bims-mitrat 2025-04-27 papers

Mitochondrion. 2025 Apr 18. pii: S1567-7249(25)00039-X. [Epub ahead of print] 102042

Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling.

Elly H Shin, Quinn Le, Rachel Barboza, Amanda Morin, Shiva M Singh, Christina A Castellani.

Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several complex diseases and disorders, including cardiovascular, cardiometabolic, neurodegenerative diseases and some cancers. The risk for these diseases and disorders is often associated with mitochondrial dysfunction, particularly the quantitative and qualitative features of the mitochondrial genome. Emerging results implicate mito-nuclear crosstalk as the mechanism by which mtDNA variation affects complex disease outcomes. Experimental approaches are emerging for the targeting of mitochondria as a potential therapeutic for several of these diseases, particularly in the form of mitochondrial transplantation. Current approaches to mitochondrial transplantation generally involve isolating healthy mitochondria from donor cells and introducing them to diseased recipients towards amelioration of mitochondrial dysfunction. Using such a protocol, several reports have shown recovery of mitochondrial function and improved disease outcomes post-mitochondrial transplantation, highlighting its potential as a therapeutic method for several complex, severe and debilitating diseases. Additionally, the mitochondrial genome can be modified prior to transplantation to target disease-associated site-specific mutations and to reduce the ratio of mutant-to-WT alleles. These promising results may underlie the potential impact of mitochondrial transplantation on mito-nuclear genome interactions in the setting of the disease. Further, we recommend that mitochondrial transplantation experimentation include an assessment of potential impacts on remodelling of the nuclear genome, particularly the nuclear epigenome and transcriptome. Herein, we review these and other triumphs and challenges of mitochondrial transplantation as a potential novel therapeutic for mitochondria-associated diseases.

Keywords: Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial transplantation; Nuclear epigenome; Nuclear transcriptome

DOI: https://doi.org/10.1016/j.mito.2025.102042

J Mol Med (Berl). 2025 Apr 24.

New mesenchymal stem/stromal cell-based strategies for osteoarthritis treatment: targeting macrophage-mediated inflammation to restore joint homeostasis.

María Jesús Araya-Sapag, Eliana Lara-Barba, Cynthia García-Guerrero, Yeimi Herrera-Luna, Yesenia Flores-Elías, Felipe A Bustamante-Barrientos, Guillermo G Albornoz, Consuelo Contreras-Fuentes, Liliana Yantén-Fuentes, Noymar Luque-Campos, Ana María Vega-Letter, Jorge Toledo, Patricia Luz-Crawford.

Macrophages are pivotal in osteoarthritis (OA) pathogenesis, as their dysregulated polarization can contribute to chronic inflammatory processes. This review explores the molecular and metabolic mechanisms that influence macrophage polarization and identifies potential strategies for OA treatment. Currently, non-surgical treatments for OA focus only on symptom management, and their efficacy is limited; thus, mesenchymal stem/stromal cells (MSCs) have gained attention for their anti-inflammatory and immunomodulatory capabilities. Emerging evidence suggests that small extracellular vesicles (sEVs) derived from MSCs can modulate macrophage function, thus offering potential therapeutic benefits in OA. Additionally, the transfer of mitochondria from MSCs to macrophages has shown promise in enhancing mitochondrial functionality and steering macrophages toward an anti-inflammatory M2-like phenotype. While further research is needed to confirm these findings, MSC-based strategies, including the use of sEVs and mitochondrial transfer, hold great promise for the treatment of OA and other chronic inflammatory diseases.

Keywords: Homeostasis; Macrophages; Osteoarthritis

DOI: https://doi.org/10.1007/s00109-025-02547-8

Shock. 2025 Apr 16.

SVF mediates immunometabolic alterations in burn-induced hypermetabolic adipose tissue via mitochondrial transfer.

Lauar de Brito Monteiro, Shayahati Bieerkehazhi, Ayesha Aijaz, Carly M Knuth, Graham Rix, Ju Hee Lee, Hoon-Ki Sung, Mahmoud Farahat, Marc G Jeschke.

