Mitochondrial‐derived vesicles: Recent insights

Abstract

The generation of vesicles is a constitutive attribute of mitochondria inherited from bacterial ancestors. The physiological conditions and mild oxidative stress promote oxidation and dysfunction of certain proteins and lipids within the mitochondrial membranes; these constituents are subsequently packed as small mitochondrial‐derived vesicles (MDVs) (70–150 nm in diameter) and are transported intracellularly to lysosomes and peroxisomes to be degraded. In this way, MDVs remove the damaged mitochondrial components, preserve mitochondrial structural and functional integrity and restore homeostasis. An outline of the current knowledge on MDVs seems to be necessary for understanding the potential impact of this research area in cellular (patho)physiology. The present synopsis is an attempt towards the accomplishment of this demand, highlighting also the still unclear issues related to MDVs. Here, we discuss (i) MDVs budding and generation (molecules and mechanisms), (ii) the distinct cargoes packed and transported by MDVs, (iii) the MDVs trafficking pathways and (iv) the biological role of MDVs, from quality controllers to the involvement in organellar crosstalk, mitochondrial antigen presentation and peroxisome de novo biogenesis. These complex roles uncover also mitochondria integration into the cellular environment. As the therapeutic exploitation of MDVs is currently limited, future insights into MDVs cell biology are expected to direct to novel diagnostic tools and treatments.

The Potential Use of Mitochondrial Extracellular Vesicles as Biomarkers or Therapeutical Tools

“…It is believed that mitochondrial discharge by MitoEVs operates as a first line of defense against partially depolarized mitochondria, before complete depolarization. Moreover, under stress conditions, lysosomal degradation might be exceeded and the MDV containing dysfunctional parts of the damaged mitochondria could then accumulate and act as pro-inflammatory damage-associated molecular patterns (DAMPs) [ 28 , 69 ]. Cells will prevent this chaos by packaging MDVs into multivesicular bodies to be extracellularly discharged as MitoEVs, which are degraded by surrounding macrophages.…”

MitoEVs: A new player in multiple disease pathology and treatment

“…MDVs (∼70-150 nm in diameter) are generated through mitochondrial membrane budding under both steady and stress conditions, which was initially identified as a potential way for eliminating damaged mitochondrial components (Peng et al, 2022). The formation of MDVs may be mediated by the Parkinson's disease-associated protein PINK1/Parkin-(mitophagy)-dependent or dynamin-related protein 1 (DRP1)-dependent pathway, which has been well reviewed previously (Heyn et al, 2023;Peng et al, 2022;Popov, 2022). The failed PINK1 import into mitochondria recruits Parkin to trigger mitophagy and subsequently regulate MDV formation, which is supported by translocase of outer mitochondrial membrane 20 (TOM20) and microtubule-associated protein 1A/1B-light chain 3 (LC3) positive EV subpopulations from platelets (De Paoli et al, 2018) and a PINK1-dependent release of mtDNA-containing EVs from breast cancer cells (Rabas et al, 2021).…”

“…During this process, some pathways are involved. For example, the transport of MDVs to lysosomes can be affected by PINK1, Parkin, Tollip or syntaxin-17 (STX17) signalling (McLelland et al, 2014(McLelland et al, , 2016Peng et al, 2022;Ryan et al, 2020), and transport to peroxisomes can be regulated by Vps35 and mitochondrial-anchored protein ligase (MAPL) (Braschi et al, 2010;Mohanty et al, 2021), while the fusion of MDVs to MVBs and then release into the extracellular space as EVs may be mediated by cluster of differentiation 38 (CD38)/cyclic ADP ribose (cADPR) signalling (Suh et al, 2023), sorting nexin 9 (SNX9) signalling, optic atrophy 1 (OPA1) and inhibition by Parkin (Peng et al, 2022;Todkar et al, 2021), which have been well summarized before (Heyn et al, 2023;Peng et al, 2022;Popov, 2022;Sugiura et al, 2014). Stress conditions are likely to promote the selective incorporation of mitochondrial contents into MDVs, such as oxidative stress (McLelland et al, 2014;Todkar et al, 2021), remote ischemic preconditioning (Lv et al, 2020), hypoxia (Li et al, 2020), cannabidiol treatment (Ramirez et al, 2022), lipopolysaccharide (LPS) (Matheoud et al, 2016) and heat stress (Matheoud et al, 2016).…”

Elimination of FKBP51 attenuates CCl4-induced liver injury via enhancement of mitochondrial function by increased Parkin activity

“…5D KO panel, 6D and E) after CCl4 treatment. The formation of mitochondrial-derived vesicles (MDVs) serves as a defense mechanism to remove harmful mitochondrial components and as a mechanism of immune tolerance and immune response (Popov, 2022;Towers et al, 2021). MDVs were observed both but more often in KO compared to WT mice after CCl 4 treatment (Fig.…”