bims-mitrat 2025-06-15 papers

J Cereb Blood Flow Metab. 2025 Jun 11. 271678X251349304

Extracellular vesicle-mediated mitochondria delivery: Premise and promise.

Devika S Manickam, Paromita Paul Pinky, Purva Khare.

Mitochondrial transfer is highly significant under physiological as well as pathological states given the emerging recognition of mitochondria as cellular "processors" akin to microchip processors that control the operation of a mobile device. Mitochondria play indispensable roles in healthy functioning of the brain, the organ with the highest energy demand in the human body and therefore, loss of mitochondrial function plays a causal role in multiple brain diseases. In this review, we will discuss various aspects of extracellular vesicle (EV)-mediated mitochondrial transfer and their effects in increasing recipient cell/tissue bioenergetics with a focus on these processes in brain cells. A subset of EVs with particle diameters >200 nm, referred to as medium-to-large EVs (m/lEVs), are known to entrap mitochondria during EV biogenesis. The entrapped mitochondria are likely a combination of either polarized, depolarized mitochondria or a mixture of both. We will also discuss engineering approaches to control the quality and quantity of mitochondria entrapped in the m/lEVs. Controlling mitochondrial quality can allow for optimizing/maximizing the therapeutic potential of m/lEV mitochondria-a novel drug with immense potential to treat a wide range of disorders associated with mitochondrial dysfunction.

Keywords: Extracellular vesicles (EVs); medium-to-large EVs; microvesicles; mitochondria; small EVs

DOI: https://doi.org/10.1177/0271678X251349304

Cell Transplant. 2025 Jan-Dec;34:34 9636897251347391

Comparative analysis of mitochondrial and mesenchymal stem cell transplantation for angiogenesis and muscle regeneration.

Mi Jin Kim, Jung Wook Hwang, Chang-Koo Yun, Ikhyun Lim, Kyunghoon Min, Yong-Soo Choi.

Mitochondrial transplantation has emerged as a promising strategy for treating ischemic diseases by restoring mitochondrial function in damaged tissues. This study investigated the therapeutic potential of mitochondria isolated from placenta-derived mesenchymal stem cells (PD-MSCs) in a murine critical limb ischemia (CLI) model. The isolated mitochondria were characterized to confirm their structural integrity, purity, and ATP production capacity before transplantation into an ischemic hindlimb. Results showed that mitochondrial transplantation significantly improved blood flow and muscle regeneration compared with MSC transplantation, as evidenced by laser Doppler perfusion imaging and histological analysis. Enhanced ATP production and increased oxidative phosphorylation complex protein levels were observed, supporting energy metabolism in ischemic conditions. Mitochondrial transplantation also reduced mitochondrial reactive oxygen species (mROS) levels and increased antioxidant enzyme expression, including SOD-2, leading to reduced oxidative stress and apoptosis, as indicated by decreased Bax, cytosolic cytochrome c, and cleaved caspase-3 levels. Furthermore, mitochondrial transplantation promoted angiogenesis and increased vascular density in ischemic muscles by enhancing endothelial cell function. Overall, PD-MSC-derived mitochondrial transplantation demonstrated proved more effective over MSC transplantation in reducing inflammation, restoring mitochondrial function, and supporting tissue recovery, highlighting its promise as an effective therapeutic approach for CLI and other ischemic conditions by directly addressing mitochondrial dysfunction and overcoming the limitations of conventional cell therapies.

Keywords: angiogenesis; ischemia; mitochondria; mitochondrial transplantation; tissue regeneration

DOI: https://doi.org/10.1177/09636897251347391

Biochem Biophys Res Commun. 2025 Jun 04. pii: S0006-291X(25)00871-X. [Epub ahead of print]775 152157

Potential Therapy for Alzheimer's Disease: Modulating Tunneling Nanotube Dynamics Restores Mitochondrial Transport and Ameliorates Aβ-induced Toxicity.

Jing Chen, Qianya Zhang.

