bims-mitrat 2025-07-27 papers

Biomaterials. 2025 Jul 18. pii: S0142-9612(25)00482-X. [Epub ahead of print]325 123563

Therapeutic mitochondrial transfer via mesenchymal stem cell-derived microvesicles for macrophage modulation in myocardial infarction complicated by diabetes.

Zixuan Dong, Song Liu, Xiaobing Liu, Dong He, Qi Chu, Linjie Zhong, Xiangyu Yu, Xiaoling Fu.

Diabetes is closely associated with the onset and prognosis of myocardial infarction (MI). However, current treatment strategies primarily focus on addressing MI, often neglecting the detrimental effects of hyperglycemia, a hallmark of diabetes. Hyperglycemia disrupts the crucial transition of macrophages from the M1 to M2 phenotype, thereby exacerbating MI-induced tissue damage and impeding myocardial repair. Mitochondria have emerged as key regulators of macrophage phenotype, suggesting the potential for modulating macrophages through mitochondria transfer. In this study, we developed microvesicles containing active mitochondria (Mito@euMVs), derived from enucleated mesenchymal stem cells. We found that 71.7 % of the Mito@euMVs contained mitochondria, with no nuclear material present. Mito@euMVs effectively delivered mitochondria into macrophages, facilitating their transit from M1 to M2 phenotype, even in hyperglycemia. Further in vivo study using a diabetic rat model of MI confirmed their cardiac repair properties. Treatment of Mito@euMVs led to 24.55 ± 4.33 % improvement in ejection fraction and 15.48 ± 4.04 % in fractional shortening 28 days post-MI in diabetic rats. Additionally, Mito@euMVs mitigated infarcted left ventricular wall thinning and fibrosis, enhanced M2 macrophage phenotype, promoted cardiomyocyte survival. Our study emphasizes the effective modulation of macrophage phenotype via mitochondrial transfer with Mito@euMVs and highlights their promising potential in treating MI.

Keywords: Diabetes; Enucleated MSC-Derived microvesicles; Macrophage phenotype; Mitochondrial transfer; Myocardial infarction

DOI: https://doi.org/10.1016/j.biomaterials.2025.123563

Mol Metab. 2025 Jul 16. pii: S2212-8778(25)00118-8. [Epub ahead of print] 102211

Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer.

Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Luke D Flewwelling, Nathaniel J Andrews, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Leslie Ogilvie, Stavroula Tsitkanou, Jeremy A Simpson, Nicholas P Greene, Arthur J Cheng, Jim Petrik, Christopher G R Perry.

Muscle loss with cancer causes weakness, worsens quality of life, and predicts reduced overall survival rates. Recently, muscle weakness was identified during early-stage cancer before atrophy develops. This discovery indicates that mechanisms independent of muscle loss must contribute to progressive weakness. While mitochondrial stress responses are associated with early-stage 'pre-cachexia' weakness, a causal relationship has not been established. Here, using a mouse model of metastatic ovarian cancer cachexia, we identified that the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents muscle weakness occurring before the development of atrophy in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. These findings indicate that atrophy-independent mechanisms of muscle weakness occur in different muscle types throughout ovarian cancer. Ovarian cancer reduced flexor digitorum brevis (FDB) whole muscle force production and myoplasmic free calcium ([Ca2+]i) during contraction in intact single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout ovarian cancer. These discoveries identify that muscle weakness can occur independent of atrophy throughout ovarian cancer in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force early during ovarian cancer during the pre-atrophy period and in late stages once cachexia has become severe.

Keywords: Ovarian cancer cachexia; mitochondria; skeletal muscle

DOI: https://doi.org/10.1016/j.molmet.2025.102211

Nat Commun. 2025 Jul 19. 16(1): 6666

RIPK4-mediated MFN2 degradation drives osteogenesis through mitochondrial fragmentation and restricts myelopoiesis by blocking mitochondrial transfer.

