bims-mitrat 2025-12-28 papers

Alzheimers Dement. 2025 Dec;21 Suppl 1 e102364

Sara Yunta-Sánchez, Regina Mengual-Fenollar, Juan Pedro Bolaños, Rubén Quintana-Cabrera.

BACKGROUND: In the nervous system, mitochondria can be transferred between neural cells through intercellular tunneling nanotubes (TNTs), microvesicles, or as free organelles. This transfer not only alters the mitochondrial content and respiration of recipient neural cells but also triggers a profound rewiring of their physiology, with glial cells and immune responses playing key roles in this reconfiguration.
METHOD: Primary co-cultures of neurons and glial cells, along with in vivo analysis of mitochondrial transfer in mouse brains, were monitored using kinetic microscopy, flow cytometry, and metabolic flux analyses to explore the physiological changes in neural cells. Mitochondrial DNA (mtDNA) transmission was tracked through RT-PCR and ARMS-PCR to examine hierarchical transfer and acquisition.
RESULT: Communication between neural cells, particularly through TNTs, shows dynamic mitochondrial transfer, regulated by mitochondrial transport, fusion, and fission events. These events respond to structural and signaling changes in intercellular communication, mainly via TNTs. As a result, transmitted mitochondria reconfigure the content, metabolism, and mtDNA composition in recipient neurons and astrocytes. Notably, we observe a significant role of microglia and astrocytes upon mitochondrial acquisition in mouse brains, suggesting inflammatory events that may coordinate mitochondrial transfer as key regulators of metabolic rewiring and cognitive effects in the nervous system.
CONCLUSION: Our findings provide evidence that a multilayered mitochondrial transfer is a critical mechanism for reconfiguring neural metabolism, immune responses, and overall neural physiology.

DOI: https://doi.org/10.1002/alz70855_102364

Adv Sci (Weinh). 2025 Dec 25. e13474

A Conjugation Delivery System of Macrophages and Platelet Pharmacytes Promotes Regeneration After Spinal Cord Injury.

Haoli Wang, Hao Hu, Yijun Li, Lintao Hu, Chenhui Gu, Yiwei Zhu, Jing Huang, Na Li, Shuqi Jiang, Shouyan Zu, Jiachen Xu, Yining Wang, Ke Yang, Pengfei Chen, Liqing Shangguan, Yongcheng Wang, Shunwu Fan, Xianfeng Lin, Qingqing Wang.

Mitochondrial dysfunction occurs in macrophages with efferocytosis defects, which hinders recovery from tissue injury. Targeting intercellular mitochondrial transfer is a promising therapy for augmenting cellular therapy. Here, this work elucidates the stress resistance capabilities of mitochondria in anucleate platelets and shows that platelets transfer mitochondria to macrophages under cellular stress, which restores impaired efferocytosis. This work devises a delivery system in which platelets are loaded with cationic polymers (NPs) for PPARγ overexpression and conjugated to macrophages (M-P-NPs@PPARγ). In this system, activated platelets induce mitochondrial transfer and release NPs into macrophages, increasing ATP production and maintaining lipid homeostasis. As a proof-of-concept, in representative efferocytosis-deficit central nervous system disease spinal cord injury model, impaired efferocytosis is reversed by M-P-NP@PPARγ, resulting in neural regeneration and remyelination and ultimately promoting motor function recovery. In summary, this work has developed a strategy combining mitochondria and gene delivery to restore macrophage efferocytosis postinjury by regulating energy and lipid metabolism.

Keywords: cellular combination delivery system; efferocytosis; gene delivery; mitochondria transfer; spinal cord injury

DOI: https://doi.org/10.1002/advs.202513474

Nat Commun. 2025 Dec 23.

Leveraging engineered mitochondria through intercellular communication network for accelerated transport and delivery.

Yiwei Peng, Datong Gao, Yiliang Yang, Yitian Du, Zhenzhen Yang, Jiajia Li, Meng Lin, Yanxia Zhou, Xinru Li, Xianrong Qi.

