bims-mitrat 2026-11-08 papers

Front Endocrinol (Lausanne). 2026 ;17 1978936

Bidirectional mitochondrial transfer in the osteoimmune microenvironment: mechanisms and therapeutic perspectives.

Lei Huang, Xin Chen, Yuqin Guo, Fang Guo, Yanfan Zhang, Xuanyi Li, Zhili Dong, Xiaoxing Kou.

The maintenance of bone homeostasis relies on a dynamic interplay between skeletal and immune cells. Traditional paracrine and receptor-based models cannot fully explain the reciprocal communication that underpins bone remodeling. Intercellular mitochondrial transfer refers to the movement of one or more mitochondria from a donor cell to a recipient cell. In this review, this term is distinguished from the intercellular transfer of mitochondrial components, which is described separately according to the nature of the transferred material. Mitochondrial transfer occurs via three primary pathways: direct contact, extracellular vesicles (EVs), and free mitochondrial release. Emerging evidence positions intercellular mitochondrial transfer as a novel form of organelle-level communication in the regulation of bone homeostasis. Although mitochondrial transfer has been documented extensively in bone-related pathologies, its context-dependent, bidirectional regulatory roles within the osteoimmune microenvironment have yet to be systematically elucidated. To address this gap, we systematically summarize the molecular mechanisms governing mitochondrial transfer within the osteoimmune microenvironment, with a particular emphasis on the bidirectional communication network between skeletal cells and immune cells. We further discuss its dual pathophysiological roles in bone-related disorders and highlight emerging therapeutic strategies based on mitochondrial transfer. We also propose a novel framework for bone remodeling interventions that centers on precise control of both transfer directionality and mitochondrial quality. This conceptual integration provides a theoretical foundation and translational guidance for precision regenerative medicine and immunometabolic therapies in bone-related diseases.

Keywords: bone metabolism; immunometabolism; mitochondrial quality control; mitochondrial transfer; osteoimmunology

DOI: https://doi.org/10.3389/fendo.2026.1978936

Exp Mol Pathol. 2026 Oct 31. pii: S0014-4800(26)00072-9. [Epub ahead of print]148 105093

Mitochondrial transfer enhances the metabolic fitness and antitumor activity of primary NK cells.

Min-Jeong Park, Mi Jin Kim, Mina Lim, Eun-Seo Back, Young June Jeon, Da-Yoon Kim, Chang-Koo Yun, Young Jik Kwon, Junho Park, Yong-Soo Choi.

Natural killer (NK) cell therapy has emerged as a promising approach for cancer treatment. However, its efficacy is often limited by metabolic dysfunction, poor persistence, and reduced activity within the tumor microenvironment. Here, we investigated whether mitochondrial transfer could improve the metabolic fitness and antitumor activity of peripheral blood-derived primary NK cells. Using a simple centrifugation-based approach, mitochondria isolated from NK cells or umbilical cord-derived mesenchymal stem cells (UC-MSCs) were transferred into primary NK cells. Mitochondrial transfer significantly enhanced oxidative phosphorylation, glycolysis, and ATP production, leading to improved cytokine secretion and cytotoxicity against both hematologic and solid tumor targets. In xenograft models, mitochondrial transfer significantly suppressed tumor growth, with UC-MSCs-derived mitochondria producing the greatest therapeutic benefit. Proteomic analysis further revealed enrichment of pathways associated with immune activation, cellular migration, and cytoskeletal remodeling. Collectively, these findings demonstrate that mitochondrial transfer enhances NK-cell metabolic fitness and antitumor activity, highlighting its potential as a practical non-genetic strategy for improving NK cell-based cancer immunotherapy.

Keywords: Cell therapy; Immunometabolism; Metabolic reprogramming; Mitochondrial transfer; Natural killer cells; cancer immunotherapy

DOI: https://doi.org/10.1016/j.yexmp.2026.105093

bioRxiv. 2026 Oct 28. pii: 2026.10.23.761277. [Epub ahead of print]

Cancer cells hijack mitochondria from Bhlhe40+ T cells for immune evasion.

Hailong Hu, Yuhao Tan, Irina Shkundina, Richard Madnick, Jing Hu, Hongyi Zhang, Ziqi Yang, Tong Wang, Xuexin Yu, Julia Fleming, Mingyao Pan, Yizhou Wang, Yuanyuan Pang, Drew Weissman, Bo Li.

Cancer cells hijack mitochondria from T cells via tunneling nanotubes (TNTs) to promote immune evasion, yet the underlying mechanisms of mitochondrial-loss remain poorly understood. Here, through targeted screening of relevant genes, we demonstrated that CD38 is a potent regulator of TNT formation through interaction with its cognate ligand, CD31. Conditional knockdown of Cd38 in murine models leads to CD8 + T cell-dependent tumor shrinkage. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that cancer cells preferentially target the Bhlhe40+ effector subset. Bhlhe40 is a transcription factor that upregulates the expression of S100a4, a reported chemoattractant of nanotubes. Bhlhe40 upregulation creates mitochondrial-loss vulnerability for tumor neoantigen-specific T cells. Dual mitochondria transfer blockade with Cd38 knockdown and S100a4 inhibitor trifluoperazine markedly suppressed tumor growth. Collectively, our findings identified the Bhlhe40-S100a4 cascade as a critical regulator of cancer/T cell mitochondrial transfer, providing insights for the development of new cancer immunotherapies.

