bims-mitrat 2025-12-07 papers

Eur J Pharmacol. 2025 Dec 03. pii: S0014-2999(25)01187-2. [Epub ahead of print] 178433

Intercellular Mitochondrial Transfer: A Novel Neuroprotective Strategy in Stroke Management.

Xihang Piao, Xiaolei Tang, Li Li, Ying Zhang, Haiyan Li.

Stroke remains a leading cause of death and long-term disability worldwide. Although revascularization therapies have transformed acute care, effective neuroprotective strategies are still lacking. Intercellular mitochondrial transfer has recently gained attention as a promising endogenous repair mechanism. Through tunneling nanotubes, extracellular vesicles, or cell fusion, healthy mitochondria can be transferred from donor to recipient cells, helping restore bioenergetic homeostasis in injured neurons. This phenomenon, functionally comparable to organelle-level metabolic rescue, offers several advantages. It avoids the ethical concerns associated with genetic manipulation, leverages intrinsic intercellular communication for targeted delivery, and provides mitochondrial DNA complementation to correct metabolic defects. Here, we integrate current evidence on the cellular sources, transfer routes, and regulatory mechanisms underlying poststroke mitochondrial exchange; delineate the coordinated contributions of astrocytes, mesenchymal stem cells, microglia, and endothelial cells to this process; and critically evaluate its translational promise alongside the key barriers that must be addressed for successful clinical application.

Keywords: Mitochondrial transfer; multicellular cooperation; stroke; therapeutic strategies; tunneling nanotubes

DOI: https://doi.org/10.1016/j.ejphar.2025.178433

Respir Res. 2025 Dec 02. 26(1): 342

The role of mitochondrial transfer in lung disease.

Kun Yang, Mei Luo, Wenbin Dong.

Keywords: Extracellular vesicles; Lung disease; Mesenchymal stem cells; Mitochondrial transfer/Transplantation; Tunneling nanotubes

DOI: https://doi.org/10.1186/s12931-025-03408-1

ACS Nano. 2025 Nov 30.

Sequential Mitochondrial Transplantation for Myocardial Ischemia-Reperfusion Injury Treatment.

Ziyu Wu, Zichun Zhao, Ronghuang Yu, Yuning Sun, Wenyan Guo, Jun Wang, Chun Mao, Mimi Wan, Min Zhou.

The treatment of myocardial ischemia-reperfusion injury (IRI) requires urgent improvement of mitochondrial dysfunction and sustained energy supply to restore cardiac function, but currently, there is a lack of effective strategies to meet these needs. Here, we transplanted mitochondria to treat myocardial IRI by a sequential administration approach. First, nanomotors with chemotactic target ability are modified on the surface of mitochondria to obtain engineered mitochondrial nanomotors. Then, denatured bovine serum albumin is modified outside the nanomotor, enabling mitochondria to hitchhike on activated neutrophils to accumulate in the damaged heart. During reperfusion, immediate intramyocardial injection of these mitochondria can stabilize energy supply and rescue dying cardiomyocytes from IRI. In the subsequent tissue repair stage, the mitochondria injected intravenously can achieve stepwise targeting to the damaged heart by hitchhiking on activated neutrophils and chemotactic behavior of nanomotors, thereby continuously supplementing energy to cardiomyocytes and enhancing cardiac function. In addition, in vivo results show that sequential administration reduces adverse reactions such as arrhythmia caused by high-dose mitochondrial transplantation. Compared with existing treatment methods, this design of sequential administration is a special strategy targeting the specific needs and inflammatory microenvironment of myocardial IRI, better promoting the clinical translation of mitochondrial transplantation.

Keywords: mitochondrial transplantation; myocardial ischemia-reperfusion injury; nanomotor; neutrophil hitchhiking; sequential therapy

DOI: https://doi.org/10.1021/acsnano.5c10203

Nat Commun. 2025 Dec 04. 16(1): 10891

Mitochondria-targeted gene delivery using fluorinated lipid nanoparticles to alleviate Leber's hereditary optic neuropathy.