Inspired by the non-transmembrane transfer of mitochondria in cell-to-cell communications, herein, we report an original exploration to accelerate mitochondrial intercellular transport, and its application to exogenous cargo delivery. We discover that deliberate PINK1-targeted mitophagy downregulation elevates mitochondrial transit capacity via multifaceted drivers-morphological adaptation, metabolic reprogramming, and respiratory enhancement. Capitalizing on this, we engineer high-speed mitochondrial vehicles for photosensitizer hitchhiking, with spatiotemporal tracking elucidating its dynamic intercellular transit and physiological impacts. Through mitochondria's communication network-tunneling nanotubes (TNTs), the mitochondria-photosensitizer cotransporter achieves reinforced intercellular delivery, thereby inducing deep tumor penetration and enhanced photodynamic killing. Our work establishes a transformative mitochondria-hitchhiking platform for overcoming biological barriers in drug delivery and provides mechanistic insights into manipulating intercellular organelle transport for therapeutic applications.

DOI: https://doi.org/10.1038/s41467-025-67837-8

Exp Neurol. 2025 Dec 23. pii: S0014-4886(25)00474-1. [Epub ahead of print]398 115609

Investigating the therapeutic potential of nasal administration of mitochondria on blood-brain barrier integrity and vasogenic brain Edema in a rat ischemic stroke model.

Nooshin Sadeghian, Hamdollah Panahpour, Mohammad Reza Alipour, Fereshteh Farajdokht, Javad Shadman.

Mitochondrial dysfunction is an early and critical factor in the development of ischemic stroke. This study investigated the therapeutic potential of intranasally delivered mitochondria to reduce vasogenic cerebral edema and protect blood-brain barrier (BBB) integrity in a rat model of ischemic stroke. Male rats underwent 60 min of middle cerebral artery occlusion to induce stroke and then received daily intranasal mitochondrial treatment (750 μg/50 μl) for two days. Cerebral edema was measured by the wet/dry method, and BBB permeability was assessed using Evans blue dye extravasation. Mitochondrial function was evaluated by assessing mitochondrial swelling, mitochondrial membrane potential (MMP), succinate dehydrogenase (SDH) activity, and reactive oxygen species (ROS) production. Protein levels of matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1), and markers of apoptosis were examined by immunofluorescence. The treatment significantly reduced infarct size, improved sensorimotor function, decreased cerebral edema, and preserved BBB integrity. These benefits correlated with improved mitochondrial function-demonstrated by reduced swelling and ROS, and restoration of MMP and SDH activity. Additionally, mitochondrial therapy lowered apoptosis and decreased expression of MMP-9 and ICAM-1. These findings suggest that intranasal mitochondrial administration mitigates cerebral edema and BBB disruption after ischemic stroke. This protective effect is likely achieved by enhancing mitochondrial function and lowering levels of inflammation-related proteins, suggesting a promising neuroprotective strategy targeting mitochondrial dysfunction in stroke.

Keywords: Blood-brain barrier; Brain edema; Intranasal administration; Ischemic stroke; Mitochondria

DOI: https://doi.org/10.1016/j.expneurol.2025.115609

Mol Biol Cell. 2025 Dec 24. mbcE25040188

A new subset of mitochondrial-derived vesicles perform inter-mitochondrial communications.

Priyanka Adla, Vani Bshivakumar, Dheeraj Pathak, Ushodaya Mattam, Prasad Tammineni, Thanuja Krishnamoorthy, Naresh B V Sepuri.

Mitochondria have a fascinating array of tools in their armory for maintaining cellular homeostasis, of which the formation of Mitochondrial-Derived Vesicles (MDVs) is the least energy-intensive. MDVs have become the 'go-to' vesicles for mitochondria to perform functions such as ferrying damaged mitochondrial proteins to lysosomes and regulating peroxisomal morphology. In a corollary to the increasing number of MDV functions, the discovery of MDV subsets has also increased. However, all the known MDV communications have been from mitochondria to other organelles. Using purified mitochondria from rat liver, we show that MDVs can be generated in vitro, and proteomic analyses reveal that liver MDVs are enriched in metabolic proteins mirroring the liver's metabolic hub status. Intriguingly, live cell imaging studies in HepG2 cells reveal a new subset of MDVs that are TOMM70+ve but TOMM20-ve. This subset of MDVs harbors metabolic enzymes, such as ALDH7A1, an aldehyde dehydrogenase. Remarkably, this class of MDVs facilitates communication between mitochondria, revealing a previously unknown communication channel. [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-04-0188