Mitochondria, Oxidative Stress, and Psychiatric Disorders: An Integrative Perspective on Brain Bioenergetics

Psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia are now recognized as complex systemic conditions in which mitochondrial dysfunction and oxidative stress are key contributors to their pathophysiology. Mitochondria, beyond their role in ATP synthesis, are critical for calcium regulation, immune responses, and apoptosis, and their impairment affects brain function. This review examines current evidence from transcriptomics, metabolomics, neuroimaging, and preclinical studies, which consistently show disruptions in oxidative phosphorylation, mitochondrial fragmentation, altered mitochondrial DNA, and heightened inflammatory activity across these disorders. We integrate recent advances with the understanding of mitochondrial bioenergetics in the brain, the contribution of redox imbalance to neural dysfunction, the crosstalk between mitochondria and immune mechanisms, and the relevance of these processes to clinical symptoms. Furthermore, we highlight the promise of bioenergetic biomarkers and emerging interventions targeting mitochondrial pathways, including antioxidants, AMPK-SIRT1-PGC-1α axis modulators, physical exercise, and mitoprotective agents. Peripheral metabolic signatures and neuroimaging modalities are also discussed as tools for diagnostic refinement and individualized therapeutic approaches. These insights underscore the centrality of mitochondrial health in psychiatric disease and support the development of precision psychiatry grounded in metabolic phenotyping.