bims-mitrat 2025-12-14 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2025–12–14
seven papers selected by
Gökhan Burçin Kubat, Başkent Üni̇versi̇tesi̇

Editorial to the special issue on extracellular vesicles and mitochondria in CNS function and disease.
LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a Drp1-STX17-dependent manner.
Astrocytic LCN2 drives neuronal dysfunction in epilepsy by suppressing tunnel nanotube-mediated mitochondrial transfer via NLRP3 inflammasome activation.
Mitochondrial Transplantation Increases Bioenergetics and Neurite Outgrowth in Healthy and P301Ltau-Expressing SH-SY5Y Cells.
Mitochondrial transplantation-a novel therapeutic strategy for erectile dysfunction: a narrative review.
Extracellular vesicles and mitochondria in central nervous system diseases.
Transcellular mitochondrial transfer from hypermetabolic astrocytes to neurons during cocaine and HIV-1 exposure.

J Cereb Blood Flow Metab. 2025 Dec 07. 271678X251400466

Editorial to the special issue on extracellular vesicles and mitochondria in CNS function and disease.

Kazuhide Hayakawa, Dirk M Hermann.

  Extracellular vesicles (EVs) have emerged as critical mediators of cell-to-cell communication. More recently, a subset of these vesicles has been found to contain mitochondria (EV-Mito). These mitochondria-bearing EVs may act as non-cell-autonomous signaling entities and serve as potential biomarkers for injury and recovery in central nervous system (CNS) pathophysiology. Mitochondria play a vital role in regulating cellular respiration, metabolism, and overall tissue function. In the context of CNS injury or disease, mitochondrial dysfunction can disrupt metabolic homeostasis, leading to cell death and inflammation. Consequently, restoring mitochondrial function represents a key therapeutic target with strong translational potential. This special issue of JCBFM presents a multidisciplinary collection of high-impact reviews and original research articles. These contributions cover a broad spectrum-from basic studies on EV-mediated mechanisms in CNS disorders and the molecular pathways underlying intercellular mitochondrial transfer, to therapeutic applications of EVs and mitochondrial transplantation in cellular and animal models. The issue also highlights the latest clinical trial developments assessing the feasibility of EV and mitochondrial transplantation in cerebral ischemia. Collectively, these articles offer valuable insights into emerging research directions and underscore the many unresolved questions that remain-particularly regarding the quantitative thresholds required for treatment efficacy and the molecular mechanisms driving beneficial tissue remodeling.

Keywords:  CNS disorders; Extracellular mitochondria; Extracellular vesicles; Therapy

DOI:  https://doi.org/10.1177/0271678X251400466
Transl Neurodegener. 2025 Dec 08. 14(1): 64

LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a Drp1-STX17-dependent manner.

Mei Ding, Fen Wang, Lan-Lan Jiang, Chao Ma, Yu-Wan Qi, Jun-Yi Liu, Juan Li, Mei-Xia Wang, Hong Jin, Jin-Ru Zhang, Cheng-Jie Mao, Xiao-Kang Li, Chun-Feng Liu, Xiao-Yu Cheng.

   BACKGROUND: Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation.
METHODS: DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S.
RESULTS: Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival.
CONCLUSIONS: The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets.

Keywords:   LRRK2 G2019S mutation; Astrocyte; Dopaminergic neuron; Induced pluripotent stem cell; Membrane fusion-related protein STX17; Mitochondrial transfer; Parkinson’s disease

DOI:  https://doi.org/10.1186/s40035-025-00525-1
Free Radic Biol Med. 2025 Dec 05. pii: S0891-5849(25)01406-6. [Epub ahead of print]244 84-106

Astrocytic LCN2 drives neuronal dysfunction in epilepsy by suppressing tunnel nanotube-mediated mitochondrial transfer via NLRP3 inflammasome activation.

Zixian Zhou, Pengcheng Zhang, Yanlin Jiang, Yingchun Xu, Fangzhou Liu, Xinyu Chen, Deng Chen, Wenfu Tang, Rujia Liao, Ling Liu.