Yi Wang, Min Zhao, Hai-Xin Xie, Hao-Yuan Yu, Jing-Song Yang, Lu-Xin Qie, Na-Hui Liu, Jia-Qi Chen, Zi-Juan Yi, Tian-Jiao Zhou, Lei Xing, Xian Wu Cheng, Hu-Lin Jiang.

Mutations in mitochondrial DNA (mtDNA) lead to various mitochondrial diseases for which no cure is currently available. Despite the promising potential of mtDNA correction to treat these disorders, the double mitochondrial membranes have proven to be a tough barrier to overcome. Here, we develop fluorinated lipid nanoparticles with a mitochondrial targeting sequence (F-M-LNP) to overcome the mitochondrial barrier by virtue of their high affinity for mitochondrial membranes, thereby effectively introducing gene into mitochondria. Through the rational design of ionizable lipid structures, we synthesize 16 lipid nanoparticles (LNPs) with varying degrees of fluorination and investigate the key structural features required for efficient mitochondria-targeted gene delivery. As fluorinated ionizable lipid-mediated mitochondrial transport is independent of mitochondrial membrane potential (MMP), F-M-LNPs deliver gene to mitochondria under pathological conditions where MMP is impaired, resulting in a 3.8-fold increase in functional protein expression compared to non-fluorinated LNPs. In a male mouse model of genetically induced mitochondrial disease, F-M-LNP demonstrate functional complementation of mutant mtDNA, alleviating disease symptoms. Together, our results show that modifying vectors with fluorinated groups offers valuable tools for correcting mitochondrial genome defects.

DOI: https://doi.org/10.1038/s41467-025-65874-x

Cancer Res. 2025 Dec 02.

Transfer of Damaged Mitochondria from Cancer Cells to Cancer-Associated Fibroblasts Promotes Tyrosine Kinase Inhibitor Tolerance in EGFR-Mutant Lung Cancer.

Tongyan Liu, Shiyi Huang, Zhitong Li, Jianyu Li, Qinhong Sun, Qinglin Wang, Ziyang Shen, Zhijun Xia, Fanchen Meng, Youtao Xu, Wenjia Xia, Jing Tan, Rong Yin.

Drug-tolerant persister (DTP) cells drive therapeutic resistance in EGFR-mutant lung adenocarcinoma. Using single-cell RNA sequencing, we identified a clinically significant RGS5+MYL9+ cancer-associated fibroblast (CAF) population that was associated with EGFR tyrosine kinase inhibitor (TKI) resistance and poor prognosis. These CAFs were recruited to DTP niches via CCL11 signaling, and they formed tunneling nanotubes through Miro1/RhoA activation induced by TKI-generated mitochondrial reactive oxygen species (ROS). Remarkably, RGS5+MYL9+ CAFs functioned as "metabolic sinks" by accepting tumor-derived damaged mitochondria, thereby promoting DTP survival. Treatment with fasudil, a Rho kinase inhibitor, effectively blocked mitochondrial transfer and restored sensitivity to the EGFR-TKI osimertinib in vivo. Together, this work reveals targetable stromal-tumor crosstalk that sustains DTP populations, proposing a combination therapy for overcoming EGFR-TKI resistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0433

Nat Commun. 2025 Dec 05.

Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.

Bowen Liu, Yue Han, Yuan Jin, Meng Ye, Zeliang Yang, Jingyi Yang, Minglu Zhu, Xuyang Zhao, Yan Jin, Yuxin Yin.

The quality control network in type 2 alveolar epithelial cells (AEC2s) is essential to respond to intrinsic and extrinsic challenges. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain unclear understood. Here, we report a role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Utilizing mice models, we demonstrate that the disruption of GPRC5A specifically in AEC2s aggravates lung injuries. We further observe that GPRC5A deficiency in AEC2s reduces secretion of mitochondrial components in small-EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis.

DOI: https://doi.org/10.1038/s41467-025-66901-7