ABSTRACT: Adipose tissue (AT) browning promotes systemic alterations in energy expenditure as a response to catecholamine-induced hypermetabolism in severe burn trauma. The AT is composed of the stromal vascular fraction (SVF) and adipocytes. SVF contains a vast population of immune cells that maintain AT homeostasis. Despite evidence that local immune cell accumulation contributes to hypermetabolism, the underlying mechanism of persistent browning response is not known. Thus, we hypothesized that a specific cellular communication between adipocytes and SVF can mediate the severe metabolic alterations associated with hypermetabolism. Therefore, we used a murine burn model to show that post-burn hypermetabolism compromises mitochondria respiration and alters the immune cell profile of the AT-SVF. We found that adipocyte-derived signals promote metabolic reprogramming and inflammatory responses by SVF after burns in both mice and humans. Interestingly, adipocytes transfer mitochondria to cells in the SVF including different immune cells (macrophages, T cells, B cells) uptake mitochondria from adipocytes. Such data was replicated in human samples as well. These results indicate that adipocytes play a major role in immunometabolic reprogramming following severe burns through crosstalk with the adipose immune cell population. Therefore, targeting immune cell metabolism restoration is a potential strategy to mitigate the detrimental effects of post-burn hypermetabolism on systemic energy balance.

Keywords: Adipose tissue; Browning; Hypermetabolism; Immunometabolism; Inflammation; Mitochondria biology

DOI: https://doi.org/10.1097/SHK.0000000000002608

Trends Cancer. 2025 Apr 22. pii: S2405-8033(25)00094-9. [Epub ahead of print]

Mitochondrial transfer drives immune evasion in tumor microenvironment.

Qiang Cai, Xiaojun Cai, Quazi T H Shubhra.

Tumors subvert T cell metabolism through diverse mechanisms. Ikeda et al. reveal mitochondrial transfer as a tumor-driven immune evasion strategy, where cancer cells deliver dysfunctional mitochondria to T cells, impairing metabolism and inducing exhaustion. These findings highlight mitochondrial dynamics as a promising therapeutic target to improve immunotherapy outcomes.

Keywords: T cell exhaustion; cancer immunotherapy; mitochondrial transfer; tumor microenvironment

DOI: https://doi.org/10.1016/j.trecan.2025.04.002

Front Cell Neurosci. 2025 ;19 1541347

Mitochonic acid 5 mitigates age-related hearing loss progression by targeting defective 2-methylthiolation in mitochondrial transfer RNAs.

Teppei Kouga, Toru Miwa, Fan-Yan Wei, Kishiko Sunami, Kazuhito Tomizawa.

Introduction: Age-related hearing loss (ARHL) is linked to dementia, with mitochondrial dysfunction playing a key role in its progression. Deficient mitochondrial tRNA modifications impair protein synthesis and energy metabolism, accelerating ARHL. Mitochonic acid 5 (MA-5) has shown promise as a therapeutic candidate by improving mitochondrial function, reducing oxidative stress, and stabilizing membrane potential.
Methods: In this study, we investigated the effects of MA-5 on ARHL in cyclin-dependent kinase 5 regulatory subunit-associated protein 1 (Cdk5rap1) knockout (KO) mice, which exhibit early-onset ARHL due to abnormalities in mitochondrial transfer RNA (mt-tRNA) modifications.
Results: MA-5 treatment effectively attenuated ARHL progression in Cdk5rap1-KO mice by improving auditory brainstem response thresholds and distortion product otoacoustic emissions. It also reduced spiral ganglion and outer hair cell loss, while preserving the cochlear structural integrity by preventing mitochondrial degeneration in spiral ligament fibrocytes. Mechanistically, MA-5 upregulated the expression of silent information regulator sirtuin 1 and promoted the nuclear translocation of yes-associated protein, both of which are involved in regulating mitochondrial function and cellular senescence. Metabolomics analysis further demonstrated that MA-5 restored mitochondrial metabolism, reduced lactate accumulation, and maintained mitochondrial integrity.
Conclusion: These findings suggest that MA-5 is a viable treatment option for ARHL and other age-related disorders associated with mitochondrial dysfunction.

Keywords: 2-methylthiolation; age-related hearing loss; cyclin-dependent kinase 5 regulatory subunit-associated protein 1; mitochondrial dysfunction; mitochonic acid 5

DOI: https://doi.org/10.3389/fncel.2025.1541347