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MitoEVs: What are mitochondria-derived extracellular vesicles?

2023-04-30

Here is the paper introduced today.

MitoEVs: A new player in multiple disease pathology and treatment

Xiyue Zhou, Shuyun Liu, Yanrong Lu, Meihua Wan, Jingqiu Cheng, Jingping Liu

First published: 31 March 2023

Handle Redirect

doi.org

First of all,

Explanation of terms

MitoEVs

MitoEVs are extracellular vesicles (EVs) that contain mitochondrial components. They promote cell-to-cell communication and can affect the metabolism and phenotype of recipient cells. Changes in MitoEV production under pathological conditions suggest their potential as disease biomarkers and therapeutic targets.

Extracellular vesicles

Extracellular vesicles (EVs) are liposome-like, cell-derived structures that promote cell-to-cell communication and carry bioactive cargo (such as nucleic acids, proteins, and lipids) to influence the function and phenotype of recipient cells. EVs have potential value in medical applications such as disease diagnosis, therapeutic targeting, and drug delivery. Exosomes are a subset of EVs.

Mitochondria

Mitochondria are intracellular structures responsible for specific functions, playing important roles in cellular processes such as energy production, metabolic processes, and the regulation of cell death. Mitochondria are the principal site of ATP generation and carry out aerobic cellular respiration, the process of breaking down organic molecules using oxygen to supply energy. Mitochondria also possess their own mitochondrial DNA and have an evolutionary origin distinct from other intracellular structures. Mitochondrial dysfunction is associated with many diseases, aging, and metabolic disorders.

A brief explanation of this paper.

This paper is a review article. It is a paper that summarizes the latest findings in an accessible way. To summarize this paper briefly, it explains the role of mitochondria-derived extracellular vesicles (EVs) in exerting functional effects on various cells under various conditions. It also touches on the potential of MitoEVs as biomarkers or therapies, with an eye toward clinical application.

What are mitochondria-derived EVs

  1. Mitochondrial components are present in nearly all types of extracellular vesicles (EVs) derived from cultured cells and human body fluids.
  2. These components include mtDNA fragments, full-length mtDNA, mitochondrial proteins, and even intact mitochondria.
  3. EV-mediated mitochondrial transfer may serve as an important messenger of cell-to-cell communication and may be affected by disease states.
  4. The release and characteristics of MitoEVs may be influenced by multiple factors, such as the type of cell/tissue of origin, the state of the donor cell/tissue, and the isolation method.

How are MitoEVs produced and released?

  1. MitoEVs are difficult to separate from EVs and exosomes.
  2. After being generated, MitoEVs may fuse with other exosomes and be released outside the cell.
  3. EV-mediated release of mitochondrial contents may serve as a means of maintaining the homeostasis of donor cells.
  4. Mitovesicles, a newly discovered EV subtype enriched in mitochondrial contents found in brain tissue, have characteristics quite different from standard EVs.
  5. By regulating the process of EV-mediated mitochondrial component delivery, desired mitochondrial components can be selectively sorted into EVs for therapeutic purposes.

Identification of MitoEVs

  1. Various methods such as ultracentrifugation, gradient centrifugation, PEG-based precipitation, and size-exclusion chromatography can be used for EV isolation, but because there are no definitive characteristics, specific isolation methods for MitoEVs are limited.
  2. General methods of EV characterization, such as morphology, size, and surface markers, can be detected using NTA, EM, FC, and immunoblotting, but the size and mitochondrial contents of MitoEVs are highly heterogeneous.
  3. Mitochondrial components delivered from donor cells by EVs may be incorporated into the mitochondrial network of recipient cells and exert biological functions such as metabolic regulation and immune regulation.
  4. Further research is needed to evaluate the ideal methods for isolating MitoEVs from different types of biological samples and from large MitoEVs.

What are the biological effects of MitoEVs?

Metabolic regulation

Mitochondria play an important role in cellular energy and metabolism, and abnormalities can have serious consequences. EV-mediated mitochondrial delivery has been shown to restore the mitochondrial function of recipient cells, as seen in studies where activated platelets transplant respiration-competent mitochondria into mesenchymal stem cells, and where EVs from MSCs restore the mtDNA copy number and bioenergetic deficits of renal tubular cells. These findings suggest that packaging functional mitochondria into EVs and transferring them to recipient cells can improve cellular function.

Immunomodulatory function

  1. The immune response is important for protecting against disease, but damaged mitochondrial components released from EVs may induce inflammation and suppress T-cell function.
  2. However, EV-mediated mitochondrial transfer can also enhance the function of immune cells and maintain tissue homeostasis.
  3. Mitochondrial damage and MitoEVs play important roles in the pathogenesis of various diseases, including cancer, liver disease, infections, and cardiovascular disease.

