Melatonin Modulation of Oxidative Stress Responses

Melatonin, an endogenously produced indoleamine, exerts a multifaceted role in the control of oxidative stress. Acting both through high-affinity receptors and as a direct free-radical scavenger, it neutralises reactive oxygen and nitrogen species while upregulating key antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. At the organelle level, melatonin accumulates in mitochondria, where it inhibits opening of the mitochondrial permeability transition pore, stabilises membrane potential, activates uncoupling proteins and promotes biogenesis via the AMPK-PGC-1α-SIRT3 signalling axis. This mitochondrial targeting preserves ATP production under hypoxic or metabolic stress and limits lipid peroxidation. In parallel, melatonin synchronises circadian rhythms of antioxidant defences, coordinating cellular redox balance with environmental light–dark cycles. Such dual actions—systemic and organelle-specific—underpin its protective effects across a spectrum of oxidative pathologies, including ischaemia–reperfusion injury, neurodegeneration, metabolic disorders and age-related decline. Preclinical models consistently demonstrate attenuation of inflammation, preservation of mitochondrial function and reduction of oxidative damage, while early translational studies support its safety and potential as an adjuvant in cardiovascular and neurological therapies.

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Melatonin Modulation of Oxidative Stress Responses publication trend

The graph below shows the total number of articles in melatonin modulation of oxidative stress responses across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Highly reactive oxygen-containing molecules capable of damaging cellular components when in excess.

Oxidative stress: A state in which oxidant production overwhelms antioxidant defences, leading to molecular and cellular damage.

Ferroptosis: An iron-dependent form of regulated cell death characterised by accumulation of lipid peroxides.

Mitochondrial permeability transition pore (mPTP): A high-conductance channel whose opening collapses mitochondrial membrane potential and precipitates cell death.

AMPK-PGC-1α-SIRT3 axis: A signalling network that couples energy sensing to mitochondrial biogenesis and antioxidant enzyme regulation.

References

1. Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration. Molecular Neurodegeneration (2024).
2. Melatonin rescues cell respiration impaired by hypoxia/reoxygenation in aortic endothelial cells and affects the mitochondrial bioenergetics targeting the F1FO-ATPase. Redox Biology (2025).
3. Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism. Molecules (2015).
4. Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics. International Journal of Molecular Sciences (2016).
5. Mitochondria: Central Organelles for Melatonin′s Antioxidant and Anti-Aging Actions. Molecules (2018).
6. Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling. Scientific Reports (2017).