bims-mitrat 2025-11-30 papers

Biochem Biophys Res Commun. 2025 Nov 24. pii: S0006-291X(25)01760-7. [Epub ahead of print]794 153044

Mitochondrial transplantation alleviates acute pancreatitis by suppressing macrophage necroptosis.

Cai Sun, Liang Pan, Chengsi Tang, Yiyuan Liu, Sha Ran, Ying Li, Yan Shen.

Acute pancreatitis (AP) is a multifactorial disease in which mitochondrial dysfunction plays a key role by triggering inflammatory cascades and necrotic cell death. Mitochondrial transplantation has been reported to alleviate AP, however its underlying mechanisms remain unclear. To investigate the effect of mitochondrial transplantation on macrophage during AP, we stimulated macrophages with supernatant of damaged pancreatic acinar cells to mimic the inflammatory microenvironment. Upon stimulation, macrophages exhibited an enhanced capacity to internalize exogenous mitochondria. These exogenous mitochondria restored mitochondrial function in damaged macrophages by maintaining mitochondrial membrane potential, suppressing excessive reactive oxygen species production, and restoring ATP levels. Furthermore, mitochondria transplantation significantly inhibited macrophages necroptosis, as evidenced by the decreased protein expression and phosphorylation levels of the necroptosis markers RIPK1 and MLKL in macrophages and pancreatic tissue, and decreased cell necrosis. In terms of inflammation, exogenous mitochondria suppressed macrophage polarization toward the pro-inflammatory M1 phenotype and reduced the expression of pro-inflammatory cytokines. Collectively, these findings demonstrate that macrophage-centered inflammatory regulation constitutes a central mechanism underlying the therapeutic effects of mitochondrial transplantation in AP, providing a theoretical foundation for developing mitochondria-based therapeutic strategies.

Keywords: Acute pancreatitis; Macrophage; Mitochondrial transplantation; Necroptosis

DOI: https://doi.org/10.1016/j.bbrc.2025.153044

Int J Mol Sci. 2025 Nov 15. pii: 11052. [Epub ahead of print]26(22):

Mitochondria-Enriched Extracellular Vesicles (EVs) for Cardiac Bioenergetics Restoration: A Scoping Review of Preclinical Mechanisms and Source-Specific Strategies.

Dhienda C Shahannaz, Tadahisa Sugiura, Taizo Yoshida.

Mitochondrial dysfunction is a pivotal contributor to cardiac disease progression, making it a critical target in regenerative interventions. Extracellular vesicles (EVs) have recently emerged as powerful mediators of mitochondrial transfer and cardiomyocyte repair. This review highlights recent advancements in EV bioengineering and their applications in cardiac mitochondrial rescue, with a particular focus on EVs derived from induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Drawing upon a growing body of preclinical evidence, we examine the mechanisms of mitochondrial content delivery, EV uptake dynamics, and comparative bioenergetic restoration outcomes across EV sources. Special emphasis is placed on therapeutic outcomes such as adenosine triphosphate (ATP) restoration, reactive oxygen species (ROS) modulation, and improvements in contractility and infarct size. The convergence of mitochondrial biology, stem cell-derived EV platforms, and engineering innovations positions mitochondria-enriched EVs as a promising non-cellular regenerative modality for cardiovascular disease.

Keywords: cardiac regenerative therapy; cardiomyocyte repair; extracellular vesicles (EVs); heart failure; induced pluripotent stem cell (iPSCs); mitochondrial dysfunction; mitochondrial transfer; regenerative medicine; stem cell-derived exosomes; targeted organelle delivery

DOI: https://doi.org/10.3390/ijms262211052

Connect Tissue Res. 2025 Nov 25. 1-17

Mitochondrial crosstalk between bone marrow stromal cells and chondrocytes: implication for cartilage repair in osteoarthritis.

Baihui Zhang, Jiasi Zhang, Danyang Yue, Xiao Huang, Jun Pan.

