Mitochondrial DNA in Extracellular Vesicles Declines with Age

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A sizable fraction of cell signaling is conveyed via extracellular vesicles, tiny membrane-wrapped packages of molecules. Here researchers note that mitochondrial DNA is found inside extracellular vesicles, and that the amount declines with age. Other researchers have determined that entire mitochondria are exported and taken up by cells, so one has to carefully read the methods used in papers like this to ensure that researchers are in fact looking at the smaller extracellular vesicles only. These vesicles are sorted into category by size, and selecting by size is an established capability.

It is speculated that transfer of mitochondrial DNA via extracellular vesicle serves useful purposes, and observed in cell cultures that it can alter mitochondrial function in recipient cells. Additionally it can serve as a signal of damage generated by stressed and dying cells, activating the immune system to be more vigilant. Alternatively, it may be a garbage disposal mechanism to get rid of unwanted molecules, and uptake of these vesicles is a form of unwanted side-effect.

A declining presence of mitochondrial DNA in extracellular vesicles with age might be a simple reflection of a lesser number of mitochondria in cells, a part of the general faltering of mitochondrial function in old tissues, or it may be the consequence of a much more complex set of processes. The evidence to date leans in the latter direction, as is usually the case in biological systems.

Mitochondrial DNA in extracellular vesicles declines with age

The mitochondrial genome encodes 37 genes including 13 proteins, which are vital for mitochondrial oxidative phosphorylation and cellular energetics. Mitochondrial DNA (mtDNA) mutations drive premature aging in mouse models and recently have been shown to increase with human age. mtDNA copy number (the number of mtDNA molecules per cell) was also found to decline with human age in peripheral blood mononuclear cells.

Cellular mtDNA can be released outside of the cell as circulating cell-free mtDNA (ccf-mtDNA). Ccf-mtDNA can act as a damage associated molecular pattern (DAMP) molecule leading to activation of the innate immune response following cellular damage or stress. Ccf-mtDNA can be reliably measured from blood plasma and serum making it attractive for biomarker development. Elevated ccf-mtDNA levels are associated with inflammatory diseases and cancer, as well as with trauma or tissue injury, including myocardial infarction and sepsis. A recent study has shown a slight decline in ccf-mtDNA comparing levels in children to middle-aged individuals followed by a gradual increase in ccf-mtDNA in the elderly. These emerging data suggest that ccf-mtDNA may indicate and/or contribute to various physiological and pathological conditions.

Previously, we reported that EV concentration declined with age in a cross-sectional and longitudinal study. EVs isolated from older individuals were preferentially internalized by B cells compared to EVs from younger individuals. These data indicate that EVs from older individuals may contain different cargo than EVs from younger individuals.

In the current study, we examine whether mtDNA can be detected in human plasma EVs and whether mtDNA levels are altered 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.

These findings may seem at first contradictory to a previous report finding that ccf-mtDNA from plasma increased with age. However, in that paper, they report a slight decline in ccf-mtDNA levels from childhood (mean age = 6.8 years) to early adulthood (mean age = 33 years) and a gradual increase in ccf-mtDNA levels in the ~60 years (mean age = 64 years) and elderly population (older than 90 years). Our cohort at time 1 ranges from ~30-64 years and time 2 ~ 32-69 years. Therefore, we examined a largely middle-aged cohort. Also, of note, we have measured ccf-mtDNA levels within EVs not just in whole plasma. Although we detected mtDNA in EVs, our data indicate that only a fraction of the total ccf-mtDNA is contained in EVs.

Cargo in EVs may relay cellular signals but may also be a mechanism for the removal of dysfunctional or damaged mitochondrial components. It has been reported that neurodegenerative-related misfolded proteins are present in EVs. Autophagy has been shown to play a role in EV secretion. It is well known that the removal of deficient mitochondria via mitophagy is altered with aging, along with pathways related to proteostasis. Therefore, it is interesting to speculate that the decline in mtDNA EV levels that we observe may reflect a defect in the clearance of cellular material with aging.

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source https://www.fightaging.org/archives/2021/01/mitochondrial-dna-in-extracellular-vesicles-declines-with-age/