Mitochondrial-derived Vesicles Research Articles

Force-induced tail-autotomy mitochondrial fission and biogenesis of matrix-excluded mitochondrial-derived vesicles for quality control

Mitochondria constantly fuse and divide for mitochondrial inheritance and functions. Here, we identified a distinct type of naturally occurring fission, tail-autotomy fission, wherein a tail-like thin tubule protrudes from the mitochondrial body and disconnects, resembling autotomy. Next, utilizing an optogenetic mitochondria-specific mechanostimulator, we revealed that mechanical tensile force drives tail-autotomy fission. This force-induced fission involves DRP1/MFF and endoplasmic reticulum tubule wrapping. It redistributes mitochondrial DNA, producing mitochondrial fragments with or without mitochondrial DNA for different fates. Moreover, tensile force can decouple outer and inner mitochondrial membranes, pulling out matrix-excluded tubule segments. Subsequent tail-autotomy fission separates the matrix-excluded tubule segments into matrix-excluded mitochondrial-derived vesicles (MDVs) which recruit Parkin and LC3B, indicating the unique role of tail-autotomy fission in segregating only outer membrane components for mitophagy. Sustained force promotes fission and MDV biogenesis more effectively than transient one. Our results uncover a mechanistically and functionally distinct type of fission and unveil the role of tensile forces in modulating fission and MDV biogenesis for quality control, underscoring the heterogeneity of fission and mechanoregulation of mitochondrial dynamics.

Mitochondrial derived vesicles- Quo Vadis?

Mitochondria are dynamic, intracellular organelles with a separate genome originating from prokaryotes. They perform numerous functions essential for cellular metabolism and energy production. Mitochondrial-derived vesicles (MDVs) are single or double membrane-enclosed vesicles, formed and released from the mitochondrial sub-compartments into the cytosol, in response to various triggers. MDVs interact with other organelles such as lysosomes and peroxisomes or may be incorporated and excreted via extracellular vesicles (EVs). MDVs selectively incorporate diverse protein and lipid cargoes and are involved in various functions such as mitochondrial quality control, immunomodulation, energy complementation, and compartmentalization and transport. This review aims to provide a summary of the current knowledge of MDVs biogenesis, release, cargoes, and roles.

Utilizing Extracellular Vesicles for Eliminating 'Unwanted Molecules': Harnessing Nature's Structures in Modern Therapeutic Strategies.

Extracellular vesicles (EVs) are small phospholipid bilayer-bond structures released by diverse cell types into the extracellular environment, maintaining homeostasis of the cell by balancing cellular stress. This article provides a comprehensive overview of extracellular vesicles, their heterogeneity, and diversified roles in cellular processes, emphasizing their importance in the elimination of unwanted molecules. They play a role in regulating oxidative stress, particularly by discarding oxidized toxic molecules. Furthermore, endoplasmic reticulum stress induces the release of EVs, contributing to distinct results, including autophagy or ER stress transmission to following cells. ER stress-induced autophagy is a part of unfolded protein response (UPR) and protects cells from ER stress-related apoptosis. Mitochondrial-derived vesicles (MDVs) also play a role in maintaining homeostasis, as they carry damaged mitochondrial components, thereby preventing inflammation. Moreover, EVs partake in regulating aging-related processes, and therefore they can potentially play a crucial role in anti-aging therapies, including the treatment of age-related diseases such as Alzheimer's disease or cardiovascular conditions. Overall, the purpose of this article is to provide a better understanding of EVs as significant mediators in both physiological and pathological processes, and to shed light on their potential for therapeutic interventions targeting EV-mediated pathways in various pathological conditions, with an emphasis on age-related diseases.

The case for considering the term 'mitochondrial vesicle' as a misnomer in publications about assisted reproductive technologies (ART) for amphibians.

The term 'mitochondrial vesicle' was first used in 2003 in a description of anuran sperm and persists to this day throughout the literature on assisted reproductive technologies (ART) for amphibians. In the present paper, we argue that the term is inappropriate because the widely accepted definition of a 'vesicle' refers to an integral structure with an enclosing lipid bilayer/membrane. Moreover, there are no electron micrographs that show a vesicular structure encapsulating mitochondria on amphibian sperm heads in the literature. In fact, in 1993, the mitochondria in the anuran sperm head had been described as positioned in 'mitochondrial collars' or 'mitochondrial sheaths' surrounded by the plasma membrane of the sperm head. On the other hand, mitochondrial-derived vesicles are defined as vesicles shed from mitochondria surfaces, potentially creating confusion. Therefore, our view is that the term 'mitochondrial vesicle' should be avoided in describing the positioning of mitochondria on sperm.

