bims-mitrat 2024-03-31 papers

Issue of 2024‒03‒31
five papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

FEBS J. 2024 Mar 28.

Transfer and fates of damaged mitochondria: role in health and disease.

Hanbing Li, Weiyun Sun, Wenwen Gong, Yubing Han.

Intercellular communication is pivotal in mediating the transfer of mitochondria from donor to recipient cells. This process orchestrates various biological functions, including tissue repair, cell proliferation, differentiation and cancer invasion. Typically, dysfunctional and depolarized mitochondria are eliminated through intracellular or extracellular pathways. Nevertheless, increasing evidence suggests that intercellular transfer of damaged mitochondria is associated with the pathogenesis of diverse diseases. This review investigates the prevalent triggers of mitochondrial damage and the underlying mechanisms of mitochondrial transfer, and elucidates the role of directional mitochondrial transfer in both physiological and pathological contexts. Additionally, we propose potential previously unknown mechanisms mediating mitochondrial transfer and explore their prospective roles in disease prevention and therapy.

Keywords: cell communication; disease; extracellular vesicles; mitochondria; mitochondrial quality control; mitochondrial transfer

DOI: https://doi.org/10.1111/febs.17119

Int J Mol Sci. 2024 Mar 21. pii: 3562. [Epub ahead of print]25(6):

Therapeutic Applications of Stem Cell-Derived Exosomes.

Omar Abdulhakeem Ahmed Yusuf Abdulmalek, Khaled Hameed Husain, Haya Khaled Ali Abdulla AlKhalifa, Mariam Masood Abdulkarim Bahrooz Alturani, Alexandra E Butler, Abu Saleh Md Moin.

Exosomes are extracellular vesicles of endosomal origin, ranging from 30 to 150 nm in diameter, that mediate intercellular transfer of various biomolecules, such as proteins, lipids, nucleic acids, and metabolites. They modulate the functions of recipient cells and participate in diverse physiological and pathological processes, such as immune responses, cell-cell communication, carcinogenesis, and viral infection. Stem cells (SCs) are pluripotent or multipotent cells that can differentiate into various cell types. SCs can also secrete exosomes, which exhibit remarkable therapeutic potential for various diseases, especially in the field of regenerative medicine. For example, exosomes derived from mesenchymal stem cells (MSCs) contain proteins, lipids, and miRNAs that can ameliorate endocrine disorders, such as diabetes and cancer. Exosomes from SCs (sc-exos) may offer similar advantages as SCs, but with reduced risks and challenges. Sc-exos have lower tumorigenicity, immunogenicity, and infectivity. They can also deliver drugs more efficiently and penetrate deeper into tissues. In this review, we provide an overview of the recent advances in sc-exos and their therapeutic applications in various diseases, such as diabetes and cancer. We also elucidate how the biological effects of sc-exos depend on their molecular composition. We also address the current challenges and future directions of using sc-exos.

Keywords: diabetic microvascular complications; exosomes; microRNAs; precision medicine; stem cells

DOI: https://doi.org/10.3390/ijms25063562

Biomolecules. 2024 Mar 07. pii: 316. [Epub ahead of print]14(3):

Mitochondrial Transplantation Therapy Ameliorates Muscular Dystrophy in mdx Mouse Model.

Mikhail V Dubinin, Irina B Mikheeva, Anastasia E Stepanova, Anastasia D Igoshkina, Alena A Cherepanova, Alena A Semenova, Vyacheslav A Sharapov, Igor I Kireev, Konstantin N Belosludtsev.

Duchenne muscular dystrophy is caused by loss of the dystrophin protein. This pathology is accompanied by mitochondrial dysfunction contributing to muscle fiber instability. It is known that mitochondria-targeted in vivo therapy mitigates pathology and improves the quality of life of model animals. In the present work, we applied mitochondrial transplantation therapy (MTT) to correct the pathology in dystrophin-deficient mdx mice. Intramuscular injections of allogeneic mitochondria obtained from healthy animals into the hind limbs of mdx mice alleviated skeletal muscle injury, reduced calcium deposits in muscles and serum creatine kinase levels, and improved the grip strength of the hind limbs and motor activity of recipient mdx mice. We noted normalization of the mitochondrial ultrastructure and sarcoplasmic reticulum/mitochondria interactions in mdx muscles. At the same time, we revealed a decrease in the efficiency of oxidative phosphorylation in the skeletal muscle mitochondria of recipient mdx mice accompanied by a reduction in lipid peroxidation products (MDA products) and reduced calcium overloading. We found no effect of MTT on the expression of mitochondrial signature genes (Drp1, Mfn2, Ppargc1a, Pink1, Parkin) and on the level of mtDNA. Our results show that systemic MTT mitigates the development of destructive processes in the quadriceps muscle of mdx mice.

