Long COVID and Autism Spectrum Disorder- a Shared Pathophysiology-

The Role of the Malate-Aspartate Shuttle, Inflammation and Hypoxia

Dr Graham Exelby June 2025

Abstract

Long COVID and Autism Spectrum Disorder (ASD) present with overlapping neurological symptoms, suggesting potential shared pathophysiological mechanisms. This paper explores the role of the malate-aspartate shuttle (MAS) dysfunction, amino acid imbalances, and the transition from TLR/cytokine-driven to RAGE/HIF-1a-driven pathology in Long COVID.

We propose that metabolic stress and redox imbalance, exacerbated by inflammation and hypoxia, form a common pathway linking these conditions. Lymphatic dysfunction and hypoxic byproducts in the extracellular matrix (ECM) further contribute to symptom persistence.  We propose that synergistic metabolic and immunomodulatory therapies—particularly telmisartan and nicotinamide—may reverse redox imbalance and RAGE–HIF-1α amplification, with potential benefits in both Long COVID and ASD.

This synthesis highlights potential therapeutic targets and underscores the need for further research into these complex disorders.

Introduction

Long COVID, characterized by persistent symptoms following SARS-CoV-2 infection, and Autism Spectrum Disorder (ASD), a neurodevelopmental condition, share neurological symptoms such as cognitive impairment and developmental delays. Recent research suggests that metabolic dysfunction, particularly involving the malate-aspartate shuttle (MAS), may underlie these symptoms.

In ASD, MAS deficiencies disrupt amino acid metabolism and redox balance, while in Long COVID, inflammation and hypoxia, mediated by RAGE and HIF-1a, may exacerbate similar metabolic stress. This paper synthesizes current evidence to elucidate these shared mechanisms, incorporating findings from lymphatic research and brainstem hypoxia.

The Malate-Aspartate Shuttle and Its Role in Neurological Function

The malate-aspartate shuttle (MAS) is a critical biochemical pathway that transfers reducing equivalents (NADH) from the cytosol to mitochondria, supporting oxidative phosphorylation and maintaining redox balance. It involves enzymes (MDH1, MDH2, GOT1, GOT2) and transporters (AGC1, AGC2) that facilitate the exchange of malate, aspartate, and glutamate. In the brain, the MAS is essential for energy production and neurotransmitter synthesis.

In ASD, deficiencies in MAS components, such as MDH1 and AGC1, are associated with neurodevelopmental disorders, including infantile epileptic encephalopathy and developmental delays. These deficiencies disrupt aspartate and glutamate metabolism, leading to neuronal dysfunction. For example, AGC1 deficiency reduces N-acetyl aspartate, impairing myelination and neuronal respiration.

Long COVID Pathophysiology: From Inflammation to Hypoxia

Long COVID involves a transition from an acute TLR/cytokine-driven inflammatory phase to a chronic state involving RAGE and HIF-1a. RAGE, a receptor for advanced glycation end products, amplifies inflammation by interacting with damage-associated molecular patterns (DAMPs) like HMGB1. HIF-1a, activated under hypoxic conditions, regulates genes involved in energy metabolism and angiogenesis, contributing to vascular and neurological symptoms.

Lymphatic research indicates that hypoxic byproducts accumulate in the ECM, contributing to post-exertional malaise (PEM). Brainstem hypoxia may further impair metabolic pathways, including the MAS, exacerbating neurological symptoms.

Shared Pathophysiology: Metabolic Stress and Redox Imbalance

The shared pathophysiology between Long COVID and ASD centres on metabolic stress and redox imbalance. In ASD, MAS dysfunction leads to elevated glutamate and glycerol-3-phosphate, disrupting neuronal energy production. In Long COVID, hypoxia and inflammation may similarly affect the MAS, as cells adapt to low oxygen by altering energy metabolism. This is supported by studies showing altered NAD+/NADH ratios in MAS-deficient cells.

