bims-mitrat 2025-12-21 papers

Nephron. 2025 Dec 19. 1-18

Mitochondria to the rescue: organelle trafficking in renal health and disease.

Luca Perico, Giuseppe Remuzzi, Ariela Benigni.

BACKGROUND: Mitochondria are central regulators of cellular metabolism, redox signaling, and apoptosis. Their dysfunction plays a pivotal role in the pathogenesis of kidney diseases, including acute kidney injury and diabetic nephropathy.
SUMMARY: Recent advances have unveiled horizontal mitochondrial transfer as a novel intercellular communication by which renal cells exchange mitochondria to promote tissue repair through the modulation of metabolic processes, oxidative stress, apoptosis, and fibrosis.
KEY FINDINGS: Horizontal mitochondrial transfer, mediated by tunneling nanotubes and extracellular vesicles, has emerged as a potential homotypic rescue mechanism between injured tubular and glomerular cells. In addition, heterotypic mitochondrial transfer from mesenchymal stromal cells to renal cells has been described. These findings open new perspectives for exploring therapeutic mitochondrial transplantation in both acute and chronic kidney diseases. Nonetheless, significant challenges remain, including elucidating the poorly characterized biological mechanisms underlying mitochondrial transfer, optimizing delivery strategies, and defining the long-term safety and efficacy of mitochondrial-based therapies.

DOI: https://doi.org/10.1159/000550092

Neuroprotection. 2025 Sep;3(3): 253-265

Mitochondrial transfer as a novel therapeutic approach in ischemic stroke treatment: Current challenges and future perspectives.

Shuchen Meng, Min Bai, Changsheng Ma, Bo Han, Mengyuan Duan, Liying Zhang, Jinfen Guo, Changku Shi, Ke Li, Maotao He.

Ischemic stroke, the second leading cause of human mortality, presents a formidable challenge to healthcare. Following ischemic insult, the brain undergoes intricate pathological transformations, prominently marked by mitochondrial damage, including swelling, fission, and mitophagy, collectively termed mitochondrial quality control disorder. Mitochondria, pivotal in energy regulation and oxidative stress modulation, play a critical role in neuronal apoptosis post-stroke. To solve the problems caused by mitochondrial quality control disorders, mitochondrial transfer has become a new therapeutic strategy for central nervous system diseases. Mitochondrial transfer refers to the process by which certain cell types export their mitochondria and pass them on to other cell types, a process also known as intercellular mitochondrial transfer. Mechanistically, mitochondrial transfer occurs via tunneling nanotubes, extracellular vesicles, and free mitochondrial transfer, exerting multifaceted effects such as anti-inflammatory, anti-lipid peroxidation, ferroptosis modulation, and enhancement of mitochondrial metabolism. This review explores the therapeutic efficacy, current obstacles, and future prospects of mitochondrial transfer in ischemic stroke, offering insights to researchers and instilling hope in patients for conquering this debilitating condition.

Keywords: ischemic stroke; mitochondrial dysfunction; mitochondrial therapy; mitochondrial transfer

DOI: https://doi.org/10.1002/nep3.70004

Exp Mol Med. 2025 Dec 17.

Hv1 inhibition rescues AD pathology by restoring microglial mitochondrial function and enhancing mitochondrial transfer.

Jiayuan Lin, Huayun Han, Kexin Wu, Xingyu Wu, Juwen Shen, Yiqing Mo, Qiansen Zhang, Huaiyu Yang, Zhihua Yu.

Hyperphosphorylated tau aggregation and neuroinflammation are hallmark pathologies of Alzheimer's disease (AD), with microglia playing a critical role in modulating these processes through maintaining immune homeostasis and clearing pathological tau, both of which depend on mitochondrial health. However, the mechanisms underlying microglial mitochondrial dysfunction in AD remain poorly understood, limiting therapeutic development. Hydrogen voltage-gated channel 1 (Hv1), expressed in microglia within the central nervous system, regulates intracellular pH and reactive oxygen species generation. Here we observe that Hv1 is upregulated in activated microglia in AD mouse models. Remarkably, Hv1 contributes to electron transport chain abnormalities, leading to mitochondrial oxidative stress, loss of mitochondrial membrane potential, impaired ATP production and deficient mitophagy in tau pathology. These deficits impair tau clearance through phagocytosis and autophagy but can be significantly reversed by the Hv1-specific inhibitor YHV98-4. Furthermore, YHV98-4 enhances microglia-to-neuron mitochondrial transfer, promoting the delivery of functional mitochondria to rescue neuronal damage and improve cognitive function. Collectively, our study underscores the pivotal role of Hv1 in microglial mitochondrial dysfunction in AD and identifies YHV98-4 as a promising therapeutic candidate.

DOI: https://doi.org/10.1038/s12276-025-01593-z

Nat Commun. 2025 Dec 14.

Activation of the RSAD2-YTHDF1 axis in smooth muscle causes inflammatory bowel disease via intercellular mitochondrial transfer.

Wen-Di Zhang, Dan-Dan Zhang, Xu Wang, Chen-Yang Li, Fan-Qin Li, Xin-Long Liu, Shi-Zhen Zhang, Wei Sun, Li-Jing Li, Han-Bing Wang, Peng Kong, Xiao-Qin Liu, De-Min Liu, Xiao-Lan Zhang, Ya-Bin Liu, Mei Han.

Colonic smooth muscle cell (CSMC) hypertrophy and hyperplasia have been described in both human ulcerative colitis (UC) and animal models. The deletion of smooth muscle (SM) 22α induces the phenotypic switching of SMCs. Here, we report that Sm22α-deficient mice develop spontaneous colitis, which is characterized by radical S-adenosyl-methionine domain-containing 2 (RSAD2)-driven mitochondrial dysfunction and inflammation in CSMCs and ferroptosis in the colonic mucosa. Mechanistically, RSAD2 mediates YTH m6A RNA-binding protein 1 (YTHDF1) methylation and activation, thereby increasing the mRNA N6-methyladenosine (m6A) modification and translation of dynamin-related protein 1 (DRP1), resulting in mitochondrial fragmentation in CSMCs. Inflammatory CSMC-derived mitochondrial extracellular vesicles trigger intestinal epithelial ferroptosis by inducing ROS production. The ablation of RSAD2 in mice with SMC-specific Sm22α knockout alleviates colitis severity in this experimental model. Importantly, increases in both RSAD2 expression and the ferroptotic signature are observed in serum and/or colonic samples from UC patients. Overall, this study shows a mitochondrial mechanism underlying the ability of dysfunctional smooth muscle to drive colitis and highlights the potential of targeting the RSAD2-YTHDF1 axis as an innovative therapeutic strategy for colitis.

DOI: https://doi.org/10.1038/s41467-025-67707-3