bims-tofagi 2026-05-31 papers

Issue of 2026–05–31
seven papers selected by
Michele Frison, University of Cambridge

EMBO J. 2026 May 26.

Transmembrane domain switching controls PINK1 import and fate in mitochondria.

James S Lorriman, Rhiannon J Hughes, Adam G Grieve, Robin A Corey, Ian Collinson.

Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported into the mitochondrial matrix. Structural modelling predicts that PINK1's transmembrane domain (TMD) is conformationally plastic, forming either an α-helix or α/β-hybrid at the interface between Tim17 of the TIM23-complex for engagement of either ROMO1 or PARL. These mutually exclusive assemblies define distinct protein-import channels with differing biological roles. PINK1's α-helical TMD adopts a pose suggestive of translocation through the ROMO1/Tim17-channel, while the α/β-hybrid engages PARL and is cleaved. We propose that TMD structural plasticity determines whether PINK1 is imported into the matrix or cleaved and retro-translocated. The results expand the role of PINK1 beyond that of a damage sensor and imply a role in healthy mitochondrial function with potential relevance to Parkinson's disease.

DOI: https://doi.org/10.1038/s44318-026-00789-x

Nat Plants. 2026 May 28.

Ubiquitin-dependent mitochondrial protein degradation ensures seedling emergence by regulating ER-mitochondrial interaction and mitophagy.

Zhen Tian, Yawen Huo, Chengyang Li, Qiwei Zheng, Fan Hu, Jing Li, Juncai Ma, Xiaolu Qu, Yunjiang Cheng, Byung-Ho Kang, Patrick Duckney, Pengwei Wang.

Seedling emergence is a pivotal step of plant survival, requiring rapid hypocotyl elongation for soil penetration1,2. This energy-demanding process necessitates active mitochondrial respiration, which inevitably induces oxidative damage3-6. Plants have therefore evolved a quality-control mechanism that selectively removes dysfunctional mitochondria through the mitophagy pathway. Here we identified SPL2, a mitochondrial E3 ligase that is essential for hypocotyl elongation and seedling emergence through degrading mitochondrial outer membrane proteins, such as TRB1 and FIS1A. Intriguingly, these proteins also interact with an endoplasmic reticulum (ER) protein, VAP27-1, forming a complex at the ER-mitochondria contact sites, which is essential for mitophagy initiation. The spl2 mutant exhibits enhanced ER-mitochondrial tethering and mitophagy activation, whereas the overexpression of SPL2 has the opposite effects. The expression of SPL2 increases after light perception, in agreement with the reduced mitophagy. Collectively, our findings reveal mechanistic insights into seedling emergence, which is coordinated through protein ubiquitination, ER-mitochondrial interaction and mitophagy.

DOI: https://doi.org/10.1038/s41477-026-02306-8

Cell Rep. 2026 May 28. pii: S2211-1247(26)00541-3. [Epub ahead of print]45(6): 117463

Prohibitin 2 links damaged mitochondria to intracellular bacteria to trigger xenophagy independent of mitophagy.

Jing Yang, Yitian Ying, Huiwen Ye, Meiyi Chen, Xia Liu, Ganlu Wei, Jiayue She, Xinyu Lin, Muyang Wan, Xun Tan.

Mitophagy and xenophagy, two selective autophagy pathways sharing common E3 ligases, have been proposed to intersect in host defense against invading pathogens. Here, we show that mitochondrial damage, but not mitophagy, is essential for triggering xenophagy via the inner mitochondrial membrane protein prohibitin 2 (PHB2). Upon bacteria-induced disruption of the outer mitochondrial membrane, PHB2 bridges mitochondria to bacteria by binding bacterial surface proteins, while concurrently interacting with either auto-ubiquitinated E3 ligase ARIH1 or Parkin, two well-characterized mitophagy-associated E3 ligases. This interaction positions polyubiquitin chains near PHB2-targeted bacteria to recruit selective autophagy receptors for initiating xenophagy, leading to the co-autophagic degradation of bacteria and mitochondria, a process unaffected by mitophagy inhibition. Our findings establish an uncovered mechanism of mitochondria-dependent antibacterial autophagy, positioning mitochondrial PHB2 as both a bacterial sensor and an E3 ligase scaffold, and unveiling a previously unidentified process governing the recruitment of mitophagy-associated E3 ligases to intracellular bacteria.