Both conditions exhibit amino acid imbalances, particularly involving aspartate and glutamate, which are critical for MAS function and neurotransmission. In Long COVID, RAGE-driven inflammation and HIF-1a-mediated hypoxia may exacerbate these imbalances, leading to symptoms like brain fog that mirror ASD-related cognitive impairments.

Hypoxia-Driven Pathophysiology

Hypoxia plays a central role in the transition from early immune activation to chronic metabolic and neurovascular dysfunction in both Long COVID and ASD. Sustained or intermittent hypoxic stress—whether due to microvascular constriction, brainstem perfusion deficits, or mitochondrial impairment—stabilizes Hypoxia-Inducible Factor 1-alpha (HIF-1α), which in turn reprograms cellular metabolism toward glycolysis and suppresses oxidative phosphorylation. This not only reduces ATP output but also impairs the malate-aspartate shuttle (MAS) by disrupting NAD⁺/NADH balance, diminishing aspartate availability, and contributing to excitotoxicity via elevated glutamate.

Crucially, hypoxia-induced stabilization of HIF-1α also synergizes with Receptor for Advanced Glycation End Products (RAGE) activation. RAGE is triggered by endogenous damage signals such as HMGB1, S100 proteins, and AGEs—all of which accumulate under oxidative and hypoxic conditions. This RAGE–HIF-1α feedforward loop sustains chronic inflammation, endothelial dysfunction, and neuroimmune sensitization. In the brainstem and deep cortical areas, where collateral circulation is poor, this pathway can induce persistent autonomic dysregulation, cognitive fog, and sensorimotor abnormalities.

In ASD while overt hypoxia may not be as acute as in Long COVID, developmental hypoxia, impaired cerebral oxygen utilization, or mitochondrial hypometabolism can similarly activate HIF-1α and RAGE, contributing to impaired synaptic pruning, altered neurodevelopment, and central sensitization.

Notably, both conditions show shared downstream signatures, including elevated glutamate, low GABA, reduced aspartate, and redox imbalance—all of which may reflect a convergent hypoxia–RAGE–metabolic axis.

Lymphatic Dysfunction and Hypoxia

Lymphatic research in Long COVID by Ms Michelle Hill suggests that hypoxic byproducts in the ECM contribute to symptom persistence. This accumulation may reflect impaired clearance of metabolic waste, potentially including MAS-related byproducts. Brainstem hypoxia, a feature of Long COVID, could further disrupt MAS function, as the brain relies heavily on this shuttle for energy.

Therapeutic Implications

Therapeutic strategies targeting MAS dysfunction, neuroinflammation, and hypoxia show emerging promise. Initial management includes Nicotinamide Riboside (as a precursor to NAD⁺ and SIRT4 activation) combined with Magnesium Glycinate to support PDH complex function, mitochondrial redox balance, and neurotransmitter homeostasis. Taurine may be added based on amino acid profiling to support osmolyte balance and neuromodulation. Complex amino acid dysfunction may require targeted metabolic management developed by molecular biologist Dr Valerio Vittone.

Notably, the combination of telmisartan and nicotinamide appears particularly synergistic in clinical management of Long COVID.  Telmisartan, via AT1R blockade and PPAR-γ activation, mitigates hypoxia-induced HIF-1α stabilization and suppresses RAGE–NF-κB signalling in neurovascular tissues.

In parallel, nicotinamide riboside restores NAD⁺ levels, modulates SIRT1/SIRT4 activity, and stabilizes mitochondrial biogenesis and redox cycling—critical for the reactivation of the malate-aspartate shuttle.

This dual therapy may therefore correct redox imbalance, support glutamate–GABA recycling, and suppress the maladaptive inflammatory amplification loop seen in both ASD and Long COVID. Clinical observation suggests it is particularly effective when introduced during the subacute to early chronic phase, prior to irreversible neuroimmune and ECM toxicity.

In ASD, ketogenic diets have shown benefit by bypassing MAS blockages through enhanced β-oxidation and alternative substrate use, particularly in AGC1-deficient patients. This further validates the role of energy metabolism and redox correction as key therapeutic avenues.

