Kynurenines and Mitochondrial Disturbances in Multiple Sclerosis
Abstract
:1. Introduction
2. Overview of the Kynurenine Pathway
2.1. Tryptophan Metabolism and Kynurenine Pathway
2.2. Key Enzymes and Metabolites
3. Roles of the Kynurenine Pathway in MS Pathophysiology
3.1. Pathogenic Roles of Individual KP Metabolites in MS
3.1.1. Quinolinic Acid (QUIN)
- 1.
- Excitotoxicity: QUIN acts as an NMDA receptor agonist, directly triggering excitotoxicity in neurons and oligodendrocytes, a process known as endogenous excitotoxicity [14]. Pathologically elevated QUIN levels, reaching micromolar concentrations within MS lesions, excessively activate neuronal NMDA receptors. QUIN-induced NMDA receptor activation triggers sustained neuronal depolarization and calcium overload, causing excitotoxic injury and contributing directly to axonal transections observed in acute MS lesions. This calcium overload initiates detrimental cascades, including the activation of calpains and caspases, generation of reactive nitrogen and oxygen species, mitochondrial dysfunction, and ultimately neuronal apoptosis or necrosis [9,15,16]. Because QUIN selectively overstimulates the NMDA receptor subunits NR2A/NR2B, neurons in the cortex and spinal cord that abundantly express these subunits are particularly vulnerable to excitotoxic damage. This selective susceptibility may explain the pronounced neuronal degeneration observed in MS lesions [9,10,15,17]. As a direct consequence, pharmacological blockade of NMDA receptor activation with specific antagonists effectively prevents QUIN-induced neuronal death, providing strong evidence that excitotoxicity is the primary mechanism underlying QUIN-mediated neurodegeneration [9,16].
- 2.
- Glutamate dysregulation: QUIN promotes excessive neuronal glutamate release and inhibits astrocytic glutamate uptake, specifically by impairing glutamate transporters and glutamine synthetase [19,20]. This perturbation leads to elevated ambient glutamate levels, creating an excitotoxic environment detrimental to oligodendrocytes and neurons. The resulting glutamate excess in MS white matter directly correlates with oligodendrocyte death and subsequent demyelination [21,22,23].
- 3.
- Oxidative damage: QUIN acts as a potent pro-oxidant, catalysing the formation of hydroxyl radicals through metal chelation (e.g., Fe2+) and subsequent Fenton reactions [12]. By interacting synergistically with reactive oxygen species in the mitochondria, QUIN exacerbates lipid peroxidation and cellular energy depletion [24,25,26]. Exposure to QUIN leads to the formation of toxic lipid peroxidation products such as malondialdehyde and 4-hydroxynonenal (4-HNE) in oligodendrocyte membranes, which directly contribute to myelin destruction [27,28]. In addition, QUIN induces inducible nitric oxide synthase (iNOS) in microglia, which increases peroxynitrite (ONOO-) formation, further exacerbating the oxidative DNA and protein damage observed in MS lesions [29,30].
- 4.
- Energy failure: Although QUIN normally serves as a precursor for NAD+ synthesis, excessive accumulation paradoxically leads to energy failure [31]. Intracellular QUIN inhibits mitochondrial respiratory complexes and induces opening of the mitochondrial permeability transition pore (PTP) by calcium overload [32,33]. It also consumes NAD+ in futile pathways if not effectively rescued to NAD+, thereby depleting cellular energy reserves [34].
- 5.
- Cytoskeletal disruption: Recent evidence highlights the role of QUIN in aberrant phosphorylation of neuronal cytoskeletal proteins. QUIN induces hyperphosphorylation of tau proteins through phosphatase inhibition and NMDA receptor-mediated kinase activation, leading to microtubule destabilisation, aggregate formation, impaired axonal transport, and neuronal dysfunction. Abnormal tau phosphorylation correlates strongly with axonal degeneration in MS lesions. QUIN also promotes neurofilament phosphorylation, further disrupting neuronal integrity and contributing to the characteristic axonal swelling seen in MS plaques [9].
