bims-tofagi 2026-07-19 papers

Issue of 2026–07–19
five papers selected by
Michele Frison, University of Cambridge

J Neuroinflammation. 2026 Jul 13.

Microglial mitophagy as an immunometabolic checkpoint in alzheimer's disease: linking mitochondrial quality control to neuroinflammation.

Mingyue Zou, Tengyu Zhao, Weidong Wu, Jian Zhang, Pengyu Pan, Jingdong Yan, Quan Li, Yanyan Zhou.

AD is a complex neurodegenerative disorder characterized by chronic neuroinflammation. Microglia, the brain's resident immune cells, centrally regulate AD pathophysiology. Recent studies have highlighted microglial mitophagy as an important interface linking mitochondrial quality control to innate immune responses.Intact mitophagy facilitates the timely clearance of damaged mitochondria, thereby limiting the release of mitochondrial DAMPs (e.g., mtDNA and mtROS) and helping restrain aberrant activation of the cGAS-STING pathway and the NLRP3 inflammasome.In the AD pathological milieu, however, factors including Aβ deposition, tau pathology, and genetic risk variants such as TREM2 and APOE4 disrupt mitophagy at multiple levels-from initiation and recognition to lysosomal degradation. This review systematically summarizes the molecular regulatory network of microglial mitophagy, with a particular focus on the mechanisms by which AD-associated pathological factors impair this process. We further discuss potential mechanisms through which mitophagic dysfunction may contribute to the amplification of neuroinflammation, including the release of mitochondrial DAMPs, the reprogramming of TBK1 signaling, and intercellular interactions. Finally, we outline current therapeutic strategies aimed at restoring mitophagy and discuss their potential to modulate neuroinflammatory responses and AD-related pathological processes, while highlighting the challenges and future directions in this emerging field.

Keywords: Alzheimer's disease; CGAS-STING; Immunometabolism; Microglia; Mitophagy; NLRP3 inflammasome; Neuroinflammation

DOI: https://doi.org/10.1186/s12974-026-03946-5

Acta Pharmacol Sin. 2026 Jul 15.

RNF10 deficiency in cardiomyocytes impairs mitophagy and drives pathological hypertrophy.

Jia-Ni Song, Tong-Tong Qiu, Lei Zhang, Jin-Can Huang, Yu-Jie Zhang, Yin-Liang Zhang, Yong-Sheng Chang.

Mitophagy-mediated mitochondrial quality control is essential for normal cardiac physiology. In this study, we observed that cardiac RNF10 expression was induced by multiple chronic stressors, including aging, angiotensin II (Ang II) exposure, and obesity. Cardiac-specific RNF10 knockout (RNF10-CKO) mice developed cardiac hypertrophy with aging, characterized by cardiomyocyte enlargement, exacerbated myocardial fibrosis, and impaired cardiac function. Aged RNF10-CKO mice exhibited elevated reactive oxygen species (ROS) levels and reduced mitochondrial membrane potential in cardiomyocytes. Transmission electron microscopy revealed mitochondrial rounding, matrix expansion, and cristae disorganization. Similarly, compared with control mice, Ang II-exposed RNF10-CKO mice exhibited cardiomyocyte hypertrophy, increased fibrosis, and cardiac dysfunction, accompanied by mitochondrial membrane potential depolarization, ROS accumulation, and mitochondrial morphological abnormalities equivalent to those in aged RNF10-CKO mice. Mechanistically, chronic stressors upregulated RNF10 expression, which subsequently mediated the K63-linked polyubiquitination of the mitochondrial outer membrane protein mitofusin 2 (MFN2). This modification stabilized MFN2 on mitochondria and facilitated Parkin recruitment. The accumulated Parkin in mitochondria further promoted the robust recruitment of the autophagy adaptor sequestosome 1 (SQSTM1/p62), leading to increased LC3-II lipidation and the initiation of mitophagy. Notably, this RNF10-mediated mitophagy is dependent on MFN2. However, the effects of RNF10 are independent of those of PINK1. This study identifies RNF10 as a critical regulator of cardiac mitophagy, suggesting that targeting cardiac RNF10 may represent a therapeutic strategy for treating cardiac pathologies.

Keywords: MFN2; Parkin; RNF10; cardiac hypertrophy; mitophagy; ubiquitination

DOI: https://doi.org/10.1038/s41401-026-01838-1

Nat Commun. 2026 Jul 17.

ZnF-UBP domains regulate deubiquitinase activity by relieving ubiquitin product inhibition.

Jack A Alexandrovics, Rashmi Agrata, Jan André Hane, Philipp Schenk, Anthony Cerra, Ueli Nachbur, Malte Gersch, Jeffrey J Babon, David Komander.

Most ubiquitin specific protease (USP) deubiquitinases (DUBs) combine non-selective catalytic domains with one or multiple 'exo'-domains that contribute substrate specificity and localisation, but are generally poorly characterised. Zinc-Finger UBP (ZnF-UBP) domains exist in 12 USP DUBs, yet their function is unclear. We here comprehensively analyse human ZnF-UBP domains, and reveal that 8 of 14 bind ubiquitin (Ub) via an unattached Ub C-terminal GlyGly motif. We focus on USP16, a nucleosome DUB with activity for Ub and Ub-like modifiers, and show that its ZnF-UBP domain can bind substrates, but is also a crucial contributor to enzyme kinetics. Slow Ub release from the catalytic domain after cleavage causes product inhibition, which is overcome in cis by ZnF-UBP-mediated product release. Interestingly, supplying a high affinity product-capturing ZnF-UBP domain in trans, activates USP16 and other USP enzymes. Our data shows the importance of product inhibition as a regulatory mechanism in DUBs, and exemplifies the unappreciated role of exo-domains in regulating DUB function beyond substrate binding.

DOI: https://doi.org/10.1038/s41467-026-75469-9

Sci Rep. 2026 Jul 17.

Docosahexaenoic acid attenuates cisplatin nephrotoxicity by restoring mitophagy.

Yuxian Zhuang, Zhenying Zuo, Chen Yang, Shangmei Li, Huafeng Liu, Kaipeng Jing.

Cisplatin exhibits potent antitumor efficacy but also causes dose-dependent nephrotoxicity mediated through apoptosis of renal tubular epithelial cells, which limits its clinical application. Cisplatin induces significant mitophagy in these cells; however, the mechanisms underlying its effects on apoptotic processes remain incompletely elucidated. This study investigated the mechanism by which the polyunsaturated fatty acid docosahexaenoic acid (DHA) modulates mitophagy to alleviate cisplatin nephrotoxicity. A cisplatin-induced (15 mg/kg, intraperitoneal) acute kidney injury model was established in C57BL/6J mice, with the intervention group receiving albumin-conjugated DHA (4 mg/kg). Systematic analyses revealed that cisplatin perturbed lysosomal degradation, which led to accumulation of dysfunctional mitochondria and increased apoptosis due to impaired mitophagic flux. DHA ameliorated lysosomal dysfunction, enhanced clearance of dysfunctional mitochondria, and suppressed apoptosis. Our findings suggest that blockade of mitophagic flux is a pivotal mechanism underlying cisplatin nephrotoxicity and that DHA-mediated restoration of mitophagy is a promising therapeutic strategy.

Keywords: Acute kidney injury (AKI); Apoptosis; Cisplatin; Docosahexaenoic acid (DHA); Mitophagic flux

DOI: https://doi.org/10.1038/s41598-026-62168-0