Keywords: Duchenne muscular dystrophy; lipid peroxidation; mitochondrial dysfunction; mitochondrial transplantation; muscle force; skeletal muscle

DOI: https://doi.org/10.3390/biom14030316

Front Biosci (Schol Ed). 2024 Mar 14. 16(1): 7

A Two-Genome Portrayal of Mitochondrial Disorders: A Review with Clinical Presentations.

Jude M Abadie.

Disorders of mitochondrial function are responsible for many inherited neuromuscular and metabolic diseases. Their combination of high mortality, multi-systemic involvement, and economic burden cause devastating effects on patients and their families. Molecular diagnostic tools are becoming increasingly important in providing earlier diagnoses and guiding more precise therapeutic treatments for patients suffering from mitochondrial disorders. This review addresses fundamental molecular concepts relating to the pathogenesis of mitochondrial dysfunction and disorders. A series of short cases highlights the various clinical presentations, inheritance patterns, and pathogenic mutations in nuclear and mitochondrial genes that cause mitochondrial diseases. Graphical and tabular representations of the results are presented to guide the understanding of the important concepts related to mitochondrial molecular genetics and pathology. Emerging technology is incorporating preimplantation genetic testing for mtDNA disorders, while mitochondrial replacement shows promise in significantly decreasing the transfer of diseased mitochondrial DNA (mtDNA) to embryos. Medical professionals must maintain an in-depth understanding of the gene mutations and molecular mechanisms underlying mitochondrial disorders. Continued diagnostic advances and comprehensive management of patients with mitochondrial disorders are essential to achieve robust clinical impacts from comprehensive genomic testing. This is especially true when supported by non-genetic tests such as biochemical analysis, histochemical stains, and imaging studies. Such a multi-pronged investigation should improve the management of mitochondrial disorders by providing accurate and timely diagnoses to reduce disease burden and improve the lives of patients and their families.

Keywords: maternal inheritance; mitochondrial disorders; mitochondrial genome

DOI: https://doi.org/10.31083/j.fbs1601007

Cancer Sci. 2024 Mar 26.

Impacts of tissue context on extracellular vesicles-mediated cancer-host cell communications.

Nao Nishida-Aoki, Takahiro Ochiya.

Tumor tissue is densely packed with cancer cells, non-cancerous cells, and ECM, forming functional structures. Cancer cells transfer extracellular vesicles (EVs) to modify surrounding normal cells into cancer-promoting cells, establishing a tumor-favorable environment together with other signaling molecules and structural components. Such tissue environments largely affect cancer cell properties, and so as EV-mediated cellular communications within tumor tissue. However, current research on EVs focuses on functional analysis of vesicles isolated from the liquid phase, including cell culture supernatants and blood draws, 2D-cultured cell assays, or systemic analyses on animal models for biodistribution. Therefore, we have a limited understanding of local EV transfer within tumor tissues. In this review, we discuss the need to study EVs in a physiological tissue context by summarizing the current findings on the impacts of tumor tissue environment on cancer EV properties and transfer and the techniques required for the analysis. Tumor tissue environment is likely to alter EV properties, pose physical barriers, interactions, and interstitial flows for the dynamics, and introduce varieties in the cell types taken up. Utilizing physiological experimental settings and spatial analyses, we need to tackle the remaining questions on physiological EV-mediated cancer-host cell interactions. Understanding cancer EV-mediated cellular communications in physiological tumor tissues will lead to developing interaction-targeting therapies and provide insight into EV-mediated non-cancerous cells and interspecies interactions.

Keywords: cellular spatial distribution; exosomes; extracellular vesicles; organotypic 3D culture models; tumor microenvironment

DOI: https://doi.org/10.1111/cas.16161