The development of therapies for Alzheimer's disease (AD) has long been constrained by the limitations of single-target strategies. Based on the core pathological features of AD-the cascade amplification effects of β-amyloid (Aβ) transcellular transport and mitochondrial dysfunction-combined with recent breakthrough discoveries: ① In vivo observation of tunneling nanotubes (TNTs) formation in the cerebral cortex of mouse models, ② Aβ-induced TNTs formation, ③ TNTs-mediated intercellular propagation of Aβ pathology, ④ TNTs-driven compensatory transfer of functional mitochondria between cells, this review proposes an innovative dual-directional regulatory strategy that precisely targets the molecular mechanisms of TNTs to simultaneously suppress Aβ pathological propagation and enhance mitochondrial rescue in diseased cells. By systematically elucidating: ① The molecular mechanisms underlying TNTs-mediated specific transport of Aβ and functional mitochondria, ② The molecular basis for directional regulation of TNTs transport, this strategy aims to develop potential therapeutic agents for AD, offering a novel intervention paradigm to overcome the current therapeutic impasse in AD treatment.

Keywords: Alzheimer's disease; Mitochondria; Tunneling nanotubes; β-Amyloid

DOI: https://doi.org/10.1016/j.bbrc.2025.152157

MedComm (2020). 2025 Jun;6(6): e70253

Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases.

Xinglu Miao, Pei Jiang, Zhaoping Wang, Weihua Kong, Lei Feng.

Advances in mitochondrial biology have led to the development of mitochondrial transplantation as a novel and promising therapeutic strategy. This review provides a comprehensive analysis of the multifaceted roles of mitochondria in health and disease, highlighting their central functions in energy production, antioxidant defense, calcium signaling, apoptosis regulation, and mitochondrial homeostasis maintenance. We explore the mechanisms by which transplanted mitochondria exert their therapeutic effects, including restoring ATP production, attenuating oxidative stress, modulating inflammatory responses, reducing cellular apoptosis, promoting cell repair and regeneration, facilitating neural circuit reconstruction, and exhibiting antitumor properties. Key preclinical studies demonstrating the efficacy of mitochondrial transplantation across in vitro and in vivo disease models are discussed, along with the status of clinical trials. The review also critically compares mitochondrial transplantation with other mitochondria-targeted therapies, evaluating their relative advantages and limitations. Finally, we discuss the current challenges of translating this innovative therapy into clinical practice, such as mitochondrial isolation and purification, storage, targeted delivery, potential immune responses, and long-term safety and efficacy concerns. This review aims to stimulate further research and development in this promising field, paving the way for novel therapeutic interventions for various diseases.

Keywords: disease therapy; mitochondria; mitochondrial transplantation; therapeutic strategy

DOI: https://doi.org/10.1002/mco2.70253

J Orthop Translat. 2025 May;52 441-450

Mitochondrial Transplantation/Transfer: Promising Therapeutic Strategies for Spinal Cord Injury.

Xiaochun Xiong, Chao Zhou, Yijun Yu, Qiong Xie, Linying Xia, Qingping Li, Hongming Lin, Songou Zhang, Wenqing Liang.

Spinal cord injury (SCI) remains an unresolved and complex medical challenge. In SCI, mitochondrial dysfunction leads to calcium overload and an increase in reactive oxygen species (ROS). Intercellular mitochondrial transfer has the potential to rescue surviving neurons, while exogenous mitochondrial transplantation can be performed through direct injection or cell-assisted methods. This review explored the current state of research on mitochondrial transplantation and transfer as potential treatments for SCI. It also analyzed the therapeutic implications, influencing factors, and advanced delivery methods for both endogenous mitochondrial transfer and exogenous mitochondrial transplantation. Furthermore, future research directions, including optimizing mitochondrial delivery methods, determining optimal dosages for different delivery approaches, were discussed based on larger animal models and clinical trials. The goal of this review was to introduce novel concepts and prospects for SCI therapy and to contribute to the advancement of medical research in this field.
The Translational Potential of This Article: At present, SCI lacks effective therapies, with mitochondrial dysfunction playing a central role in neuronal damage. Mitochondrial transplantation holds promise for restoring bioenergetic function. However, key challenges remain, including optimizing delivery methods, determining appropriate dosages, scalability, donor mitochondrial sourcing, regulatory hurdles and ensuring successful integration. Addressing these issues requires non-invasive platforms, validation in large-animal models, and clinical trials. This approach may bridge mitochondrial biology with translational engineering, thereby advancing the development of regenerative therapies for SCI.

Keywords: Autologous; Exogenous; Mitochondrial transplantation; Spinal cord injury

DOI: https://doi.org/10.1016/j.jot.2025.04.017