Early Life Stress Induces Brain Mitochondrial Dynamics Changes and Sex‐Specific Adverse Effects in Adulthood

Early life stress exposure exerts detrimental effects in adulthood and is a risk factor for psychiatric disorders. Studies addressing the molecular mechanisms of early life stress have primarily focused on hormones and stress circuits. However, little is known on how mitochondria and mitochondrial dynamics (i.e., the orchestration of mitochondrial fission, fusion, mitophagy, and biogenesis) modulate early life stress responses. Here, we used a maternal separation with early weaning (MSEW) paradigm to investigate the behavioral and molecular early life stress-elicited effects in male and female C57BL/6 mice in adulthood. We first applied a behavioral test battery to assess MSEW-driven, anxiety-related and stress-coping alterations. We then looked for MSEW-induced, mitochondria-centered changes in cingulate cortex, hippocampus and cerebellum, as well as in plasma by combining protein, mRNA, mitochondrial DNA copy number (mtDNAcn) and metabolomics analyses. We found that MSEW mice are more anxious, show decreased antioxidant capacity in the cingulate cortex and have higher mRNA levels of the fission regulator Fis1 and the mitophagy activator Pink1 in the hippocampus, indicating a shift towards mitochondrial degradation. Hippocampal mRNA level alterations of apoptotic markers further suggest an MSEW-driven activation of apoptosis accompanied by a dysregulation of purine catabolism in the cerebellum in MSEW mice. Sex-specific analysis revealed distinct MSEW-induced changes in male and female mice at the molecular level. Our work reveals a previously unexplored role of mitochondrial dynamics in regulating early life stress effects and highlights a mitochondria-centered dysregulation as a persistent outcome of early life stress in adulthood.