Peng Ding, Xing Wang, Chuan Gao, Yuehan Wei, Gan Li, Wenlei Zhu, Ni Wang, Wan Fu, Qihang Fang, Meng Yao, Yigang Huang, Chenyi Jiang, Youshui Gao, Jing Zhang, Junjie Gao, Qing Zhong, Changqing Zhang.

Human RIPK4 mutation leads to Bartsocas-Papas syndrome (BPS), characterized by severe skin, craniofacial and limb abnormalities. Currently, our understanding of RIPK4's function has focused on epidermal differentiation and development, whether RIPK4 regulates skeletal homeostasis remains largely elusive. Herein, through global RIPK4 ablation in adult mice, we demonstrate that RIPK4 deficiency leads to osteoporosis, promotes myeloid-biased hematopoiesis and osteolineage RIPK4 plays a crucial role in bone formation and myeloid hematopoiesis. Further detailed investigation pinpoints that RIPK4 interacts with mitochondrial fusion protein MFN2 in a kinase-dependent manner. RIPK4 facilitates the phosphorylation of MFN2, which subsequently undergoes degradation through the proteasome pathway and disrupts the dynamic equilibrium of mitochondrial fission and fusion. Additionally, we also show that osteolineage RIPK4 maintains bone marrow myelopoiesis by MFN2-mediated mitochondrial transfer. More interestingly, while osteocytic RIPK4 could modestly influence the osteogenesis, it is insufficient to sustain bone marrow myelopoiesis owing to the limited amount of mitochondria transfer. These findings decipher the essential role of RIPK4 in maintaining skeletal homeostasis and unveil an unappreciated mechanism of RIPK4-MFN2 axis in regulating osteogenesis and bone marrow myelopoiesis.

DOI: https://doi.org/10.1038/s41467-025-61808-9

J Neurooncol. 2025 Jul 21.

Tunneling nanotubes between glioblastoma cells and T cells and hijack of mitochondria.

Yanamandra Venkataratnam, Victor Mukherjee, Nikhil Rai, Mahesh Mahalingaswamy, Diksha Shandilya, Subhas Konar, Nandeesh Bevinahalli Nanjegowda, Girish Waghmare, Nandakumar Dalavaikodihalli Nanjaiah.

PURPOSE: Glioblastoma is a highly aggressive and invasive brain tumor that can interact dynamically with its surrounding tumor microenvironment, including resident and infiltrating-immune cells. These interactions largely govern glioblastoma progression and resistance to therapy. Glioblastoma cells can actively modulate immune cell functions, either by inhibiting immune responses or reprogramming immune cells. This study explores the dynamic interaction between glioblastoma cells and T cells.
METHODS: The connections between glioblastoma cells and T cells were analyzed by immunohistochemistry, immunofluorescence and scanning electron microscopy. Inhibition of tunneling nanotubes (TNTs) between glioblastoma cells and T cells was performed using carbenoxolone. Fluorogenic probes were used for mitochondrial membrane potential and reactive oxygen species (ROS) in mitochondria, glioblastoma cells and T cells after co-culture. Viability and LAG-3 levels were analyzed in T cells.
RESULTS: Glioblastoma cells show connections between themselves and forms physical connections with T cells through TNTs. Glioblastoma cells hijack mitochondria from T cells through these connections and effect was reversed on using carbenoxolone. Glioblastoma cells show increased mitochondrial membrane potential and decreased mitochondrial ROS after co-culture, while ROS was increased in glioblastoma cells and decreased in T cells.
CONCLUSION: We show for the first time that glioblastoma cells and T cells physically connect through TNTs. Most importantly, glioblastoma cells hijack the mitochondria of T cells for its own advantage. By focusing on these complex tumor-immune cell interactions, this study aims to uncover a novel mode of physical communication in glioblastoma microenvironment.

Keywords: Glioblastoma; Immune cells; Mitochondrial transport; Tumor microenvironment; Tunneling nanotubes

DOI: https://doi.org/10.1007/s11060-025-05150-6