Keywords: ARIH1; CP: cell biology; CP: molecular biology; Listeria; PHB2; Salmonella; Staphylococcus aureus; mitochondria; mitophagy; parkin; ubiquitin; xenophagy

DOI: https://doi.org/10.1016/j.celrep.2026.117463

Autophagy. 2026 May 28.

MEN1/menin deficiency suppresses hepatocellular carcinogenesis via disrupting mitophagy-mediated mitochondrial homeostasis.

Chaochun Chen, Dafang Yu, Dekun Tang, Mengyuan Liu, Jiamei Zhu, Xuyan Wang, Guixue Dan, Lan Chen, Shumei Tang, Qianting Tian, Houmei Wang, Fuxue Meng, Tuo Zhang, Bing Guo, Tengxiang Chen, Haiyang Li, Bangming Jin.

Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with complex pathogenesis intertwined with metabolic and mitochondrial dysfunction. MEN1/menin is a protein with context-dependent functions in liver diseases. While MEN1 has been linked to HCC progression and mitochondrial homeostasis, its precise regulatory mechanism in these processes remains incompletely understood. Here, we report that MEN1 localizes to the outer mitochondrial membrane (OMM) in HCC cells, which is mediated by its N-terminal mitochondrial targeting sequence and the TOMM20 translocase complex. In a genetically engineered DEN- and CCl4-induced HCC mouse model, hepatocyte-specific men1 deficiency significantly suppressed tumorigenesis, a phenotype associated with impaired mitochondrial homeostasis. Mechanistically, MEN1 deficiency disrupted mitochondrial function by manifesting as promoted mitochondrial fission, impaired oxidative phosphorylation, reduced ATP levels, and elevated reactive oxygen species during energy stress. Critically, MEN1 loss inhibited mitophagy via downregulating the PINK1-PRKN/Parkin pathway, which impaired clearance of dysfunctional mitochondria and promotes their cytotoxic accumulation. Moreover, MEN1 expression was upregulated in human HCC tissues, correlated with poor clinical outcomes and was positively associated with autophagy signatures. Notably, pharmacological activation of mitophagy reversed the tumor-suppressive effects of MEN1 deficiency in vitro and in vivo. These findings identified a noncanonical role of mitochondrial MEN1 in driving HCC progression via regulating mitophagy homeostasis, and highlight the MEN1-mitophagy axis as a potential therapeutic target for HCC. Abbreviations: Alb-Cre: albumin promoter-driven recombinase Cre; Baf A1: bafilomycin A1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; CCl4: carbon tetrachloride; Co-IP: co-immunoprecipitation; CQ: chloroquine; DEN: diethylnitrosamine; DNM1L: dynamin 1 like; DQ-BSA: self-quenched BODIPY-conjugated bovine serum albumin; Gal: galactose; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic - pyruvic transaminase; HCC: hepatocellular carcinoma; WT: wild type; HMKO: hepatocyte-specific men1 knockout; IF: immunofluorescence; IHC: immunohistochemistry; IMM: inner mitochondrial membrane; KEGG: Kyoto Encyclopedia of Genes and Genomes; MEFs: mouse embryonic fibroblasts; MEN1-FL: full-length MEN1; MFF: mitochondrial fission factor; MFN1: mitofusin 1; MTS: mitochondrial targeting sequence; OCR: oxygen consumption rate; OMM: outer mitochondrial membrane; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced kinase1; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKN: parkin RBR E3 ubiquitin protein ligase; qPCR: RNA extraction and quantitative polymerase chain reaction; RNA-seq: RNA-sequencing; ROS: reactive oxygen species; shMEN1: small hairpin RNA-mediated MEN1 knockdown; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TOMM20: translocase of outer mitochondrial membrane 20.

Keywords: Energy metabolism; MEN1; mitochondrial MEN1; mitochondrial fission; mitophagy

DOI: https://doi.org/10.1080/15548627.2026.2677182

Autophagy. 2026 May 24. 1-19

NMN/NAD+ enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.

Jie Cui, Shifeng Ren, Bingjie Wang, Nan Zhang, Shanshan Zhu, Yajun Zhang, Xiangqing Qi, Weixue Meng, Liwei Shao, Shan Gao, Lijie Xing, Zengjun Li, Xiaodong Mu.

