Biological psychiatry global open science · 2025
Decreased Mitochondrial DNA Integrity and Elevated Inflammatory Markers in Late-Life Depression: A Longitudinal Study.
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Mendes-Silva Ana Paula, El-Ahmad Perla, Costa Ana Paula, Balbuena Lloyd Cenon, Nikolova Yuliya Stoycheva, Rajji Tarek, Kennedy James Lowery, Vieira Erica Leandro, Gonçalves Vanessa Faria, Diniz Breno Satler
Аннотация
BACKGROUND: Late-life depression (LLD) is a prevalent and severe mental disorder. The biological mechanisms underlying LLD are not fully understood, but increasing evidence suggests that mitochondria play a significant role. Impaired mitochondrial function leads to excessive production of reactive oxygen species and the release of circulating cell-free mitochondrial DNA (ccf-mtDNA). The ccf-mtDNA activates the toll-like receptor system, which triggers a systemic proinflammatory response. However, there is limited understanding of the impact of ccf-mtDNA integrity, such as deletions, on LLD pathological conditions.
METHODS: We included 90 older individuals (50 LLDs, 40 nondepressed healthy control participants [HCs]), with a subset of individuals followed up at 30 months (13 LLDs, 13 HCs). Plasma was separated from blood, and DNA was extracted. Mitochondrial genes MT-ND2 and MT-ND4 were targeted to evaluate ccf-mtDNA levels and deletion using real-time quantitative polymerase chain reaction. Plasma interleukins (ILs) 1β, 5, and 6 were quantified via multiplex immunoassay.
RESULTS: LLD was linked to increased ccf-mtDNA instability at baseline (deletion: F 88,1 = 7.105, p = .009; levels: F 88,1 = 6.885, p = .01), which was associated with more severe depressive symptoms and greater medical comorbidity burden. Longitudinal analysis revealed significant effects of diagnosis and time on ccf-mtDNA levels and the deletion rate. Additionally, higher deletion rates at baseline predicted IL-5 and IL-6 levels at 30 months (p adjusted = .13, p adjusted = .12, respectively).
CONCLUSIONS: Increased ccf-mtDNA instability may heighten vulnerability to emotional dysregulation and medical burden in individuals with LLD. Further research is needed to validate our findings and elucidate the mechanisms that connect mitochondrial instability and inflammation in LLD.
METHODS: We included 90 older individuals (50 LLDs, 40 nondepressed healthy control participants [HCs]), with a subset of individuals followed up at 30 months (13 LLDs, 13 HCs). Plasma was separated from blood, and DNA was extracted. Mitochondrial genes MT-ND2 and MT-ND4 were targeted to evaluate ccf-mtDNA levels and deletion using real-time quantitative polymerase chain reaction. Plasma interleukins (ILs) 1β, 5, and 6 were quantified via multiplex immunoassay.
RESULTS: LLD was linked to increased ccf-mtDNA instability at baseline (deletion: F 88,1 = 7.105, p = .009; levels: F 88,1 = 6.885, p = .01), which was associated with more severe depressive symptoms and greater medical comorbidity burden. Longitudinal analysis revealed significant effects of diagnosis and time on ccf-mtDNA levels and the deletion rate. Additionally, higher deletion rates at baseline predicted IL-5 and IL-6 levels at 30 months (p adjusted = .13, p adjusted = .12, respectively).
CONCLUSIONS: Increased ccf-mtDNA instability may heighten vulnerability to emotional dysregulation and medical burden in individuals with LLD. Further research is needed to validate our findings and elucidate the mechanisms that connect mitochondrial instability and inflammation in LLD.