorders.

Glutamate and Aspartate Dysfunction in Dysautonomia and PEM

Glutamate and aspartate are critical to synaptic signalling, mitochondrial ATP generation, and metabolic homeostasis. In POTS, CFS/ME, and Long COVID, patients often present with excess extracellular glutamate and low aspartate, a profile that disrupts mitochondrial function and exacerbates autonomic instability.

Excess glutamate overstimulates NMDA receptors, promoting intracellular calcium influx, mitochondrial overload, and excitotoxic stress.(Nguyen et al 2011(1)) Simultaneously, aspartate deficiency impairs the malate-aspartate shuttle (MAS), limiting NADH transfer and oxidative phosphorylation (OXPHOS). This hinders ATP production in autonomic centres such as the brainstem and spinal cord, compromising baroreflex sensitivity and vascular tone.(1) The downstream effect includes orthostatic intolerance, fatigue, and postural tachycardia.(1)(Hillen & Heine 2020 (2))

Post-exertional malaise (PEM) arises from this energetic vulnerability and metabolic bottleneck in post-exertional recovery.(Davis et al 2025 (3))   Aspartate is indispensable for ATP regeneration post-exertion. Its absence prolongs metabolic fatigue and intensifies PEM.  Mitochondrial carriers (AGC2) regulate aspartate transport for energy metabolism and myelin synthesis. Dysfunction here links to seizures, spasticity, and myelin deficits. (Hillen & Heine 2020 (2))

GABA deficiency arises from mitochondrial ATP shortages (limiting glutamate decarboxylase activity) and gut microbiome alterations (reduced GABA-producing Bacteroides.)   This removes inhibitory control over sympathetic output, worsening tachycardia and HRV instability.( Kaczmarski et al 2023 (4))(Sen et al 2016 (5))

Glutamate also amplifies central and peripheral neuroinflammation, especially in the brainstem and vagal nuclei. This triggers heightened pain sensitivity, cognitive dysfunction, and extended recovery periods.

Furthermore, mast cells and glial cells, under chronic inflammatory activation, fail to clear excess glutamate due to EAAT1/2 transporter downregulation.( Nguyen et al 2011(1))  Histamine and tryptase from mast cells also sensitize NMDA receptors, compounding neuroexcitotoxicity and mitochondrial injury. These findings underscore the role of glutamate/aspartate imbalance as a metabolic bottleneck in PEM pathogenesis.

GABA/Glutamate Imbalance and Mitochondrial Impairment

The GABA/glutamate axis serves as a neural and metabolic fulcrum. GABA inhibits sympathetic output and sustains vagal tone, whereas glutamate provides excitatory drive. In dysautonomia, this balance is disrupted—glutamate dominates, and GABA synthesis is impaired.  The GABA-glutamate imbalance disrupts the glutamine cycle in astrocytes, impairing energy recovery and neurotransmitter recycling. (Sen et al 2016 (5))

GABA production depends on glutamate decarboxylase (GAD) and mitochondrial ATP availability. Mitochondrial dysfunction hampers both, depleting GABA and enabling unchecked sympathetic activation. This promotes tachycardia, HRV instability, orthostatic intolerance, and gastrointestinal dysmotility.

Mitochondrial enzymes like α-ketoglutarate dehydrogenase (α-KGDH) are also compromised, reducing glutamate metabolism into α-ketoglutarate and diminishing TCA cycle flux. Oxidative stress further impairs mitochondrial enzymes, reinforcing the cycle of ATP depletion and excitotoxic stress. RAGE-inflammasome signalling, frequently activated in hypoxic and post-infectious states, amplifies glutamate-driven damage.

In PEM, the failure to mount a GABAergic inhibitory response post-exertion results in prolonged excitotoxicity, autonomic dysfunction, and metabolic collapse. EAAT dysfunction perpetuates glutamate accumulation, while impaired astrocyte metabolism interrupts the glutamate-glutamine cycle and energy recovery.

Therapeutic Targets: Restoring Amino Acid Balance

Several interventions may help restore homeostasis:

• Nicotinamide riboside (SIRT4 activation): Enhances mitochondrial glutamate oxidation.

• Liposomal GABA: Restores inhibitory tone and dampens excitotoxicity.(5)

• Aspartate + Magnesium: Revives MAS function and ATP generation.(2)

• Taurine and NAC: Promote EAAT-mediated glutamate clearance.(3)

• NMDA antagonists: Magnesium, memantine, ketamine protect against calcium-mediated mitochondrial stress.(1)

• 
  

By rebalancing the GABA/glutamate ratio, replenishing aspartate, and supporting mitochondrial metabolism, these agents may reduce PEM severity, stabilize autonomic output, and improve clinical outcomes.

Conclusion: Amino Acid Dysregulation as a Core Pathology in Dysautonomia

The glutamate-GABA-aspartate axis represents a central driver of the energetic, autonomic, and neuroimmune disturbances seen in POTS, Long COVID, and CFS/ME. Aspartate depletion cripples mitochondrial energy transfer, GABA deficiency removes inhibitory control over the sympathetic nervous system, and excess glutamate induces excitotoxicity, ROS generation, and neuroinflammation.

This integrated metabolic dysfunction explains the delayed, energy-depleted crashes of PEM and the persistent autonomic instability seen in dysautonomia syndromes. It also reveals a therapeutic frontier—targeting these amino acid imbalances offers a promising strategy to restore mitochondrial integrity and autonomic resilience.

By addressing the root molecular dysfunctions—rather than their downstream manifestations—clinicians may achieve more durable symptom relief and functional restoration in patients suffering from these debilitating conditions.

References:

1.     Nguyen D, Alavi MV, Kim KY, et al. A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics. Cell Death Dis. 2011;2(12):e240. Published 2011 Dec 8. doi:10.1038/cddis.2011.117

2.     Hillen AEJ, Heine VM. Glutamate Carrier Involvement in Mitochondrial Dysfunctioning in the Brain White Matter. Front Mol Biosci. 2020;7:151. Published 2020 Jul 21. doi:10.3389/fmolb.2020.00151

3.     Davis L, Higgs M, Snaith A, Lodge TA, Strong J, Espejo-Oltra JA, Kujawski S, Zalewski P, Pretorius E, Hoerger M, Morten KJ. Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia. Front Neurosci. 2025 Mar 10;19:1498981. doi: 10.3389/fnins.2025.1498981. PMID: 40129725; PMCID: PMC11931034.

4.     Kaczmarski P, Sochal M, Strzelecki D, Białasiewicz P, Gabryelska A. Influence of glutamatergic and GABAergic neurotransmission on obstructive sleep apnea. Front Neurosci. 2023 Jul 13;17:1213971. doi: 10.3389/fnins.2023.1213971. PMID: 37521710; PMCID: PMC10372424.

Sen S, Roy S, Bandyopadhyay G, Scott B, Xiao D, Ramadoss S, Mahata SK, Chaudhuri G. γ-Aminobutyric Acid Is Synthesized and Released by the Endothelium: Potential Implications. Circ Res. 2016 Aug 19;119(5):621-34. doi: 10.1161/CIRCRESAHA.116.308645. Epub 2016 Jun 28. PMID: 27354210