ErZhiTianGui Decoction alleviates age-related ovarian aging by regulating mitochondrial homeostasis and inhibiting ferroptosis

AimThis study was designed to investigate the pharmacological effects and mechanisms of ErZhiTianGui Decoction (EZTG) for age-related ovarian aging in mice.MethodsThis study used naturally aging mice as a model, and EZTG was used for intragastric administration. Ovarian pathological changes, as well as follicular reserve were assessed by hematoxylin and eosin staining, and serum hormone levels (anti-mullerian hormone, follicle-stimulating hormone), mitochondrial reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage marker 8-hydroxy-2′-deoxyguanosine(8-OHdG), and lipid peroxidation markers glutathione(GSH) and malondialdehyde(MDA) were determined by enzyme-linked immunosorbent assay. Mitochondrial membrane potential (MMP) levels in ovaries were determined using flow cytometry. The levels of PINK1 and Parkin were observed using immunofluorescence staining. Mitochondrial-derived vesicles (MDVs) and mitochondrial morphology were observed using electron microscopy. Prussian blue staining was used to observe iron ion aggregation in ovarian tissue. The Iron assay kits detected total iron levels. Western blot was used to detect the expression of proteins related to mitochondrial and ferroptosis related genes.ResultsAfter EZTG treatment, aged mice showed increased ovarian reserve, improved serum hormone levels, increased MMP, GSH levels, and decreased mitochondrial ROS, 8-OHdG, and MDA levels. Immunofluorescence staining showed decreased levels of PINK1 and Parkin, and the same trend was observed for the Western blot. Meanwhile, electron microscopy showed that EZTG improved the mitochondrial morphology in the ovaries of aged mice. EZTG also decreased the total iron and protein levels of Acyl-CoA synthetase long-chain family4 (ACSL4) and increased the protein level of glutathione peroxidase 4 (GPX4) in the ovaries of aged mice.ConclusionsEZTG can maintain PINK1/Parkin-mediated mitochondrial homeostasis, reduce the lipid peroxidation caused by the accumulation of ROS, and inhibit the occurrence of ferroptosis and delaying ovarian aging. These findings suggest that EZTG may be a promising drug for treating age-related ovarian aging in females.

Knocking out Fkbp51 decreases CCl4-induced liver injury through enhancement of mitochondrial function and Parkin activity

Background and aimsPreviously, we found that FK506 binding protein 51 (Fkbp51) knockout (KO) mice resist high fat diet-induced fatty liver and alcohol-induced liver injury. The aim of this research is to identify the mechanism of Fkbp51 in liver injury.MethodsCarbon tetrachloride (CCl4)-induced liver injury was compared between Fkbp51 KO and wild type (WT) mice. Step-wise and in-depth analyses were applied, including liver histology, biochemistry, RNA-Seq, mitochondrial respiration, electron microscopy, and molecular assessments. The selective FKBP51 inhibitor (SAFit2) was tested as a potential treatment to ameliorate liver injury.ResultsFkbp51 knockout mice exhibited protection against liver injury, as evidenced by liver histology, reduced fibrosis-associated markers and lower serum liver enzyme levels. RNA-seq identified differentially expressed genes and involved pathways, such as fibrogenesis, inflammation, mitochondria, and oxidative metabolism pathways and predicted the interaction of FKBP51, Parkin, and HSP90. Cellular studies supported co-localization of Parkin and FKBP51 in the mitochondrial network, and Parkin was shown to be expressed higher in the liver of KO mice at baseline and after liver injury relative to WT. Further functional analysis identified that KO mice exhibited increased ATP production and enhanced mitochondrial respiration. KO mice have increased mitochondrial size, increased autophagy/mitophagy and mitochondrial-derived vesicles (MDV), and reduced reactive oxygen species (ROS) production, which supports enhancement of mitochondrial quality control (MQC). Application of SAFit2, an FKBP51 inhibitor, reduced the effects of CCl4-induced liver injury and was associated with increased Parkin, pAKT, and ATP production.ConclusionsDownregulation of FKBP51 represents a promising therapeutic target for liver disease treatment.Graphical

Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.

Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.

