Mitochondrial dysfunction in depression: Mechanisms and targeted therapy strategies

Major depressive disorder (MDD) is a severe mental illness with complex pathophysiology. Growing evidence highlights mitochondrial dysfunction as a key player in MDD, influencing neuroinflammation, synaptic plasticity, and energy metabolism. This review summarizes recent advances in understanding how mitochondrial defects—including mtDNA mutations, impaired mitophagy, disrupted dynamics, altered biogenesis, and metabolic dysregulation—contribute to depressive pathogenesis. We also evaluate mitochondria-targeted therapeutic strategies, encompassing both pharmacological agents (e.g., antioxidants, CoQ10, NAD+ precursors, SSRIs, and natural compounds) and non-pharmacological interventions (e.g., exercise, ketogenic diet, photobiomodulation, and electroacupuncture). Importantly, we emphasize the interplay between mitochondrial processes and the need to balance anabolic and catabolic functions. While preclinical results are promising, further clinical translation is essential. This review underscores mitochondrial health as a central theme in MDD research and therapy development.