Generation and Release of Mitochondrial-Derived Vesicles in Health, Aging and Disease

Abstract

Mitochondria are intracellular organelles involved in a myriad of activities. To safeguard their vital functions, mitochondrial quality control (MQC) systems are in place to support organelle plasticity as well as physical and functional connections with other cellular compartments. In particular, mitochondrial interactions with the endosomal compartment support the shuttle of ions and metabolites across organelles, while those with lysosomes ensure the recycling of obsolete materials. The extrusion of mitochondrial components via the generation and release of mitochondrial-derived vesicles (MDVs) has recently been described. MDV trafficking is now included among MQC pathways, possibly operating via mitochondrial–lysosomal contacts. Since mitochondrial dysfunction is acknowledged as a hallmark of aging and a major pathogenic factor of multiple age-associated conditions, the analysis of MDVs and, more generally, of extracellular vesicles (EVs) is recognized as a valuable research tool. The dissection of EV trafficking may help unravel new pathophysiological pathways of aging and diseases as well as novel biomarkers to be used in research and clinical settings. Here, we discuss (1) MQC pathways with a focus on mitophagy and MDV generation; (2) changes of MQC pathways during aging and their contribution to inflamm-aging and progeroid conditions; and (3) the relevance of MQC failure to several disorders, including neurodegenerative conditions (i.e., Parkinson’s disease, Alzheimer’s disease) and cardiovascular disease.

Biomarkers of Physical Frailty and Sarcopenia: Coming up to the Place?

“…Recent findings by our group support the hypothesis of mitochondrial impairment among the underlying pathogenetic mechanisms of sarcopenia [18]. In particular, as a result of failing quality control systems [91,[95][96][97], the release of oxidized cell-free mtDNA and other mitochondrial components within MDVs have been associated with systemic inflammation in older adults with PF&S [7].…”

Bioactive DNA from extracellular vesicles and particles

“…In reviewing intra-and extra-cellular mtDNA secretion, Perez-Trevino et al 53 theorised that mitochondria-derived vesicles generated from oxidative damage could be targeted to endosomal pathways, where their DNA contents are packaged into S-EVs 53 . Picca et al 54 further postulated that lysosomal vesicles resulting from mitochondrial autophagy, and thus rich in mitochondrial contents, may themselves be released as EVs. More work is needed to elucidate the ways in which both gDNA and mtDNA are loaded into and released via EV/EPs.…”

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

“…A set of unidentified proteins would finalize the process, eventually culminating in the release of a vesicle [68]. Hence, all cell constituents, including those of mitochondrial origin, may potentially be extruded into the circulation as DAMPs in the form of cell-free molecules or packaged within vesicles [19].…”

“…In particular, in response to various stressors, mitochondrial DNA (mtDNA) can be displaced into intra-or extracellular compartments [18]. Albeit the mechanisms whereby mtDNA is unloaded from mitochondria are largely unclear, several lines of evidence indicate that mtDNA can be shuttled toward the extracellular compartment via the generation and release of extracellular vesicles (EVs) [18][19][20][21]. Along with mtDNA and other mitochondrial components, cell-free intact mitochondria have been found in the blood of healthy people [21].…”