bims-tofagi 2026-07-26 papers

Issue of 2026–07–26
five papers selected by
Michele Frison, University of Cambridge

Trends Mol Med. 2026 Jul 23. pii: S1471-4914(26)00172-3. [Epub ahead of print]

Mitochondrial transfer: quality dictates immune-metabolic fate.

Horizontal mitochondrial transfer (HMT) outcomes are shaped by donor fitness and transfer context. We propose a post-transfer quality checkpoint that integrates membrane potential, oxidative damage, mitophagy, fusion, and fission to determine the recipient-cell's response. Depending on donor quality and recipient thresholds, HMT may drive bioenergetic restoration, inflammation, or tumor immune escape. This framework extends route-centered accounts of HMT toward a testable, quality-governed model for therapeutic intervention.

Keywords: immune-metabolic fate; mitochondrial quality; mitochondrial transfer; quality checkpoint

DOI: https://doi.org/10.1016/j.molmed.2026.07.002

Cell Signal. 2026 Jul 24. pii: S0898-6568(26)00420-1. [Epub ahead of print] 112763

Impaired mitochondrial quality control and stress signalling machinery modulate senescence induction by genotoxic challenge.

Mia Simons Weston, Marta Dominguez Prieto, Nicoleta Moisoi.

Cellular senescence is a hallmark of ageing and age-related disease and is closely associated with mitochondrial dysfunction and the accumulation of DNA damage. However, the contribution of mitochondria-nucleus communication, mitochondrial quality control (mtQC) and stress signalling to senescence remains incompletely understood. Here, we investigated the interplay between mtQC pathways and cellular stress responses in DNA damage-induced senescence using mouse embryonic fibroblasts (MEFs). MEFs deficient in the mitochondrial protease HtrA2 (proteostasis), the transcription factor Chop (integrated stress response; ISR) or the mitophagy regulator Pink1 were exposed to three mechanistically distinct DNA-damaging agents: bleomycin, etoposide and doxorubicin. Senescence was characterised using multiple complementary markers, including the proportion of high senescence-associated β-galactosidase-positive cells, nuclear size, total and nuclear p21 abundance, and transcriptional analysis of p16, p21 and genes associated with cell-cycle regulation and stress signalling. Mitochondrial dysfunction through mtQC impairment enhanced sensitivity to senescence with HtrA2 and Pink1 loss promoting increased senescence under DNA damage. Although DNA damage response (DDR) was activated as seen by changes in p21 homeostasis, this did not always correlate with senescence levels, which indicates that DDR alone cannot account for all senescence characteristics. The ISR played a modulatory role in the senescence induction, with Chop loss of function reducing senescence induction following DNA damage despite DDR activation. The different DNA damaging drugs produced different senescence outcomes, thus highlighting the importance of the stressor context in addition to the cellular homeostasis mechanisms in the overall senescence profile. This approach allowed, for the first time, to identify senescence subtypes dependent of mtQC and ISR integrity in the context of genotoxic stress.

Keywords: Genotoxic stress; Integrated stress response; Mitochondria quality control; Senescence subtypes

DOI: https://doi.org/10.1016/j.cellsig.2026.112763

EMBO Rep. 2026 Jul 23.

The role of E3 ubiquitin ligases in selective types of macroautophagy.

Monja Müller, Konstanze F Winklhofer, Fulvio Reggiori.

In contrast to the ubiquitin (Ub)-proteasome-system, which only degrades individual proteins, macroautophagy can eliminate protein complexes or aggregates, organelles and even pathogens. Terms such as mitophagy, aggrephagy, lysophagy and xenophagy have been coined based on the targeted substrate. In Ub-dependent selective macroautophagy, cargo selectivity is specified by E3 Ub ligases that append Ub chains that in turn are recognized by selective autophagy receptors (SARs), driving sequestration into autophagosomes. While several Ub-dependent SARs have been identified and characterized, the E3 Ub ligases that ultimately decide target fate remain poorly studied. In this review, we summarize what is known about the E3 Ub ligases involved in selective macroautophagy, with a particular emphasis on the degradation of mitochondria, protein aggregates, lysosomes and pathogens. A better characterization of these enzymes could improve therapeutic strategies for targeted degradation in acute and chronic diseases.

DOI: https://doi.org/10.1038/s44319-026-00887-1

Autophagy. 2026 Jul 22.

HTLV-1 Tax induces PINK1-PRKN/parkin-dependent mitophagy to mitigate activation of the CGAS-STING1 pathway.

