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  • Perspective
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Aerobic glycolysis in Schizophrenia: Developmental rescue or energetic breakdown?

Abstract

Aerobic glycolysis (AG) refers to the preferential use of glucose through glycolysis and not oxidative phosphorylation (OxPhos) despite the presence of oxygen. Originally described in cancer cells as the Warburg effect, AG is now recognized as a broader physiological mechanism extending beyond cancer biology. This process is less efficient than OxPhos in terms of ATP yield, but supports biosynthesis, neural plasticity, oxidative stress reduction, and synaptogenesis under metabolically demanding conditions. Building on this physiological role and current findings, we propose that in schizophrenia (SZ), AG remains elevated in adulthood, likely reflecting a compensatory response to reduced brain biomass and mitochondrial dysfunction. Neuroimaging, spectroscopy, and postmortem studies link the presence of AG in the brain to impaired OxPhos, reductive stress and defective neuron-glia coupling. Oligodendrocyte dysfunction and white matter damage also additionally compromise energy homeostasis and connectivity. Though AG supports repair, its persistent activation may destabilize synaptic structures and function. This Perspective proposes that AG in SZ represents a mismatch between developmental demands and adult metabolic function, compensatory in early stages but ultimately (mal)adaptive. Understanding when, where and why AG persists may reveal new entry points for restoring energetic balance in vulnerable brain circuits.

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Funding

F.D. and D.O. received research funding from the National Institutes of Health (R01MH114982 [Du/Ongur], P50MH115846 [Ongur], R01AG066670 [Du/Forester], and R01MH135093 [Du/Ongur]). V.-A.C. received funding from the Baszucki Group.

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OM, MSG, V-AC, FD, and DO contributed to the conception and intellectual development of the manuscript and drafted or revised the work for intellectual content. OM, MSG, and DO prepared the figures. All authors approved the final version and agree to be accountable for all aspects of the work.

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Correspondence to Dost Ongur.

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Memetoglu, O., Goyal, M.S., Chouinard, VA. et al. Aerobic glycolysis in Schizophrenia: Developmental rescue or energetic breakdown?. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03460-3

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