ALS-linked SOD1 mutations impair mitochondrial-derived vesicle formation and accelerate aging

Oxidative stress (OS) is regarded as the dominant theory for aging. While compelling correlative data have been generated to support the OS theory, a direct cause-and-effect relationship between the accumulation of oxidation-mediated damage and aging has not been firmly established. Superoxide dismutase 1 (SOD1) is a primary antioxidant in all cells. It is, however, susceptible to oxidation due to OS and gains toxic properties to cells. This study investigates the role of oxidized SOD1 derived from amyotrophic lateral sclerosis (ALS) linked SOD1 mutations in cell senescence and aging. Herein, we have shown that the cell line NSC34 expressing the G93A mutation of human SOD1 (hSOD1G93A) entered premature senescence as evidenced by a decreased number of the 5-ethynyl-2′-deoxyuridine (EdU)-positive cells. There was an upregulation of cellular senescence markers compared to cells expressing the wild-type human SOD1 (hSOD1WT). Transgenic mice carrying the hSOD1G93A gene showed aging phenotypes at an early age (135 days) with high levels of P53 and P16 but low levels of SIRT1 and SIRT6 compared with age-matched hSOD1WT transgenic mice. Notably, the levels of oxidized SOD1 were significantly elevated in both the senescent NSC34 cells and 135-day hSOD1G93A mice. Selective removal of oxidized SOD1 by our CT4-directed autophagy significantly decelerated aging, indicating that oxidized SOD1 is a causal factor of aging. Intriguingly, mitochondria malfunctioned in both senescent NSC34 cells and middle-aged hSODG93A transgenic mice. They exhibited increased production of mitochondrial-derived vesicles (MDVs) in response to mild OS in mutant humanSOD1 (hSOD1) transgenic mice at a younger age; however, the mitochondrial response gradually declined with aging. In conclusion, our data show that oxidized SOD1 derived from ALS-linked SOD1 mutants is a causal factor for cellular senescence and aging. Compromised mitochondrial responsiveness to OS may serve as an indicator of premature aging.

Cardiac fibroblasts-mtExosomes-macrophages axis aggravates ventricular remodeling after acute myocardial infarction

Abstract Background Intercellular communication between cardiac fibroblasts (CFs) and macrophages plays an important role in the progression of ventricular remodeling after acute myocardial infarction (AMI). Following intense oxidative stress, activation of mitochondrial quality control (MQC) systems is necessary to eliminate damaged components. Recent studies have highlighted the emergence of a new form of MQC called mitochondrial-derived vesicles (MDVs), which can be released into the extracellular space via exosomes. Our previous research has revealed that exosomes derived from fibroblasts treated with oxygen-glucose deprivation (OGD) contained mitochondrial damage components, which we named "mtExosomes". The uptake of mtExosomes by macrophages can significantly promote inflammatory response. Purpose To explore the specific effects of CFs-mtExosomes-macrophages communication axis on ventricular remodeling after AMI. Methods Male C57 mice underwent left anterior descending coronary artery-ligation surgery for orthotopic myocardial injection of CFs derived exosomes. Primary neonatal mouse CFs were isolated and cultured for 24h in sugar-free medium with 1% O2 (OGD) to mimic ischemic injury in vitro. Conditioned medium was separated to obtain exosomes by ultracentrifugation. Label-free quantitative proteomics was used to identify differentially expressed proteins in exosomes. The damaged mitochondrial components in the exosomes were identified using mito-tracker and nanoflowmetry. After co-culture with OGD-CFs derived exosomes for 24h, RNA-seq was performed to analyze the activated inflammatory signaling pathways in bone marrow-derived macrophages. Results OGD-CFs derived exosomes significantly reduced cardiac function post-surgery day 3 in model mice, and fibrotic remodeling was observed at 28 days. In vitro co-culture experiments revealed that the conditioned medium from OGD-CFs increased the expression and secretion of IL-1β and IL-6 in macrophages. Separation of secretory components by differential centrifugation suggested that exosomes had the most significant pro-inflammatory effect on macrophages. Exosome proteomics showed that fibroblast-derived exosomes were rich in mitochondrial proteins. A significant fluorescence signal was detected by nanoflowmetry after incubation of OGD-CFs-derived exosomes with Mito-tracker. OGD-CFs derived exosomes also had higher mtDNA, mtROS, and ATP levels. RNA-seq enrichment analysis revealed significant activation of Toll-like receptor and NOD-like receptor signaling pathways in macrophages. Western blot analysis further confirmed the up-regulation of NLRP3/Caspase-1/IL-1β and TLR9/NF-κB/IL-6 signaling pathways. Conclusion Following ischemic injury, CFs in infarction area release exosomes rich in damaged mitochondria (mtExosomes). The uptake of mtExosomes by macrophages promotes the secretion of IL-6 and IL-1β via NLRP3/Caspase-1/IL-1β and TLR9/NF-κB/IL-6 signaling pathways, leading to ventricular remodeling after AMI.Graphical Abstract

Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.