DOI: https://doi.org/10.64898/2026.10.23.761277

J Cachexia Sarcopenia Muscle. 2026 Dec;pii: e70416. [Epub ahead of print]17(6):

Mitochondrial Transplantation Preserves Regenerative Capacity of Denervated Skeletal Muscle by Disrupting a Ca2+ Overload-Mitophagy-Ferroptosis Circuit.

Haiqi Ding, Jiagu Huang, Jiayao Zhang, Zhizhen He, Jun Luo, Zhao Lin, Linhai Yang, Yibin Su, Mingjuan Zhang, Fuli Wen, Yuan Lin, Cheng Chang, Hanhao Dai, Xuehui Ge, Jie Xu.

BACKGROUND: Denervation-induced muscle atrophy progresses during the interval between nerve injury and reinnervation, and depletion of muscle satellite cells (MuSCs) contributes to impaired functional recovery. Although mitochondrial dysfunction and impaired quality control are implicated in muscle wasting, whether excessive mitochondrial turnover drives MuSC failure after denervation remains unclear. This study aimed to identify the pathogenic mechanisms underlying MuSC depletion and determine whether mitochondrial transplantation therapy (MTT) preserves regenerative capacity.
METHODS: A sciatic nerve transection model was established in mice to induce denervation-associated muscle atrophy. Mitochondria isolated from differentiated MuSCs were transplanted into denervated gastrocnemius muscles beginning 6 h after injury and repeated every 3 days for 6 weeks. RNA sequencing, calcium imaging, mitochondrial ultrastructural analysis, mito-mKeima-based mitophagic flux assessment, flow cytometry and molecular analyses were performed to investigate disease mechanisms and therapeutic effects. In vitro calcium overload models combined with Mdivi-1 treatment and Pink1 knockdown were used to define the regulatory pathway linking calcium stress, mitophagy and ferroptosis.
RESULTS: Denervated muscle exhibited early calcium dyshomeostasis (Fluo-4 AM fluorescence increased 6.7-fold vs. Sham, p < 0.0001) and mitochondrial dysfunction within 3 days, followed by iron accumulation (nonheme iron increased 1.5-fold, p = 0.0046) and ferroptotic changes by 2 weeks. Mechanistically, sustained calcium overload activated the Ampk-Tsc2-mTorc1 pathway in MuSCs, inducing Pink1-dependent excessive mitophagic flux. Mito-mKeima flow cytometry confirmed increased mitophagic flux after denervation, with approximately tenfold elevation at Day 3 and persistent activation at 2 weeks. Excessive mitophagy promoted Fth1 degradation (reduced by 47.5%, p = 0.0181) and increased Tfr1 expression (1.9-fold, p = 0.0035), thereby enhancing ferroptotic susceptibility. Inhibition of mitochondrial fission or Pink1 knockdown reduced iron accumulation (Fe2+ fluorescence reduced by 58.3% and 69.2%, respectively, both p < 0.01) and protected MuSCs from ferroptosis. MTT restored mitochondrial homeostasis by reducing calcium overload (73.7% decrease vs. A23187, p < 0.0001), increasing ATP production (36.9%, p < 0.01), suppressing excessive mitophagic flux, normalizing iron metabolism (39.9% reduction, p = 0.0015) and preserving MuSCs (30.0% increase vs. DN_PBS, p = 0.0196). Consequently, MTT attenuated denervation-induced muscle fibre atrophy and improved functional recovery following delayed nerve repair.
CONCLUSIONS: This study identifies an early pathogenic cascade linking calcium overload, excessive mitophagic flux and ferroptotic susceptibility as a critical driver of MuSC dysfunction during denervation-induced muscle wasting. MTT preserves regenerative capacity by interrupting this degenerative circuit and restoring mitochondrial quality control, providing a potential therapeutic strategy for denervation-associated muscle atrophy and other muscle wasting disorders.

Keywords: calcium overload; denervation atrophy; ferroptosis; mitochondrial transplantation therapy; mitophagy; muscle satellite cells

DOI: https://doi.org/10.1002/jcsm.70416

Free Radic Biol Med. 2026 Nov 03. pii: S0891-5849(26)01249-9. [Epub ahead of print]258 185-200

Mechanistic study on neurotoxicity induced by neodymium oxide exposure via TNT-mediated transfer of damaged mitochondria.

Xiaoyan Du, Zhonghe Ren, Xiaocheng Gao, Yan Guo, Jing Cao, Shaoqing Zhao, Mengyao Zhang, Yanrong Gao, Lei Gao, Bingtao Xia, Yang Deng.

