bims-mitrat 2025-01-26 papers

ACS Nano. 2025 Jan 24.

Nanoenzyme-Anchored Mitofactories Boost Mitochondrial Transplantation to Restore Locomotor Function after Paralysis Following Spinal Cord Injury.

Runxiu Wei, Yiman Chen, Qiang Yang, Tongge Wang, Yanyun He, Na Yin, Liya Yang, Yifei Gao, Ling Guo, Min Feng.

Mitochondrial transplantation is a significant therapeutic approach for addressing mitochondrial dysfunction in patients with spinal cord injury (SCI), yet it is limited by rapid mitochondrial deactivation and low transfer efficiency. Here, high-quality mitochondria microfactories (HQ-Mitofactories) were constructed by anchoring Prussian blue nanoenzymes onto mesenchymal stem cells for effective mitochondrial transplantation to treat paralysis from SCI. Notably, the results demonstrated that HQ-Mitofactories could continuously produce vitality-boosting mitochondria with highly interconnected and elongated network structures under oxidative stress by scavenging excessive ROS. Furthermore, HQ-Mitofactories enabled efficient transfer of therapeutic mitochondria to injured neurons primarily via gap junctions, resulting in the restoration of mitochondrial homeostasis and thereby suppressing intracellular ROS burst and facilitating neuronal repair. After i.v. administration, HQ-Mitofactories migrated to the injured spinal cords of SCI mice and subsequently promoted neuronal regeneration and remyelination. Consequently, HQ-Mitofactory-treated mice successfully recovered locomotor function within 4 weeks, with 40% of the mice fully restoring walking after hindlimb paralysis. Conversely, untreated SCI exhibited completely abolished hindlimb movements. In light of real-time generation of vitality-boosting mitochondria even under oxidative stress and enabling targeted mitochondrial transfer, HQ-Mitofactories have promising therapeutic potential in the context of mitochondrial transplantation to reduce SCI-related paralysis, and more broadly impact the field of neuroregenerative medicine.

Keywords: gap junctions; locomotor function; mitochondrial activity; mitochondrial transplantation; oxidative stress damage; spinal cord injury

DOI: https://doi.org/10.1021/acsnano.4c12557

Neural Regen Res. 2024 Dec 07.

Mitochondrial transplantation: a promising strategy for the treatment of retinal degenerative diseases.

Jing Chi, Bin Fan, Yulin Li, Qing Jiao, Guang-Yu Li.

The retina, a crucial neural tissue, is responsible for transforming light signals into visual information, a process that necessitates a significant amount of energy. Mitochondria, the primary powerhouses of the cell, play an integral role in retinal physiology by fulfilling the high-energy requirements of photoreceptors and secondary neurons through oxidative phosphorylation. In a healthy state, mitochondria ensure proper visual function by facilitating efficient conversion and transduction of visual signals. However, in retinal degenerative diseases, mitochondrial dysfunction significantly contributes to disease progression, involving a decline in membrane potential, the occurrence of DNA mutations, increased oxidative stress, and imbalances in quality-control mechanisms. These abnormalities lead to an inadequate energy supply, the exacerbation of oxidative damage, and the activation of cell death pathways, ultimately resulting in neuronal injury and dysfunction in the retina. Mitochondrial transplantation has emerged as a promising strategy for addressing these challenges. This procedure aims to restore metabolic activity and function in compromised cells through the introduction of healthy mitochondria, thereby enhancing the cellular energy production capacity and offering new strategies for the treatment of retinal degenerative diseases. Although mitochondrial transplantation presents operational and safety challenges that require further investigation, it has demonstrated potential for reviving the vitality of retinal neurons. This review offers a comprehensive examination of the principles and techniques underlying mitochondrial transplantation and its prospects for application in retinal degenerative diseases, while also delving into the associated technical and safety challenges, thereby providing references and insights for future research and treatment.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00851

Nature. 2025 Jan 22.

Immune evasion through mitochondrial transfer in the tumour microenvironment.

Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2-4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.

DOI: https://doi.org/10.1038/s41586-024-08439-0