  Epileptic seizures disrupt brain homeostasis not only by directly challenging neuronal excitability but also by impairing the intricate astrocyte-neuron cross-talk essential for metabolic support. Herein, we identify a novel pathogenic axis and a compensatory rescue mechanism that are critically interlinked. Following seizures, astrocytes initiate a protective response by forming tunneling nanotubes (TNTs) to deliver functional mitochondria to stressed neurons, thereby restoring neuronal bioenergetics. Paradoxically, this endogenous rescue pathway is suppressed by a seizure-induced, astrocyte-specific signaling cascade: the upregulation of Lipocalin-2 (LCN2) activates the NLRP3 inflammasome, triggering Gasdermin D-mediated pyroptosis and concurrently impairing TNT function. Crucially, genetic or pharmacological disruption of the LCN2/NLRP3 axis yielded dual therapeutic benefits-it robustly suppressed astrocytic pyroptosis and, unexpectedly, potentiated TNT-mediated mitochondrial transfer, leading to significant improvements in neuronal mitochondrial function and overall neurological outcomes. Our findings redefine the role of reactive astrocytes in epilepsy, revealing a single pathway that simultaneously controls an inflammatory death process and an intercellular organelle rescue system. Targeting this axis presents a promising therapeutic strategy to concurrently mitigate neuroinflammation and boost intrinsic neuroprotective mechanisms for improving post-seizure recovery.

Keywords:  Astrocyte; Epilepsy; Lipocalin-2; Mitochondrial; NOD-Like receptor protein 3; Pyroptosis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.061
Mol Neurobiol. 2025 Dec 10. 63(1): 279

Mitochondrial Transplantation Increases Bioenergetics and Neurite Outgrowth in Healthy and P301Ltau-Expressing SH-SY5Y Cells.

Aline Broeglin, Aurélien Riou, Andreas Papassotiropoulos, Anne Eckert, Amandine Grimm.

  Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation of tau protein in neurons, leading to cognitive impairment. A common feature of these disorders is mitochondrial dysfunction, which leads to bioenergetic deficits and contributes to neuronal cell death. As neurons have high energy demands, impaired mitochondrial function directly affects their viability and function. Thus, mitochondria represent an attractive target for neuroprotective strategies in tauopathies. Mitochondrial transplantation (MT) is an emerging therapeutic approach to restoring cellular bioenergetics. Although MT has shown promise in various models of brain diseases, its efficacy has not been evaluated in the context of tau-induced mitochondrial dysfunction. This study examines the impact of MT on healthy cells and in a cellular model of tauopathy. Mitochondria were freshly isolated from astrocytic cells and transplanted into healthy SH-SY5Y neuroblastoma cells and SH-SY5Y cells overexpressing the P301L tau mutation, for 24 and 48 h. Our results demonstrate that MT enhances cell viability, ATP production, mitochondrial membrane potential, and respiration in both healthy and tau-mutant SH-SY5Y cells. In addition, MT reduced mitochondrial superoxide anion levels and promoted neurite outgrowth in both cell lines. Key bioenergetic outcomes were recapitulated in neurons derived from induced pluripotent stem cells (iPSCs) carrying the P301L tau mutation. These findings suggest that MT might be a promising therapeutic strategy to counteract mitochondrial deficits in tauopathies. Importantly, this approach positions mitochondria not as a target but as the therapeutic agent itself. Further studies are warranted to advance MT toward in vivo applications in tau-related neurodegenerative disorders.

Keywords:  Bioenergetic; Mitochondria; Neurites; P301Ltau mutation; Tauopathies; Transplantation

DOI:  https://doi.org/10.1007/s12035-025-05604-y
Transl Androl Urol. 2025 Nov 30. 14(11): 3757-3770

Mitochondrial transplantation-a novel therapeutic strategy for erectile dysfunction: a narrative review.