The health issues caused by the global mining, processing, and utilization of rare earth elements are receiving increasing attention. This study examined the molecular mechanisms mediating damaged mitochondria transfer via TNTs during neodymium oxide (Nd2O3)-induced neurotoxicity. Adult Sprague-Dawley rats were administered Nd2O3 by gavage, and effects on spatial learning and memory were assessed in the Morris water maze. Primary astrocytes and whole brain tissues from SD rats were extracted to identify differentially expressed genes via RNA-seq, and qRT-PCR and Western blotting were employed to perform targeted analyses of genes and proteins involved in blood-brain barrier (BBB) maintenance, mitochondrial oxidative phosphorylation (OXPHOS), and mitochondrial dynamics. Alterations in calcium homeostasis, oxidative stress markers, and mitochondrial metabolism were measured using dedicated assay kits. TNT formation and mitochondrial migration were examined in co-cultures of primary astrocytes with HT22 neuronal cells by fluorescence staining under laser confocal microscopy. The stability of the F-actin-Myo19-Miro1 complex was evaluated using Co-IP and molecular docking, and the effects of Nd2O3 exposure on mitochondrial transport carriers and the number of TNTs were assessed. Finally, the role of TNTs in damaged mitochondria transfer was demonstrated by co-culturing astrocytes and neurons in a Transwell system and performing mitochondrial membrane potential detection. Neuronal damage was verified using TUNEL staining. Exposure to Nd2O3 caused dose-dependent spatial learning and memory impairment, reduced neural expression of core BBB genes, disrupted intracellular calcium homeostasis, induced oxidative stress, reduced OXPHOS, and promoted mitochondrial fragmentation. Astrocytes exposed to Nd2O3 formed TNTs with neurons, and damaged mitochondria were transported through TNTs containing the F-actin-Myo19-Miro1 complex, ultimately aggravating the degree of neuronal damage. We conclude that neodymium neurotoxicity involves mitochondrial oxidative stress and kinetic damage. Neodymium acts as a promoting factor through the F-actin-Myo19-Miro1 complex, transferring damaged mitochondria from astrocytes to neurons via TNTs and ultimately causing nerve damage.

Keywords: Mitochondrial transport; Neodymium; Nerve damage; Oxidative stress; Tunneling nanotubes

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.11.006

J Inflamm Res. 2026 ;19 653025

The "Invisible Killer" of Neurodegeneration: Mitochondrial Dysfunction in Neurodegenerative Disorders, Mechanisms, Emerging Pathways and Therapeutic Strategies.

Songqiang Cao, Tingting Liu, Xiangshu Cheng, Xinghua Tian, Jianshe Wei.

Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) place substantial burden on global public health. Mounting evidence identifies mitochondrial dysfunction as a central contributor to neuronal damage and progressive brain functional decline. As a narrative review, this work aims to dissect mitochondrial‑associated pathological features across these major neurodegenerative disorders, summarize under‑recognized emerging mechanisms, and highlight translational bottlenecks for mitochondrial‑targeted therapies. Mitochondria sustain neuronal survival by mediating oxidative‑phosphorylation‑driven energy production, biomolecule biosynthesis, calcium homeostasis, reactive oxygen species (ROS) metabolism, and apoptotic regulation. In PD, aggregated α‑synuclein (α‑syn) damages respiratory‑chain complex I, perturbs mitochondrial dynamics and blocks PINK1/Parkin‑dependent mitophagy. In AD, amyloid‑β together with hyper‑phosphorylated tau (p-Tau) impairs respiratory complex activity, axonal mitochondrial trafficking and mitophagic clearance. Mutant huntingtin induces multiple mitochondrial lesions in HD, while inflammation‑triggered oxidative stress secondarily compromises mitochondrial function in MS. Pathogenic mutations in ALS disrupt respiratory‑chain assembly, mitochondrial dynamics and mitophagy. Beyond classic mitochondrial defects including respiratory‑chain impairment, dynamic imbalance and defective mitophagy, emerging mechanisms such as mitocytosis, mitochondrial aminoacyl‑tRNA synthetase (mt‑aaRS) dysfunction and mitochondria‑associated membrane (MAM) disruption are discussed. Mitochondrial dysfunction drives neurodegeneration via energy exhaustion, aggravated oxidative stress, pathological protein aggregation and excessive neuronal apoptosis. We further recapitulate mitochondrial‑oriented therapeutic approaches including small‑molecule regulators, mitophagy activators, mitochondrial biogenesis promoters, gene‑editing strategies and mitochondrial transplantation. Notable translational obstacles remain, including limited blood‑brain‑barrier penetration of candidate drugs, narrow therapeutic time‑window post‑symptom onset, and prominent disease heterogeneity. By synthesizing basic experimental findings and pre‑clinical and clinical trial progress, this review provides updated insights into the pathogenesis of neurodegenerative diseases and facilitates the development of precise mitochondrial‑targeted therapeutic regimens.

Keywords: mitochondrial dysfunctions; neurodegenerative diseases; neuronal degeneration; oxidative stress; treatment

DOI: https://doi.org/10.2147/JIR.S653025