Placental mitochondrial DNA variants, copy number and telomere length alterations in relation to antenatal depressive symptoms.

Depressive symptoms during pregnancy are linked to adverse offspring outcomes, but the underlying biological mechanisms remain unclear. Evidence suggests that maternal stress may alter placental biology and function. We, therefore, examined whether placental telomere length (TL) and mitochondrial DNA alterations, including copy number and heteroplasmic burden, could be associated with antenatal depressive symptoms (ADS). Placental samples (n = 107) from the STRiDE pregnancy cohort were collected at birth. Participants were classified as ADS (n = 54) and controls (n = 53) based on PHQ-9 scores at 24-28 gestational weeks. Placental TL and mtDNA copy number (mtDNA-CN) were measured by qRT-PCR, and mitochondrial genome sequencing was performed using next generation sequencing. Placental TL (Median: 0.430 vs 0.440; p = 0.006) and mtDNA-CN (Median: 0.715 vs 0.990; p = 0.005) were significantly reduced in the ADS group compared to controls. Linear regression analyses showed that higher PHQ-9 scores were significantly associated with shorter placental TL (β = -0.012, p < 0.001) and lower placental mtDNA-CN (β = -0.072, p < 0.001) after adjusting for potential confounders. Mitochondrial genome analysis revealed a higher heteroplasmic burden, including four novel heteroplasmic variants and one deleterious mutation (m.7458G > A in MT-TS1) in ADS. In conclusion, lower placental TL and mtDNA-CN were associated with ADS, suggesting impaired mitochondrial and telomeric integrity. A higher heteroplasmic burden and the presence of a potentially deleterious variant in ADS suggest that mitochondrial genome instability could be mediated by ADS.