Caiyuzhu Wen, Yu Cheng, Zhixu Chen, Shiwen Zhang, Nan Wang, Jianshe Chen, Yafei Liu.

   Background and Objective: Phosphodiesterase-5 inhibitors (PDE5i) remain the first-line treatment for erectile dysfunction (ED). However, nearly 30% of ED patients exhibit inadequate responses or intolerable side effects. Emerging evidence indicates that mitochondrial dysfunction, characterized by bioenergetic failure, oxidative stress, and apoptosis, plays a pivotal role in the pathogenesis of ED.
Methods: This review employed a systematic literature search to comprehensively synthesize evidence on mitochondrial transplantation (MT) and mitochondrial dysfunction in the context of ED. Databases searched included PubMed, Embase, and Web of Science, covering publications from January 1, 2000 to July 1, 2025. Search strategies utilized keywords such as "mitochondrial transplantation", "erectile dysfunction", "mitochondrial dysfunction", "ROS", and "apoptosis", combined with Boolean operators (e.g., "mitochondrial transplantation AND erectile dysfunction" or "mitochondrial dysfunction OR apoptosis AND ED").
Key Content and Findings: The search initially identified 1,247 abstracts, from which 289 full-text articles were retrieved and evaluated for eligibility, ultimately yielding 58 key references incorporated into this review. This review systematically examines the potential of MT as a novel therapeutic strategy in ED. In preclinical ED models, MT restored adenosine triphosphate (ATP) levels, attenuated reactive oxygen species (ROS) accumulation, inhibited apoptotic signaling, and improved erectile hemodynamics in cavernous smooth muscle cells. Furthermore, we discuss recent advancements in mitochondrial isolation techniques, delivery optimization strategies (including nanocarriers and hydrogels), and immunological safety considerations for both autologous and allogeneic transplantation.
Conclusions: Although clinical translation faces challenges such as scalable production, dosage standardization, and long-term immunocompatibility, MT holds promise as a mechanism-based therapy for refractory ED, offering new insights beyond conventional hemodynamic approaches.

Keywords:  Erectile dysfunction (ED); apoptosis; mechanism-based therapy; mitochondrial transplantation (MT)

DOI:  https://doi.org/10.21037/tau-2025-531
J Cereb Blood Flow Metab. 2025 Dec 08. 271678X251399018

Extracellular vesicles and mitochondria in central nervous system diseases.

Ji Hyun Park, Dong Bin Back, Gen Hamanaka, Shin Ishikane, Kazuhide Hayakawa.

  Extracellular vesicles (EVs) are naturally secreted as non-cell-autonomous signals involved in regulating immune responses, aging, angiogenesis, and tissue injury and repair within the central nervous system (CNS). Consequently, EVs have emerged as promising therapeutic targets in CNS-related diseases. More recently, a subset of these vesicles has been found to contain mitochondria (mitoEVs), suggesting that vesicles carrying mitochondrial signatures may also function as non-cell-autonomous signals and serve as potential biomarkers for injury or recovery in CNS pathophysiology. In this mini-review, we summarize current findings highlighting the critical roles of EVs and their therapeutic potential as demonstrated in cellular, animal, and human studies related to CNS injury and disease.

Keywords:  CNS disease; Mitochondria; biomarker; extracellular vesicle; therapy

DOI:  https://doi.org/10.1177/0271678X251399018
Cell Commun Signal. 2025 Dec 09.

Transcellular mitochondrial transfer from hypermetabolic astrocytes to neurons during cocaine and HIV-1 exposure.

Santhanam Shanmughapriya, Taha Mohseni Ahooyi, Bahareh Torkzaban, Venkata Naga Srikanth Garikipati, Raj Kishore, Kamel Khallili, Dianne Langford, Kalimuthusamy Natarajaseenivasan.



Keywords:  Astrocytes; Cocaine; HIV-1; Mitochondria; Mitorelease; Neurotrophic; Tat

DOI:  https://doi.org/10.1186/s12964-025-02589-y