Mitochondrial DNA in extracellular vesicles declines with age

Abstract

The mitochondrial free radical theory of aging suggests that accumulating oxidative damage to mitochondria and mitochondrial DNA (mtDNA) plays a central role in aging. Circulating cell‐free mtDNA (ccf‐mtDNA) isolated from blood may be a biomarker of disease. Extracellular vesicles (EVs) are small (30–400 nm), lipid‐bound vesicles capable of shuttling proteins, nucleic acids, and lipids as part of intercellular communication systems. Here, we report that a portion of ccf‐mtDNA in plasma is encapsulated in EVs. To address whether EV mtDNA levels change with human age, we analyzed mtDNA in EVs from individuals aged 30–64 years cross‐sectionally and longitudinally. EV mtDNA levels decreased with age. Furthermore, the maximal mitochondrial respiration of cultured cells was differentially affected by EVs from old and young donors. Our results suggest that plasma mtDNA is present in EVs, that the level of EV‐derived mtDNA is associated with age, and that EVs affect mitochondrial energetics in an EV age‐dependent manner.

Extracellular Vesicles: Potential Mediators of Psychosocial Stress Contribution to Osteoporosis?

“…Thus, researchers proposed that mtDNA levels in body fluids and tissues may be a biomarker of mitochondrial dysfunction. Since mtDNA is present in EVs and can act on target cells through EVs’ transport [ 59 , 60 ], the same as miRNA, the changed mtDNA in EVs may also act as potential biomarkers for the psychosocial stress process. In the stress response, mitochondria also cooperate with the endoplasmic reticulum [ 61 ]; therefore, the endoplasmic reticulum may be involved in the stress response process.…”

Mitochondria as extracellular vesicle cargo in aging

“…Individuals in this aging cohort had donated plasma at two different time points approximately 5 years apart, which enabled us to examine both cross-sectional and longitudinal changes. In both our cross-sectional and longitudinal analyses, EV mtDNA levels decreased with advancing age [ 5 ] ( Figure 1B ).…”

“…Given these gaps in the field, we recently explored whether plasma mtDNA can be encapsulated in extracellular vesicles (EVs) [ 5 ]. EVs are lipid-bound nano-sized vesicles that are secreted outside of cells into the circulation ( Figure 1A ).…”

“…To further address this, we examined whether EVs from young and old individuals with different mtDNA levels affect mitochondrial function. Cells treated with EVs from old individuals, which contain lower mtDNA levels, had significantly lower basal and maximal respiration than cells treated with EVs from young individuals [ 5 ]. These data suggest that EVs from old individuals may impair mitochondrial function.…”

“…This data also expands upon further, broadly characterizing EVs in diverse human populations in the context of aging. Given that age-dependent changes in EVs occur [ 5 , 8 ], it is important for age to be considered when utilizing EVs as diagnostic or prognostic markers of disease.…”