Suchitra Mohanty, Sujit Suklabaidya, Nelli Mnatsakanyan, Steven Jacobson, Edward W Harhaj.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax regulatory protein plays a critical role in HTLV-1 persistence and pathogenesis; however, the underlying mechanisms are poorly understood. Here we show that Tax dynamically regulates mitochondrial reactive oxygen species (ROS) and membrane potential to trigger mitochondrial dysfunction. Tax is recruited to damaged mitochondria through its interaction with the IKK regulatory subunit IKBKG/NEMO and directly engages the ubiquitin-dependent PINK1-PRKN/parkin pathway to induce mitophagy. Tax also recruits autophagy receptors CALCOCO2/NDP52 and SQSTM1/p62 to damaged mitochondria to induce mitophagy. Furthermore, Tax requires PRKN to limit the extent of CGAS-STING1 activation and suppress type I interferon (IFN) induction. HTLV-1-transformed T-cell lines and PBMCs from HAM/TSP patients exhibit hallmarks of chronic mitophagy, and inhibition of PRKN in HTLV-1-transformed cell lines downregulates p19 Gag expression and induces cell death. Collectively, our findings suggest that Tax manipulation of the PINK1-PRKN mitophagy pathway represents a new HTLV-1 immune evasion strategy important for maintaining viral gene expression and cell survival.

Keywords: CALCOCO2/NDP52; HTLV-1; IKBKG/NEMO; PINK1; PRKN/Parkin; STING1; mitochondria; mitophagy; reactive oxygen species; tax

DOI: https://doi.org/10.1080/15548627.2026.2707897

Autophagy. 2026 Jul 23.

The ubiquitination of CD274 at MERCs enhances the anti-tumor immunity of cervical cancer.

Xin Sun, Sangni Qian, Guiqin Ye, Qin Wang, Eugene Chin Yue, Jianbin Zhang.

Mitochondria-ER contact sites (MERCs) are crucial signaling hubs, but their role in anti-tumor immunity is unclear. This study revealed that the mitophagy regulator PRKN ubiquitinated CD274 at MERCs in human cervical cancer cells, a key mechanism for anti-tumor immunity. CD274 expression inversely correlated with PRKN in cervical cancer. Upon mitophagy activation, CD274 was recruited from ER to MERCs by PINK1, enhancing its interaction with PRKN. PRKN then ubiquitinated CD274 at residues K89 and K105 within its extracellular domain. Functionally, a ubiquitination-deficient CD274 mutant promoted anaerobic glycolysis and MTOR signaling, accelerating cancer cell growth. Coculture with ubiquitination-deficient CD274 mutant-expressing cancer cells increased the CD8+ T-cells' exhaustion. Single-cell RNA sequencing of mouse tumors showed the expansion of the exhausted CD8+ T cells and myeloid-derived suppressor cells (MDSCs) with ubiquitination-deficient CD274 mutation. In vivo, a ubiquitination-deficient CD274 mutant accelerated tumor growth and reduced the therapy efficacy of immune checkpoint inhibitors. Conversely, clinical sample analysis showed that CD274 localization at MERCs or its ubiquitination levels were closely associated with the improved immunotherapy efficacy. Thus, mitophagy-dependent recruitment of CD274 to MERCs for PRKN-mediated ubiquitination is a novel pathway that activates the anti-tumor immunity and improves the immunotherapy efficacy, presenting a promising strategic target for cervical cancer treatment.Abbreviations: CCCP, carbonyl cyanide m-chlorophenylhydrazone; CD, cluster of differentiation; CHX, cycloheximide; FCCP, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GZMB, granzyme B; IFNG, interferon gamma; LDHA, lactate dehygrogenase A; MAP1LC3, microtubule-associated protein 1 light chain 3; MFN2, mitofusin 2; MHC, major histocompatibility complex; MTOR, mechanistic target of rapamycin kinase; OCR, oxygen consumption rate; PBMC, peripheral blood mononuclear cell; PDCD1, programmed cell death 1; PI, propidium iodide; PINK1, PTEN induced putative kinase 1; PKM, pyruvate kinase, muscle; RPS6, ribosomal protein S6; TNF, tumor necrosis factor; TME, tumor microenvironment.

Keywords: CD274; MERCs; PRKN; immunotherapy; tumor microenvironment; ubiquitination

DOI: https://doi.org/10.1080/15548627.2026.2708579