bims-lypmec 2026-05-24 papers

Eur J Cell Biol. 2026 May 19. pii: S0171-9335(26)00015-4. [Epub ahead of print]105(3): 151544

PQ-loop repeat-containing 2 (PQLC2) regulates mTORC1 lysosomal localization and autophagic flux.

Yun-Ji Jeung, Minsu Jang, Jiwon Ahn, Ok-Seon Kwon, Seung-Hyun Kim, Jae-Eun Kwon, Yunho Park, Seung Pil Jang, Kajung Ryu, Kyung-Sook Chung.

PQ-loop repeat-containing 2 (PQLC2) is a lysosomal transporter for cationic amino acid that plays a critical role in regulating intracellular amino acid levels. However, its role in lysosomal biogenesis and autophagy remains poorly understood. Here, we investigate the impact of PQLC2 loss on lysosomal function and autophagic flux using PQLC2 knockdown and knockout cell models. PQLC2-deficient cells exhibited enhanced nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosome, accompanied by increased expression of TFEB-lysosomal and autophagy target genes. In addition, genes related to mechanistic target of rapamycin complex 1 (mTORC1), a negative regulator of TFEB, were destabilized, leading to reduced lysosomal recruitment and impaired mTORC1 signaling. Loss of PQLC2 also resulted in lysosomal dysfunction, including defective lysosomal acidification, decreased cathepsin activity, and lysosomal enlargement. Furthermore, autophagosome maturation and autophagic flux were disrupted in PQLC2-deficient cells, as evidenced by p62 accumulation and decreased LC3-II levels. Collectively, our results highlight that PQLC2 is essential for regulating mTORC1-dependent lysosomal function and autophagy, underscoring its potential role in maintaining cellular homeostasis.

Keywords: Cathepsins; Lysosomal dysfunction; MTOR localization; MTORC1 stability; PQLC2

DOI: https://doi.org/10.1016/j.ejcb.2026.151544

J Cell Biol. 2026 Jul 06. pii: e202509040. [Epub ahead of print]225(7):

Arl8b inactivates the Rab11a recycling pathway to promote LAMP1 sorting and lysosome biogenesis.

Priya Chouhan, Yogita Phogat, Kshitiz Walia, Saikat Debnath, Sandeep Choubey, Medha Gupta, Amit Tuli, Mahak Sharma.

The small GTP-binding protein Arl8b is established as a regulator of lysosome positioning and fusion, yet its role in lysosome biogenesis remains unclear. Here, we investigate the role of Arl8b in the trafficking of newly synthesized LAMP1 to lysosomes using the Retention Using Selective Hook (RUSH) assay. We find that Arl8b localizes to post-endocytic LAMP1-containing vesicles prior to fusion with acidic lysosomes. Arl8b depletion leads to Rab11a-dependent recycling of LAMP1 to the plasma membrane, impairing its lysosomal delivery. Mechanistically, Arl8b recruits the Rab11a GAP, TBC1D9B, to LAMP1-positive membranes, and TBC1D9B depletion similarly disrupts LAMP1 sorting. Notably, TBC1D9B knockdown also impairs the retrieval of cation-independent mannose-6-phosphate receptor (CI-M6PR) from Rab11a- and Rab14-positive endosomes to the trans-Golgi network, impairing pro-cathepsin trafficking and cargo degradation. These findings reveal that Arl8b-mediated recruitment of Rab GAP TBC1D9B is crucial for inactivation of the Rab11a recycling pathway, leading to efficient sorting of lysosomal cargo to their functional location.

DOI: https://doi.org/10.1083/jcb.202509040

Autophagy. 2026 May 21.

High-fat diet exacerbates experimental colitis by inhibiting lysosomal function via the STAT3-TFEB Axis.

Haodong He, XingZhou Guo, Miao Xu, Zongbiao Tan, Chen Tan, Xiangyun Li, Zixuan Xiang, Pengzhan He, Beiying Deng, Yu Pu, Yafei Liu, Luyun Zhang, Jixiang Zhang, Weiguo Dong.