Mitophagy is crucial for maintaining mitochondrial quality. However, its assessment in vivo is challenging. The endosomal-lysosomal system is a more accessible pathway through which subtypes of extracellular vesicles (EVs), which also contain mitochondrial constituents, are released for disposal. The inclusion of mitochondrial components into EVs occurs in the setting of mild mitochondrial damage and during impairment of lysosomal function. By releasing mitochondrial-derived vesicles (MDVs), cells limit the unload of mitochondrial damage-associated molecular patterns with proinflammatory activity. Both positive and negative effects of EVs on recipient cells have been described. Whether this is due to the production of EVs other than those containing mitochondria, such as MDVs, holding specific biological functions is currently unknown. Evidence on the existence of different MDV subtypes has been produced. However, their characterization is not always pursued, which would be relevant to exploring the dynamics of mitochondrial quality control in health and disease. Furthermore, MDV classification may be instrumental in understanding their biological roles and promoting their implementation as biomarkers in clinical studies.

An Epstein-Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation

Epstein-Barr virus (EBV) causes infectious mononucleosis, triggers multiple sclerosis, and is associated with 200,000 cancers/year. EBV colonizes the human B cell compartment and periodically reactivates, inducing expression of 80 viral proteins. However, much remains unknown about how EBV remodels host cells and dismantles key antiviral responses. We therefore created a map of EBV-host and EBV-EBV interactions in B cells undergoing EBV replication, uncovering conserved herpesvirus versus EBV-specific host cell targets. The EBV-encoded G-protein-coupled receptor BILF1 associated with MAVS and the UFM1 E3 ligase UFL1. Although UFMylation of 14-3-3 proteins drives RIG-I/MAVS signaling, BILF1-directed MAVS UFMylation instead triggered MAVS packaging into mitochondrial-derived vesicles and lysosomal proteolysis. In the absence of BILF1, EBV replication activated the NLRP3 inflammasome, which impaired viral replication and triggered pyroptosis. Our results provide a viral protein interaction network resource, reveal a UFM1-dependent pathway for selective degradation of mitochondrial cargo, and highlight BILF1 as a novel therapeutic target.

Mitochondrial-derived vesicles retain membrane potential and contain a functional ATP synthase.

Vesicular transport is a means of communication. While cells can communicate with each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here, we show that functional mitochondria isolated from Saccharomyces cerevisiae release vesicles, independent of the fission machinery. We isolate these mitochondrial-derived vesicles (MDVs) and find that they are relatively uniform in size, of about 100 nm, and carry selective protein cargo enriched for ATP synthase subunits. Remarkably, we further find that these MDVs harbor a functional ATP synthase complex. We demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitochondria. Our findings reveal a possible delivery mechanism of ATP-producing vesicles, which can potentially regenerate ATP-deficient mitochondria and may participate in organelle-to-organelle communication.

Drp1 is essential for PINK1/Parkin signaling in H9c2 cardiomyocytes.

Drp1 is essential for PINK1/Parkin signaling in H9c2 cardiomyocytes.

Fumarate induces vesicular release of mtDNA to drive innate immunity

Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING)–TANK-binding kinase 1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin 9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.

Carbon monoxide preconditioning is mediated via activation of mitochondrial-derived vesicles

Preconditioning with inhalative carbon monoxide (CO) at low concentrations provides protection against hypoxic and ischemic insults in the brain and heart. The present study aims to test a hypothesis that activation of mitochondrial-derived vesicles (MDVs) is a mechanism underlying the protective effect of CO preconditioning. Here we show that CO preconditioning induced mild oxidative stress and activated massive production of MDVs. Short exposure to a low concentration of carbon monoxide-releasing molecule 2 (CORM-2), a donor of carbon monoxide, prevented oligodendrocyte precursor cells (OPCs) from subsequent death induced by high doses of CO, and protected Chinese hamster ovary (CHO) cells against oxygen-glucose deprivation (OGD)-induced cell death. Furthermore, inhibition of lysosomal activity prevented degradation of MDVs, abolished MDV-mediated mitochondrial quality control, and diminished the protective effect of CO preconditioning. Altogether, our data provide direct evidence suggesting that MDV-mediated mitochondrial quality control may have a novel role in CO preconditioning.

Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis

Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration invivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.

Mitochondrial-Derived Vesicles-Link to Extracellular Vesicles and Implications in Cardiovascular Disease.

