Sex-specific mitochondrial alterations in cognitively unimpaired older depressed individuals

Major depressive disorder (MDD) is a leading cause of disability worldwide, and depression in older adults is an increasingly urgent public health concern. While psychosocial contributors to late-life depression have been extensively studied, the underlying biochemical mechanisms remain less well understood. Mitochondria, critical for neuronal energy production, function, and survival, have been implicated in depression, and mitochondrial alterations have also been linked to changes in sex hormone levels. This is a secondary analysis of an observational study of cognitively unimpaired older adults with and without MDD (N = 112) who were followed for three years. We analyzed the baseline data of an observational study to examine the relationship between depression status and mitochondrial function, using plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) and mitochondrial DNA encapsulated in extracellular vesicles (EV-mtDNA). We also examined the association between mitochondrial function and biological sex as well as interactions with depression status. Across all participants, we observed moderately strong correlations (r = 0.42-0.53) between plasma levels of ccf-mtDNA and EV-mtDNA. Group-level analyses showed elevated levels of both EV-mtDNA and ccf-mtDNA in the depressed group, with depression severity positively associated with both measures in a sex-specific manner. Importantly, older depressed females exhibited higher EV-mtDNA levels compared to older depressed males, while older depressed males showed higher ccf-mtDNA levels compared to their female counterparts. These findings suggest that mitochondrial alterations in depression may be shaped by sex-specific biological pathways in the aging population.