The effect of NAD+ in enhancing mitochondrial function and energy metabolism in human cells is closely linked to NAD+-dependent sirtuins (i.e. SIRT1 and SIRT3). SIRT2 primarily functions in the cytoplasm, where it can serve as a key deacetylase for tubulin and modulates stability of microtubules. Microtubule plays a pivotal role in regulating mitochondrial dynamics, including mitochondrial movement, fission/fusion, repair, and mitophagy-dependent clearance. However, the potential role of NAD+ in modulating SIRT2-related microtubule stability, and the potential involvement of the NAD+-SIRT2-microtubule axis in regulating mitochondrial and mitophagy functions remains unexplored. In this study, we demonstrate that senescent muscle cells exhibit microtubule hyper-stabilization and reduced dynamics, concomitant with SIRT2 inactivation and tubulin hyperacetylation. These alterations impair microtubule-dependent mitochondrial repair and mitophagy function, resulting in mtDNA leakage, CGAS-STING1 activation and subsequently accelerated senescence. Notably, treatment with nicotinamide mononucleotide (NMN) effectively reactivates SIRT2, restores microtubule dynamics, and enhances mitochondrial quality control by promoting repair and mitophagy. Consequently, NMN mitigates CGAS-STING1-driven senescence. Our findings reveal a novel mechanism by which NMN preserves mitochondrial health in senescent cells via a SIRT2-microtubule axis, highlighting its protective role beyond canonical NAD+-sirtuin pathways, and suggesting microtubule dynamics as a promising therapeutic target for improving cellular defects associated with mitochondrial and mitophagy dysfunctions.Abbreviations: D-gal: D-galactose; EdU: 5-ethynyl-20-deoxyuridine; HDAC6: histone deacetylase 6; LAMP1: lysosome associated membrane protein 1; MSCs: mesenchymal stem/stromal cells; mtDNA: mitochondrial DNA; NAD+: nicotinamide adenine dinucleotide; NMN: nicotinamide mononucleotide; PBS: phosphate-buffered saline; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SIRT2: sirtuin 2.

Keywords: Cellular senescence; cytoskeleton; innate immunity; mechanical stress; mitochondrial damage; mitophagy dysfunction

DOI: https://doi.org/10.1080/15548627.2026.2677181

Cancer Res. 2026 May 27.

Mitophagy‑Competent Cancer‑Associated Fibroblasts Fuel Chemoresistance by Rewiring Pyrimidine Metabolism in Pancreatic Cancer.

Shaobo Zhang, Hao Yuan, Muzi Guo, Zhijun Zhou, Yumeng Hu, Gaoyuan Lv, Haoran Qi, Yuanyuan Guo, Jing Han, Michael S Bronze, Courtney W Houchen, Min Li, Mingyang Liu.

Pancreatic cancer remains one of the deadliest malignancies, with gemcitabine-based chemotherapy as a mainstay treatment for most patients, yet resistance emerges almost universally. A defining feature of pancreatic cancer is its dense, fibroblast-rich stroma, where heterogeneous cancer-associated fibroblasts (CAFs) actively shape tumor biology and therapeutic response. Here, we elucidated a stromal-metabolic mechanism through which chemoresistant CAFs confer gemcitabine resistance. A subset of mitophagy-competent CAFs enhanced pancreatic cancer gemcitabine resistance. The EMT transcription factor ZEB1 acted as a master regulator of the CAF-driven chemoresistance program, and it was upregulated and epigenetically activated through SETD1A-mediated H3K4 methylation in gemcitabine-resistant CAFs. ZEB1 promoted BNIP3-mediated mitophagy in CAFs, leading to increased secretion of nucleotides that competitively inhibited gemcitabine incorporation into cancer cells while simultaneously supplying pyrimidine metabolism substrates for pyrimidine metabolism. Concurrently, ZEB1 transcriptionally activated CXCL8, engaging the CXCR1/2-MEK/ERK pathway in tumor cells and further augmenting pyrimidine metabolism via the RRM1/E2F1/G6PD axis, collectively diminishing gemcitabine cytotoxicity. Notably, combined inhibition of CXCR1/2 or G6PD with gemcitabine robustly suppressed tumor growth and restored chemosensitivity both in vitro and in vivo. Together, these findings uncover a key stromal-metabolic axis in pancreatic cancer, linking CAF mitophagy activity to metabolic remodeling in tumor cells and identifying ZEB1 and its downstream network as actionable targets to overcome chemoresistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5716