Changes in Mitochondrial Components in Extracellular Vesicles with Age

Much of the signaling that takes place between cells is carried in extracellular vesicles, membrane-wrapped packages of various molecules that are released and taken up by cells. Of late, it has become apparent that mitochondria or mitochondrial component parts can also be released by cells. This is primarily understood as a pro-inflammatory signal resulting from the presence of stressed, damaged, or dying cells. The other functions that this might serve are not completely clear, but researchers have observed that, as is the case for other forms of cell signaling, the presence of mitochondrial DNA in extracellular vesicles changes with age. It remains to be seen as to what can be done with this information.

Many factors contribute to chronic inflammation in the elderly. Cellular damage or stress can initiate a release of mitochondrial damage-associated molecular patterns (DAMPs). As part of this process, mitochondrial DNA (mtDNA) can be released into the extracellular space as circulating cell-free mitochondria DNA (ccf-mtDNA). Due to the similarities between mtDNA and bacterial DNA, this release can in turn elicit a sterile inflammatory response through activation of the innate immune system.

Recent attention has focused on detection and characterization of ccf-mtDNA in the blood. In general, higher plasma/serum levels of ccf-mtDNA have been reported in inflammatory-related diseases, and in response to acute tissue injury such as trauma, acute myocardial infarction, or sepsis. The relationship between ccf-mtDNA and aging is more complex as one report showed an initial decline in ccf-mtDNA into middle-age and then a gradual increase after the fifth decade of life. Individuals greater than 90 years of age with high levels of ccf-mtDNA had higher levels of the proinflammatory cytokines.

Little is known about whether mtDNA is present in plasma extracellular vesicles (EVs) under normal physiological conditions or whether mitochondrial components are important functional cargo in EVs. To address this need, we isolated plasma EVs and analyzed mtDNA levels with human age. 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.

Mitochondrial dysfunction contributes to the aging process. A few recent studies have examined whether mitochondrial components may be functional cargo in EVs. These studies point to a potential mechanism whereby mtDNA in EVs can be transferred to recipient cells and elicit functional changes. However, it is not fully understood whether this is a general mechanism or specific to certain cell types or stimuli. Nevertheless, these initial studies highlight the potential importance of mtDNA in EVs. 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. These data suggest that EVs from old individuals may impair mitochondrial function.

Link: https://doi.org/10.18632/aging.203358

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