PURPOSE/AIM: Mitochondria are vital dynamic organelles released by cells into extracellular space, endocytosed in or transferred between cells in contact. Mitochondria from healthy bone marrow stem cells (MSCs) show rescue effects on chondrocytes, accordingly a concept of using healthy MSC mitochondria for cartilage regeneration is put forward. Therefore, whether mitochondria from healthy MSCs help to save chondrocytes in damaged cartilage microenvironment is intriguing. We answered this question by considering coexistent MSCs and chondrocytes, and their released mitochondria in damaged joint.
MATERIALS AND METHODS: Mitochondria were extracted from primarily cultured MSCs and chondrocytes of osteoarthritis (OA) human patients to represent mitochondria released endogenously by MSCs and chondrocytes in damaged joint. While mitochondria were extracted from healthy rats to represent mitochondria exogenously added during MSC mitochondrial repair for the inaccessibility of healthy human. The mitochondria were co-cultured with another type of cells. Endocytosing and afterward positioning of exogenous mitochondria, as well as induced alterations in mitochondria and cellular behaviors of recipient cells were assayed.
RESULT: Our results suggested that although mitochondria from healthy MSCs advantaged remedy for inflammatory chondrocytes, mitochondria from healthy and OA chondrocytes, as well as from OA MSCs disadvantaged chondrocytes remedy, no matter the mitochondria were from the same or different species. However, reactive oxygen species (ROS) modulation alleviated the disadvantage.
CONCLUSIONS: Our results provide a reminder for careful consideration of mitochondrial therapy, and explanation for unsuccessful repair of damaged cartilage by MSCs from aspect of mitochondria, as well as potential remedy through ROS modulation.

Keywords: Mitochondrial therapy; ROS; cartilage regeneration; differentiation; stem cells

DOI: https://doi.org/10.1080/03008207.2025.2590044

bioRxiv. 2025 Oct 25. pii: 2021.11.29.470476. [Epub ahead of print]

Activity-dependent mitochondrial transport in peri-synaptic glia drives motor function.

Dunham D Clark, Sonja A Zolnoski, Emily L Heckman, Michael R Kann, Sarah D Ackerman.

Neurons have an outsized metabolic demand, requiring continuous metabolic support from non-neuronal cells called glia. When this support fails, toxic metabolic byproducts accumulate, ultimately leading to excitotoxicity and neurodegeneration. Astrocytes, the primary synapse-associated glial cell type, are known to provide essential metabolites ( e.g. lactate) to sustain neuronal function. Here, we leverage the well-characterized Drosophila motor circuit to investigate another means of astrocyte-to-neuron metabolic support: activity-dependent trafficking of astrocyte mitochondria. Following optogenetic activation, motor neuron mitochondria migrate away from synapses. By contrast, astrocytic mitochondria accumulated peri-synaptically, and at times, were transferred into neighboring neurons. A genetic screen identified the mitochondrial adaptor protein Milton as a key regulator of this process. Astrocyte-specific milton knockdown disrupted regular mitochondrial trafficking, resulting in locomotor deficits, dysfunctional motor activity, and altered synapse number at the neuromuscular junction. These findings suggest that astrocytes dynamically redistribute mitochondria to buffer metabolic demand at synapses, highlighting a potential mechanism by which glia protect neural circuits from metabolic failure and neurodegeneration.

DOI: https://doi.org/10.1101/2021.11.29.470476

Nanoscale. 2025 Nov 24.

Drug delivery systems for mitochondrial targeting.

Sofia Tagliavini, Mara Filippini, Alessandro Anderlini, Riccardo Caraffi, Cecilia Baraldi, Barbara Ruozi, Giovanni Tosi, Ilaria Ottonelli, Jason T Duskey.

Mitochondria are essential organelles involved in both physiological and pathological processes. Dysfunctions in their activity, caused by gene mutations in mitochondrial or nuclear DNA or by other factors, can lead to a broad spectrum of primary and secondary mitochondrial diseases, characterized by diverse symptoms and clinical outcomes. Given the crucial role of this organelle in cellular life, the development of mitochondria-targeted delivery systems is essential to restore its function and offers a significant advantage in the treatment of mitochondria-related diseases, such as oxidative stress-induced conditions, and neurological disorders. Mitochondria can also be targeted in anticancer therapies to induce the death of tumor cells. Notwithstanding the variety of strategies linked to a mitochondrial-targeted therapy, reaching this organelle requires overcoming several biological barriers, ultimately mitochondrial membrane. A promising strategy in this regard is to use nanoparticles functionalized with specific ligands to direct the delivery of material to the mitochondrion. This review examines most recent advancements in nanosystem-based approaches for targeted delivery of nucleic acid therapeutics, including DNA and RNA, and small molecule drugs to this organelle. Overall, rationally designed nanomedicines that target mitochondria hold significant promise for precise therapeutic delivery at the subcellular level.

DOI: https://doi.org/10.1039/d5nr02199e