bims-tofagi 2026-05-24 papers

Issue of 2026–05–24
five papers selected by
Michele Frison, University of Cambridge

Mitochondrion. 2026 May 19. pii: S1567-7249(26)00061-9. [Epub ahead of print] 102171

Role of oxidative stress in the susceptibility to mitophagy of the skin fibroblasts and iPSC-derived neurons of patients with MERRF syndrome.

Yu-Ting Wu, Hui-Yi Tay, Hsiao-Hui Liao, Jung-Tse Yang, Yau-Huei Wei.

Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is mainly caused by the m.8344A > G mutation and mitochondrial dysfunction, but the pathogenesis remains unclear. In this study, we demonstrated that carbonyl cyanide m-chlorophenyl hydrazine (CCCP) induced PINK1-mediated mitophagy and accelerated mitochondrial turnover in the skin fibroblasts of MERRF patients. We found that CCCP led to more pronounced increase of PINK1 accumulation, activation of LC3B II and degradation of Mfn1, Mfn2, OSCP and OPA1 cleavage in MERRF skin fibroblasts as compared with normal skin fibroblasts. Moreover, N-acetylcysteine suppressed PINK1 accumulation and ubiquitin phosphorylation and thus impaired clearance of damaged mitochondria. This inhibitory effect was validated in MERRF patient iPSC-derived neurons harboring the m.8344A > G mutation, which displayed mitochondrial dysfunction, ROS overproduction and impaired electrophysiological function of mature neurons. These findings suggest that oxidative stress plays a crucial role in the susceptibility to mitophagy of skin fibroblasts and iPSC-derived neurons of MERRF patients and that restoring proper mitophagic flux is a potential therapeutic approach.

Keywords: MERRF syndrome; Mitophagy; N-acetylcysteine; PINK1; iPSC-derived neural stem cells (iNSCs); iPSC-derived neurons; mtDNA mutation

DOI: https://doi.org/10.1016/j.mito.2026.102171

Mol Med. 2026 May 19.

Nestin promotes imatinib resistance in gastrointestinal stromal tumors by enhancing PINK1-dependent mitophagy.

Yuehan Yin, Juzheng Peng, Zhijian Huang, Dongsheng Li, Xiangyu Li, Zhengchao Hong, Yuqing Lin, Yulong He, Jiancheng Wang.

BACKGROUND: Gastrointestinal stromal tumors (GIST) frequently develop secondary resistance to imatinib, which represents a major obstacle to achieving durable clinical benefit. However, the molecular mechanisms underlying acquired resistance remain poorly understood. Nestin, a cytoskeletal protein, has been implicated in tumor progression and cellular stress responses, but its role in imatinib-resistant GIST has not been fully elucidated.
METHODS: Patient tumor specimens, imatinib-resistant GIST cell lines, and xenograft mouse models were analyzed to evaluate Nestin expression. Functional studies were performed using RNA interference-mediated silencing of Nestin. Mitophagy flux assays were conducted to evaluate mitochondrial quality control. The effects of Nestin modulation on PINK1 stability, mitophagy activity, mitochondrial integrity, and imatinib sensitivity were evaluated both in vitro and in vivo. Clinical correlations between Nestin expression, therapeutic response, and prognosis were also analyzed.
RESULTS: Nestin expression was significantly upregulated in imatinib-resistant GIST across patient samples, resistant cell lines, and xenograft models. Mechanistically, Nestin stabilized PINK1, thereby enhancing PINK1-dependent mitophagy and preserving mitochondrial integrity under imatinib-induced stress. RNA interference suppression of Nestin reduced PINK1 accumulation, impaired mitophagy, increased mitochondrial damage, and restored imatinib sensitivity in vitro and in vivo. Clinically, elevated Nestin expression was associated with poor therapeutic response and unfavorable prognosis.
CONCLUSIONS: The Nestin-PINK1 axis is a critical driver of imatinib resistance in GIST. Targeting Nestin-mediated mitophagy may represent a promising therapeutic strategy to overcome imatinib resistance and improve clinical outcomes in patients with GIST.

Keywords: Cytoskeleton; Gastrointestinal stromal tumor; Imatinib resistance; Mitophagy

DOI: https://doi.org/10.1186/s10020-026-01509-1

Free Radic Biol Med. 2026 May 21. pii: S0891-5849(26)00787-2. [Epub ahead of print]

Mitoredox Shifts in Mitochondrial Dysfunction.

Walter H Moos, Douglas V Faller, Ioannis P Glavas, Iphigenia Kanara, Krishna Kodukula, Julie Pernokas, Mark Pernokas, Carl A Pinkert, Whitney R Powers, Konstantina Sampani, Kosta Steliou, Demetrios G Vavvas.

Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared pathological outcomes. Here, we propose that mitoredox shifts - bidirectional disruptions in mitochondrial redox homeostasis that alter mitochondrial quality control and genome-stability pathways - serve as a unifying axis linking oxidative stress, mitochondrial quality control failure, heteroplasmy dynamics, and regulated cell death. Both hyperactive and hypoactive mitochondrial states destabilize redox balance, altering PINK1/Parkin-dependent and receptor-mediated mitophagy, disrupting proteostasis, and reshaping mitochondrial network dynamics. These redox-driven perturbations influence the propagation of pathogenic mtDNA variants, modulate tissue-specific threshold effects, and bias cells toward apoptosis, ferroptosis, cuproptosis, and other regulated cell death pathways. We synthesize emerging evidence across mitochondrial genetics, bioenergetics, and redox signaling to outline how mitoredox shifts accelerate disease progression in both primary mitochondrial syndromes and secondary mitochondrial dysfunction. We further evaluate the expanding landscape of diagnostic biomarkers, including FGF21, GDF15, imaging-based oculomics, and high-throughput proteomic and genomic assays. In parallel, we highlight therapeutic strategies aimed at restoring redox balance, enhancing mitophagy, or shifting mitochondrial network composition by diluting dysfunctional organelles through mitochondrial transplantation. By emphasizing mitoredox imbalance as a recurrent feature of disease, this work synthesizes emerging diagnostic and therapeutic approaches across rare and common mitochondrial disorders.

Keywords: Biomarkers; cuproptosis; ferroptosis; heteroplasmy; mitochondria; mitophagy; mitoredox medicine; oxidative stress

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.05.307

Nat Commun. 2026 May 22.

Manganese enhances macrophage bactericidal activity in mice with Staphylococcus aureus osteomyelitis via Sirt3-mitophagy axis.

Xin Guan, Bingsheng Yang, Bowen Bai, Naiqian Cui, Muqi Wang, Jianwen Su, Xiaohu Wu, Chenghua Zhang, Hui Dai, Peng Zhao, Bin Yu, Bowei Wang.

Staphylococcus aureus (S. aureus)-induced osteomyelitis remains challenging in clinical practice, wherein macrophages with impaired bactericidal function serve as reservoirs for intracellular bacterial survival, contributing to persistent and relapsing infections. Here, we show that exogenous manganese (Mn2+) enhances the bactericidal capacity of S. aureus-infected macrophages. By repressing the mitochondrial protein Sirt3, Mn2+ inhibits S. aureus-induced mitophagy via the PTEN-induced kinase 1/parkin pathway, thereby boosting the production of mitochondrial reactive oxygen species to eradicate intracellular bacteria. Pharmacological activation or genetic overexpression of Sirt3 abolishes these effects, identifying this axis as a key molecular target of Mn2+. Based on this, we further develop a biomimetic nanotherapeutic system for targeted Mn2+ delivery. In a mouse model of osteomyelitis, this nanosystem precisely represses Sirt3 in macrophages within the infected medullary cavity, markedly reduces bacterial burden, and effectively alleviates bone destruction. Our findings implicate an immunomodulatory mechanism by which Mn2+ enhances macrophage bactericidal activity and develops a potent Mn2+-based metalloimmunotherapeutical strategy for S. aureus-induced osteomyelitis.

DOI: https://doi.org/10.1038/s41467-026-73529-8

NPJ Syst Biol Appl. 2026 May 18.

Supervised machine learning identifies impaired mitochondrial quality control in β-cells with development of type 2 diabetes.

Mirza Muhammad Fahd Qadir, Charles Dana, Madeleine Pittigher, Paul Mauvais-Jarvis, Nazmul Haque, Theodore Dos Santos, Patrick E MacDonald, Kyle J Gaulton, Franck Mauvais-Jarvis.

Defining molecular pathways driving β-cell failure in type 2 diabetes (T2D) is challenging given donor heterogeneity. We developed an interpretable machine learning framework coupling sparse rule-based classification, pathway constrained modeling, and mitochondrial fitness stratification, applied to single-cell RNAseq from 52 human islet donors. A 50-gene classifier predicted T2D at single-cell resolution, outperforming ensemble models, with donor-level scores correlating with HbA1c. We identified a resilient non-diabetic (ND) β-cell subtype with preserved β-cell identity, while T2D β-cell subtypes showed cellular stress and suppressed oxidative phosphorylation. Mitophagy emerged as the dominant cellular pathway, with PINK1, BNIP3, and FUNDC1 as predictors. At the donor level, PINK1 expression decreased with T2D score and correlated with sex‑specific mitophagy patterns. We developed a mitochondrial fitness index (MFI, R² = 0.934) integrating mitophagy, proteostasis, biogenesis, and respiration, identifying PINK1, SQSTM1, PRKN, and BNIP3 as top T2D contributors. Interpretable machine learning revealed mitophagy as central to β-cell metabolic fitness.

DOI: https://doi.org/10.1038/s41540-026-00742-y