Exosome-associated mitochondrial DNA in late-life depression: Implications for cognitive decline in older adults

Ana Paula Mendes-Silva; Yuliya S Nikolova; Tarek K Rajji; James L Kennedy; Breno S Diniz; Vanessa F Gonçalves; Erica L Vieira

doi:10.1016/j.jad.2024.06.092

Exosome-associated mitochondrial DNA in late-life depression: Implications for cognitive decline in older adults

J Affect Disord. 2024 Oct 1:362:217-224. doi: 10.1016/j.jad.2024.06.092. Epub 2024 Jun 28.

Authors

Ana Paula Mendes-Silva¹, Yuliya S Nikolova², Tarek K Rajji³, James L Kennedy⁴, Breno S Diniz⁵, Vanessa F Gonçalves⁴, Erica L Vieira⁶

Affiliations

¹ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada. Electronic address: ana-paula.silva@camh.ca.
² Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
³ Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁴ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁵ UConn Center on Aging & Department of Psychiatry, UConn School of Medicine, University of Connecticut Health Center, USA.
⁶ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.

PMID: 38945405
PMCID: PMC11316645 (available on 2025-10-01)
DOI: 10.1016/j.jad.2024.06.092

Abstract

Background: Disrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate cellular communication by transporting molecules, including mitochondrial DNA (EX-mtDNA), playing critical role in immunoregulation alongside tumor necrosis factor (TNF). Changes in EX-mtDNA are indicators of impaired mitochondrial function and might increase vulnerability to adverse health outcomes. Our study examined EX-mtDNA levels and integrity, exploring their associations with levels of TNF receptors I and II (TNFRI and TNFRII), and clinical outcomes in LLD.

Methods: Ninety older adults (50 LLD and 40 controls (HC)) participated in the study. Blood was collected and exosomes were isolated using size-exclusion chromatography. DNA was extracted and EX-mtDNA levels and deletion were assessed using qPCR. Plasma TNFRI and TNFRII levels were quantified by multiplex immunoassay. Correlation analysis explored relationships between EX-mtDNA, clinical outcomes, and inflammatory markers.

Results: Although no differences were observed in EX-mtDNA levels between groups, elevated levels correlated with poorer cognitive performance (r = -0.328, p = 0.002) and increased TNFRII levels (r = 0.367, p = 0.004). LLD exhibited higher deletion rates (F_(83,1) = 4.402, p = 0.039), with a trend remaining after adjusting for covariates (p = 0.084). Deletion correlated with poorer cognitive performance (r = -0.335, p = 0.002). No other associations were found.

Limitation: Cross-sectional study with a small number of participants from a specialized geriatric psychiatry treatment center.

Conclusion: Our findings suggest that EX-mtDNA holds promise as an indicator of cognitive outcomes in LLD. Additional research is needed to further comprehend the role of EX-mtDNA levels/integrity in LLD, paving the way for its clinical application in the future.

Keywords: Cognitive function; Exosomes; Inflammation; Late-life depression; Mitochondrial DNA.

MeSH terms

Aged
Aged, 80 and over
Biomarkers / blood
Case-Control Studies
Cognitive Dysfunction* / blood
Cognitive Dysfunction* / genetics
DNA, Mitochondrial* / blood
DNA, Mitochondrial* / genetics
Depression / blood
Depression / genetics
Exosomes* / genetics
Female
Humans
Male
Receptors, Tumor Necrosis Factor, Type I* / blood
Receptors, Tumor Necrosis Factor, Type I* / genetics
Receptors, Tumor Necrosis Factor, Type II* / blood
Receptors, Tumor Necrosis Factor, Type II* / genetics

Substances

DNA, Mitochondrial
Receptors, Tumor Necrosis Factor, Type II
Receptors, Tumor Necrosis Factor, Type I
Biomarkers

Grants and funding

R01 MH115953/MH/NIMH NIH HHS/United States