Mitochondrial DNA and inflammatory proteins are higher in extracellular vesicles from frail individuals

Abstract

Background Frailty, a clinical syndrome commencing at midlife, is a risk for morbidity and mortality. Little is known about the factors that contribute to the chronic inflammatory state associated with frailty. Extracellular vesicles (EVs) are small, membrane-bound vesicles that are released into the circulation and are mediators of intercellular communication. We examined whether mitochondrial DNA (mtDNA) and inflammatory proteins in EVs may act as damage-associated molecular pattern (DAMP) molecules in frailty. Results To address whether EVs and their associated mtDNA and inflammatory protein cargo are altered with frailty, EVs were isolated from non-frail (n = 90) and frail (n = 87) middle-aged (45–55 years) participants from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. EV concentration was highest in frail White participants. EV mtDNA levels were significantly higher in frail individuals compared to non-frail individuals. The presence of six inflammatory proteins in EVs (FGF-21, HGF, IL-12B, PD-L1, PRDX3, and STAMBP) were significantly associated with frailty. EV inflammatory proteins were significantly altered by frailty status, race, sex, and poverty status. Notably, frail White participants had higher levels of EV-associated CD5, CD8A, CD244, CXCL1, CXCL6, CXCL11, LAP-TGF-beta-1 and MCP-4 compared to frail and non-frail African American participants. Frail White participants living below poverty had higher levels of EV-associated uPA. EV-associated CCL28 levels were highest in non-frail women and CXCL1 were highest in non-frail men. Men living below poverty had higher levels of CD5, CD8A, CXCL1, LAP-TGF-beta-1, and uPA. CXCL6 levels were significantly higher in individuals living above poverty. There was a significant correlation between EV mtDNA levels and the presence of inflammatory proteins. Conclusions These data suggest that mtDNA within EVs may act as a DAMP molecule in frailty. Its association with chemokines and other inflammatory EV cargo proteins, may contribute to the frailty phenotype. In addition, the social determinant of health, poverty, influences the inflammatory cargo of EVs in midlife.

Neuroinflammatory Responses and Blood–Brain Barrier Injury in Chronic Alcohol Exposure: Role of Purinergic P2X7 Receptor Signaling

“…These genes are involved in mitochondrial respiration [100]. In the present study, signi cantly increased mtDNA concentration in EVs and proin ammatory changes in the periphery and BBB of CIE-exposed group suggest that the mtDNA carried by EVs acts as DAMP and may cause an exacerbation of neuroin ammation [99,101].…”

“…2A, Table 1). In earlier studies, the presence of mtDNA in EVs was detected using gene-speci c probes for mt-ND2, mt-ATP8, mt-Cox2, and mt-RNR2 [46,99]. These genes are involved in mitochondrial respiration [100].…”

“…no. 4331182 Mm04260181_s1) were used in this experiment [47] (Thermo Fisher Scienti c; Waltham, USA). PCRs were performed using 2 µL of 5X Absolute Q™ DNA Digital PCR Master Mix (Cat.…”

Exploration of the causality of frailty index on psoriasis: A Mendelian randomization study

“…showed that frail individuals had significantly higher levels of mitochondrial DNA in extracellular vesicles compared to non‐frail individuals. The presence of six inflammatory proteins in extracellular vesicles (FGF‐21, HGF, IL‐12B, PD‐L1, PRDX3, and STAMBP) was significantly associated with frailty 24 . Benoit et al.…”

“…The presence of six inflammatory proteins in extracellular vesicles (FGF-21, HGF, IL-12B, PD-L1, PRDX3, and STAMBP) was significantly associated with frailty. 24 Benoit et al indicated that proteome damage, particularly protein carbonylation, leads to general aging of organisms and organs during aging, while contributing to diseases such as Alzheimer's and Parkinson's diseases, diabetes, psoriasis and skin cancer. 25 Other studies have shown that frailty state can cause an imbalance in the skin flora, leading to a range of host immune-related diseases.…”