The impact of MitoEVs on disease

Cancer

  1. There is a role for extracellular vesicles (EVs) in the delivery of mitochondrial components that affect the function of cancer cells under various conditions.
  2. It has been reported that mtDNA-rich EVs are transferred from breast cancer cells to promote the invasion of recipient breast cancer cells under glutamine-deprived conditions. This is achieved by increasing the expression of matrix metalloproteinase (MMP) and α5β1 integrin.
  3. The release of MitoEVs by acute myeloid leukemia (AML) cells during cell differentiation has also been reported. Inhibiting this impairs myeloid differentiation. Furthermore, LON-overexpressing mouse melanoma cells release mtDNA-rich EVs to induce cytokine production in macrophages, thereby suppressing cytotoxic T-cell immune responses in the tumor microenvironment.
  4. A role for EV-mediated mitochondrial delivery in cancer drug resistance has also been reported. In metastatic breast cancer patients who became resistant to insulin therapy, mtDNA-rich EVs were found to be circulating. These may act as oncogenic signals that induce endocrine therapy resistance in oxidative phosphorylation-dependent breast cancer cells. EVs released from chemotherapy-resistant triple-negative breast cancer cells may deliver functional mitochondria to sensitive triple-negative breast cancer cells, increasing chemotherapy resistance and tumorigenesis. Similarly, EVs from tumor-activated stromal cells delivered mitochondria to malignant glioma cells, resulting in resistance to radiotherapy and chemotherapy for the cancer.

In summary, EV-mediated mitochondrial delivery may contribute to cancer drug resistance and promote tumor invasion and growth.

Liver disease

EV-mediated mitochondrial delivery contributes to alcoholic liver disease by inducing endoplasmic reticulum stress and inflammation through the release of mtDNA-rich microparticles and elevated mtRNA levels, further inducing the release of pro-inflammatory factors.

Cardiovascular disease

Obesity is strongly associated with cardiovascular disease, and adipocytes under heat stress release EVs carrying damaged mitochondrial components, inducing ROS bursts and mitochondrial dysfunction in cardiac muscle tissue. However, EVs from adipocytes pretreated with palmitic acid can protect cardiac cells from acute oxidative stress.

Respiratory disease

EV-mediated mitochondrial transfer may regulate inflammation in respiratory diseases. Asthma patients have higher levels of HLA-DR+ EVs, and COPD patients have higher levels of mtDNA circulating in the body. These EVs may serve as molecules that sense exposure to tobacco and the pathogenesis of COPD.

Toward clinical application

MitoEVs released by mitochondrial damage may function as disease biomarkers and, furthermore, by affecting the metabolic state of target cells, may become therapeutic agents for multiple diseases.

Biomarkers

MitoEVs released from donor cells can serve as potential biomarkers for the diagnosis or monitoring of disease by reflecting various pathological states.

Cancer
  1. Early diagnosis of cancer is difficult, but extracellular vesicles (EVs) hold potential as biomarkers.
  2. Because mitochondrial EVs (MitoEVs) contain information reflecting the state of the parent cell, they may be useful for monitoring cancer progression and treatment response.
  1. Age-related diseases are associated with oxidative stress and mitochondrial damage, and their diagnosis requires non-invasive biomarkers.
  2. Circulating mitochondrial markers such as ATP5A and NDUFS3 may serve as predictors of neuropathy and frailty in older adults.

Therapeutic strategies

Cardiovascular disease

MitoEVs may become an innovative cell-free therapeutic strategy in the treatment of cardiovascular disease because they can enhance the mitochondrial function and cell viability of damaged cardiomyocytes, probably through the expression of PGC-1α, and improve cardiac function after myocardial infarction.

Neurological diseases

  1. Neurological diseases affect the brain and neurons, and mitochondrial damage is an important factor in their onset.
  2. Mitochondria-rich extracellular vesicles (EVs) derived from neural stem cells and other types of cells are promising as therapeutic agents for neurological diseases by restoring mitochondrial function and reducing inflammation.

Impressions

MitoEVs are extremely attractive. However, as stated in this paper, it is technically quite difficult to isolate only the mitochondria-derived ones from general EVs (exosomes). At least for now. Because many EVs are lost during the isolation process, there is a high likelihood of losing many EVs. Therefore, for diagnostic and biomarker purposes, I think it is reasonable to extract only mitochondria-derived EVs and perform testing in order to reduce noise and improve the reproducibility of the data. However, for therapeutic use, I think the cost-effectiveness needs to be considered. With an innovative technological revolution, I would like to make it possible to extract large quantities of purified exosomes.