3.1.2. Kynurenic Acid (KYNA)
3.1.3. 3-Hydroxykynurenine (3-HK)
3.1.4. Picolinic Acid (PIC)
3.2. Dysregulation of the KP in MS Disease States
4. Mitochondrial Dysfunction in MS
Role of KP Metabolites in Mitochondrial Dysfunction in MS
5. Pharmacological Modulation of the KP in MS
5.1. Introduction to Pharmacological Modulation
5.2. Laquinimod as a KP Modulator
5.3. Drug Repurposing for MS Treatment: Targeting KP and Mitochondria
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Metabolite | Primary Source | Main Actions in MS | Effect |
---|---|---|---|
Quinolinic acid (QUIN) | Activated microglia and macrophages |
| 🚨 Neurotoxic |
Kynurenic acid (KYNA) | Astrocytes |
| ✅ Neuroprotective |
3-Hydroxykynurenine (3-HK) | Microglial cells |
| 🚨 Neurotoxic |
Kynurenine (KYN) | IDO-expressing immune cells |
| ⚠ Context-dependent (Immune modulation, potentially harmful) |
Picolinic acid (PIC) | Derived from ACMSD-expressing cells (neurons, astrocytes, and macrophages) |
| ✅ Neuroprotective |
MS Phenotype | Key KP Metabolic Features | Clinical/Pathological Correlation | References |
---|---|---|---|
RRMS | Surges in KYN and QUIN during relapses; some compensatory increase in KYNA during recovery | Acute inflammatory relapses with partial remission | See review Fathi et al. [43] |
SPMS | Chronic elevation of QUIN, reduced KYNA, depleted TRP | Persistent neurodegeneration, fewer apparent relapses | [50] and see review Fathi et al. [43] |
PPMS | High QUIN and 3-HK from early stages, low KYNA | Continuous progression with minimal inflammatory bursts | [18] |
Drug | Original Use | Mechanism in MS Context | Clinical Evidence in MS |
---|---|---|---|
Ibudilast | Asthma (Japan) | PDE inhibition, ↓ microglial activation | Slow down the rate of brain atrophy [86]. Reduces slowly enlarging lesions in progressive MS [87] |
Riluzole | Amyotrophic lateral sclerosis (ALS) | ↓ Glutamate release, counters excitotoxicity | A pilot study of riluzole in progressive MS showed reduced cervical cord atrophy and fewer new brain T1 hypointense lesions [88], but another study in early RRMS or CIS found no reduction in atrophy rates [89]. |
Amiloride | Potassium-sparing diuretic | Blocks ASIC1, prevents Ca2+ overload in axons | A pilot study in individuals with progressive multiple sclerosis demonstrated a significant reduction in whole-brain atrophy [90]. |
Pirfenidone | Pulmonary fibrosis | Minimise demyelination by inhibiting the production and/or action of TNF-alpha | Pirfenidone may have a significant impact on clinical disability and bladder function in patients with SPMS [91]. |
Fluoxetine | Antidepressant (SSRI) | Anti-inflammatory in microglia, possible IDO suppression | In a small, inconclusive trial, fluoxetine was associated with modest but statistically non-significant improvements in some clinical progression markers [92]. |
N-acetyl cysteine | Acetaminophen-induced hepatotoxicity | Glutathione precursor with antioxidant properties | No large MS study; Decreased lipid peroxidation and improved anxiety symptoms in MS patients [93]. |
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Pukoli, D.; Vécsei, L. Kynurenines and Mitochondrial Disturbances in Multiple Sclerosis. Int. J. Mol. Sci. 2025, 26, 5098. https://doi.org/10.3390/ijms26115098
Pukoli D, Vécsei L. Kynurenines and Mitochondrial Disturbances in Multiple Sclerosis. International Journal of Molecular Sciences. 2025; 26(11):5098. https://doi.org/10.3390/ijms26115098
Chicago/Turabian StylePukoli, Daniel, and László Vécsei. 2025. "Kynurenines and Mitochondrial Disturbances in Multiple Sclerosis" International Journal of Molecular Sciences 26, no. 11: 5098. https://doi.org/10.3390/ijms26115098
APA StylePukoli, D., & Vécsei, L. (2025). Kynurenines and Mitochondrial Disturbances in Multiple Sclerosis. International Journal of Molecular Sciences, 26(11), 5098. https://doi.org/10.3390/ijms26115098