In both disorders, therapies that target RAGE/HIF-1α, improve lymphatic clearance, and restore amino acid flux—especially of aspartate, GABA, and glutamate—may yield durable symptomatic improvement and restore neurocognitive performance.

Table: Clinical and Biochemical Characteristics of Malate-Aspartate Shuttle (MAS) Deficiencies

Disorder	Gene/Protein Affected	Clinical Phenotype	Biochemical Findings	Pathophysiological Insights
MDH1 Deficiency	MDH1 (cytosolic malate dehydrogenase)	Developmental delay, epilepsy	↑ Glutamate, ↑ Glycerol-3-phosphate, impaired cytosolic NADH shuttling	Redox imbalance and excitotoxicity; impaired MAS limits NADH delivery to mitochondria, exacerbating oxidative stress
AGC1 Deficiency	SLC25A12 (aspartate-glutamate carrier 1)	Infantile hypotonia, delayed myelination	↓ N-acetylaspartate, ↑ Myo-inositol, ↓ aspartate	Reduced NAA impairs oligodendrocyte function; cytosolic aspartate depletion affects neurotransmission and urea cycle efficiency
GOT2 Deficiency	GOT2 (mitochondrial glutamate-oxaloacetate transaminase)	Epileptic encephalopathy, movement disorder	↑ Lactate, ↓ Serine, impaired α-ketoglutarate flux	Mitochondrial MAS failure; increased anaerobic metabolism; secondary serine depletion impairs one-carbon metabolism
Functional MAS Impairment (Long COVID)	Secondary to RAGE/HIF-1α/inflammation	Brain fog, PEM, cognitive dysfunction, fatigue	↓ Aspartate, ↑ Glutamate, ↓ GABA, altered NAD⁺/NADH ratio	Hypoxia and inflammation inhibit MAS flux; impairs redox cycling and neurotransmitter clearance
Functional MAS Impairment (ASD)	Secondary to AGC1/MDH1/GOT2 variants or mitochondrial dysfunction	Developmental delay, sensory sensitivity, excitability	↓ Aspartate, ↑ Glutamate, ↓ GABA (often with normal lactate)	Early-life hypoxia or metabolic variants mimic MAS deficiency; contributes to altered synaptic transmission and neuroinflammation

Conclusion

Long COVID and ASD share a core pathophysiology driven by metabolic stress, amino acid imbalance, and neuroimmune sensitization, converging on MAS dysfunction. The shift from cytokine-driven inflammation to RAGE–HIF-1α–mediated cellular dysfunction underpins cognitive and developmental decline.

Targeted interventions that suppress RAGE signalling, restore NAD⁺ balance, and normalize aspartate and glutamate flux are now emerging as rational strategies. Among these, the combined use of telmisartan and nicotinamide appears especially promising for reversing hypoxia-driven brainstem and cortical impairment.

Lymphatic support therapies and amino acid modulation remain essential adjuncts. Further translational research is warranted to validate these approaches across clinical cohorts.

References

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• Van Karnebeek et al., 2019. GOT2 deficiency: expanding the phenotypic spectrum.

• Dahlin et al., 2015. The ketogenic diet compensates for AGC1 deficiency.

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• Li et al., 2020. Hypoxia, HIF-1α, and COVID-19: from pathogenic factors to therapeutic targets.

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• Broeks et al., 2023. The malate-aspartate shuttle is important for de novo serine biosynthesis.

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• Exelby, G. 2025. Long COVID Progression- the Transitioning of Cytokine Dysregulation to Cellular Suicide

• Exelby, G. 2025. Origin of Brainstem Hypoperfusion in POTS and Long COVID: A Dual-Gate Hypothesis Linking Mechanical and Molecular Initiation

• Exelby,G. 2025. Extracellular Matrix Toxicity and Post-Exertional Malaise

• Exelby,G., Hill, M., Calleja, D. Lymphatic Obstruction in POTS, CFS, and Long COVID: A Call for Integrated Therapeutic Approaches