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REVIEW ARTICLE

Nitrosative/oxidative stress, mitochondrial dysfunction, and redox balance in the mechanisms of neurodegenerative pathology and aging

Nina P. Kanunnikova1* ,  Andrey G. Moiseenok2
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1 Department of Technology, Physiology and Hygiene of Nutrition, Faculty of Biology and Ecology, Yanka Kupala State University of Grodno, Grodno, Belarus
2 Vitaminology and Nutraceutical Department, Institute of Biochemistry of Biologically Active Substances, National Academy of Sciences of Belarus, Grodno, Belarus
Advanced Neurology, 025100021 https://doi.org/10.36922/AN025100021
Received: 7 March 2025 | Revised: 9 June 2025 | Accepted: 9 June 2025 | Published online: 24 June 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Unraveling the complex roles of oxidation products – including reactive oxygen species, reactive nitrogen species, reactive sulfur species (RSS), metalloproteins, and iron–sulfur (Fe–S) clusters – which are integrated through the reactive species interactome (RSI), remains a key challenge in neurochemistry and neuropharmacology. These reactive species strongly influence energy metabolism and redox homeostasis in the brain, particularly during neurodegeneration. This review highlights the impact of nitrosative/oxidative stress, focusing on early events in neurodegeneration: Reduced tricarboxylic acid (TCA) cycle activity, a shift toward succinate utilization, glutamate accumulation, and redox imbalance. The resulting peroxynitrite anion impairs the mitochondrial respiratory chain complex I and the antiradical defense system. A fall in glutathione (GSH) levels and redox potential promotes an imbalance in redox couples, iron-driven Fenton reactions, and impaired Fe–S cluster biogenesis, thereby uncoupling oxidative phosphorylation and initiating redox-driven neurodegeneration. The intramitochondrial localization of the electron transport chain, Fe–S cluster biogenesis, TCA cycle enzymes, and heme biosynthesis raises questions about their regulation by nutritional and aging factors, the dichotomy of iron utilization in Fe–S clusters and heme, the role of succinyl-coenzyme A (CoA) in heme biosynthesis and succinate-driven phosphorylation, and the relationship between CoA metabolism and intraneuronal iron delivery. Addressing these issues offers the potential to stabilize energy metabolism and modulate RSI generation, where providing mitochondria with a continuous supply of reduced components and maintaining a negative redox potential support the neuroprotective actions of selected metabolic therapy agents. These include CoA biosynthesis pre-cursors with antioxidant and anti-inflammatory properties and the ability to enhance GSH biosynthesis. Progress toward effective neuroprotection in both neuropathology and aging may require an integrated strategy to modulate RSI and RSSs effects, prevent metalloproteome imbalance, and preserve the energy-producing capacity of neural structures.

Keywords
Coenzyme A
Energy production
Glutathione system
Neurodegeneration
Redox balance
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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