Mitochondria are dynamic organelles regulating metabolism, cell death, and energy production. Therefore, maintaining mitochondrial health is critical for cellular homeostasis. Mitophagy and mitochondrial reorganization via fission and fusion are established mechanisms for ensuring mitochondrial quality. In recent years, mitochondrial-derived vesicles (MDVs) have emerged as a novel cellular response. MDVs are shed from the mitochondrial surface and can be directed to lysosomes or peroxisomes for intracellular degradation. MDVs may contribute to cardiovascular disease (CVD) which is characterized by mitochondrial dysfunction. In addition, evidence suggests that mitochondrial content is present in extracellular vesicles (EVs). Herein, we provide an overview of the current knowledge on MDV formation and trafficking. Moreover, we review recent findings linking MDV and EV biogenesis and discuss their role in CVD. Finally, we discuss the role of vesicle-mediated mitochondrial transfer and its potential cardioprotective effects.

What role do extracellular vesicles play in developing physical frailty and sarcopenia? : Asystematic review.

Frailty and sarcopenia are typical geriatric conditions with acomplex pathophysiology. Extracellular vesicles (EVs) are key regulators of age-related diseases, but the mechanisms underlying physical frailty, sarcopenia, and EVs are not well understood. Asystematic literature review was conducted to examine the evidence supporting an association between EVs and physical frailty and/or sarcopenia by searching the electronic databases, including the Cochrane Library, PubMed, and Embase, from January 2000 to January 2021. Atotal of 216 cross-sectional studies were retrieved, and after the removal of 43duplicate records, the title and abstract of 167 articles were screened, identifying 6relevant articles for full-text review. Of the studies five met the inclusion criteria, and heterogeneity among studies was high. There is controversy regarding whether frailty and/or sarcopenia are related to circulating EV levels; however, the cargo of EVs has been associated with frailty and sarcopenia in various ways, such as microRNAs, mitochondrial-derived vesicles (MDVs), and protein cargoes. Recent studies, although limited, depicted that EVs could be one of the underlying mechanisms of frailty and/or sarcopenia. There is apossibility that physical frailty and sarcopenia may have specific EV concentrations and cargo profiles; however, further research is required to fully understand the mechanisms and identify potential biomarkers and early preventative strategies for physical frailty and sarcopenia.

Mitolysosome exocytosis: a novel mitochondrial quality control pathway linked with parkinsonism-like symptoms.

Quality control of mitochondria is essential for their homeostasis and function. Light chain 3 (LC3) associated autophagosomes-mediated mitophagy represents a canonical mitochondrial quality control pathway. Alternative quality control processes, such as mitochondrial-derived vesicles (MDVs), have been discovered, but the intact mitochondrial quality control remains unknown. We recently discovered a novel mitolysosome exocytosis mechanism for mitochondrial quality control in flunarizine (FNZ)-induced mitochondria clearance, where autophagosomes are not required, but rather mitochondria are engulfed directly by lysosomes, mediating mitochondrial secretion. As FNZ results in parkinsonism, we propose that excessive mitolysosome exocytosis is the cause.

Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders.

Neuroinflammation is a common hallmark in different neurodegenerative conditions that share neuronal dysfunction and a progressive loss of a selectively vulnerable brain cell population. Alongside ageing and genetics, inflammation, oxidative stress and mitochondrial dysfunction are considered key risk factors. Microglia are considered immune sentinels of the central nervous system capable of initiating an innate and adaptive immune response. Nevertheless, the pathological mechanisms underlying the initiation and spread of inflammation in the brain are still poorly described. Recently, a new mechanism of intercellular signalling mediated by small extracellular vesicles (EVs) has been identified. EVs are nanosized particles (30–150 nm) with a bilipid membrane that carries cell-specific bioactive cargos that participate in physiological or pathological processes. Damage-associated molecular patterns (DAMPs) are cellular components recognised by the immune receptors of microglia, inducing or aggravating neuroinflammation in neurodegenerative disorders. Diverse evidence links mitochondrial dysfunction and inflammation mediated by mitochondrial-DAMPs (mtDAMPs) such as mitochondrial DNA, mitochondrial transcription factor A (TFAM) and cardiolipin, among others. Mitochondrial-derived vesicles (MDVs) are a subtype of EVs produced after mild damage to mitochondria and, upon fusion with multivesicular bodies are released as EVs to the extracellular space. MDVs are particularly enriched in mtDAMPs which can induce an immune response and the release of pro-inflammatory cytokines. Importantly, growing evidence supports the association between mitochondrial dysfunction, EV release and inflammation. Here, we describe the role of extracellular vesicles-associated mtDAMPS in physiological conditions and as neuroinflammation activators contributing to neurodegenerative disorders.