Function of intramitochondrial melatonin and its association with Warburg metabolism.
Level 5 - mechanism / opinion, no new human data
Narrative review and mechanistic hypothesis paper without primary human clinical data.
PubMed 40122433 · doi:10.1016/j.cellsig.2025.111754
What was done
This is a narrative review and mechanistic synthesis examining the relationship between intramitochondrial melatonin synthesis, mitochondrial reactive oxygen species (ROS), and Warburg metabolism (aerobic glycolysis) in cancer cells.
What was found
The abstract presents mechanistic models without reporting quantitative experimental data. It outlines that inhibition of the pyruvate dehydrogenase (PDH) complex in Warburg-metabolizing cancer cells reduces acetyl-CoA, impairing intramitochondrial melatonin synthesis. The resulting melatonin deficit allows mitochondrial ROS to rise, which the authors propose activates the HIF-1α/PDK axis to maintain PDH inhibition and cancer proliferation. The authors describe how melatonin exposure reportedly counteracts this state by clearing mitochondrial ROS, inhibiting HIF-1α, and upregulating the SIRT3/FOXO/PDH axis to restore pyruvate oxidation and acetyl-CoA production.
Why it matters
The review outlines a biochemical rationale for how mitochondrial melatonin deficiency may sustain the metabolic shifts characteristic of aerobic glycolysis, proposing melatonin supplementation as a potential approach to target cancer cell metabolism.
Limits
The paper is a narrative review presenting theoretical and mechanistic hypotheses rather than original empirical human data. The abstract provides no quantitative effect sizes, statistical comparisons, or clinical validation.
Cited by
- supports Melatonin is synthesized directly inside human mitochondria.