An elevated risk for inflammatory bowel disease (IBD) has been linked to the intake of high-fat diet (HFD), yet the underlying molecular mechanisms remain unclear. The lysosome and the macroautophagy/autophagy-lysosome pathway (ALP) are critical for maintaining the intestinal epithelial barrier. By employing both an in vivo model of dextran sulfate sodium (DSS)-induced colitis in mice and an in vitro model using lipopolysaccharide (LPS)-treated NCM460 cells, we established that HFD in vivo and palmitic acid (PA) in vitro profoundly impair epithelial barrier function and amplify inflammation, which was linked to the suppression of lysosomal function and the ALP. Mechanistically, HFD in vivo and PA in vitro activated STAT3 (p-STAT3[Y705]) under DSS- and LPS-associated inflammatory stress, respectively. This led to a dual suppression of TFEB: on the one hand, activated STAT3 directly bound to the TFEB promoter to inhibit its transcription; on the other hand, it facilitated the lysosomal recruitment of MTOR and activated MTORC1, which promoted TFEB phosphorylation (p-TFEB[S211]) and hindered its nuclear translocation. This cascade resulted in lysosomal membrane permeabilization (LMP), loss of acidification, and impaired degradative function. Intestinal epithelial-specific knockout of Stat3 or pharmacological activation of TFEB restored lysosomal function, repaired the epithelial barrier, and ameliorated colitis. Conversely, rectal administration of AAV9-shTfeb reversed the protective effects conferred by stat3 knockout. Our study reveals that HFD in vivo and PA in vitro disrupt lysosomal function and the intestinal barrier through the STAT3-TFEB axis, suggesting this signaling pathway as a promising avenue for intervention in diet-associated IBD. Abbreviations: AB-PAS: Alcian blue-periodic acid-Schiff; ALP: autophagy-lysosome pathway; CD: Crohn disease; ChIP: chromatin immunoprecipitation; CLEAR: coordinated lysosomal expression and regulation; DSS: dextran sulfate sodium; HFD: high-fat diet; IBD: inflammatory bowel disease; IF: immunofluorescence; IHC: immunohistochemistry; LAMP: lysosome associated membrane protein; LGALS3/Gal3: galectin 3; LMP: lysosomal membrane permeabilization; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PA: palmitic acid; RRAG: Ras-related GTP binding; RRAG-CA: constitutively active RRAG GTPase; RT-qPCR: reverse transcription quantitative PCR; SQSTM1/p62: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TA1: TFEB activator 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; TJ: tight junction; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UC: ulcerative colitis; WB: western blot; WT: wild-type.

Keywords: Autophagy-lysosome pathway; MTORC1; STAT3; TFEB; high-fat diet; intestinal epithelial barrier; lysosome; ulcerative colitis

DOI: https://doi.org/10.1080/15548627.2026.2678426

Autophagy. 2026 May 19.

MOTS-c, a mitochondrial-derived peptide, ameliorates lysosomal membrane permeability and improves survival of soft tissue transplantation.

Jingwei Shi, Yuzhe Wu, Xian Liu, Weijie Xia, Junnan Wu, Junsheng Lou, Xuzi Zhang, Jiacheng Zhang, Ningning Yang, Weiyi Chi, Linyi Xiang, Yuheng Zhang, Yun Shu, Ruize Miao, Jiayi Zhao, Xuwei Zhu, Jianjun Qi, Jian Xiao, Kailiang Zhou.

Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c, encoded by the MT-RNR1/12S rRNA open reading frame, enhances mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing the membrane potential, potentially preserving lysosomal integrity and reducing lysosomal membrane permeabilization (LMP). This study investigated the protective effects and underlying mechanisms of MOTS-c in ischemic flaps. RNA sequencing explored MOTS-c mechanisms in ischemic flaps. Tissue clearing, laser speckle contrast imaging and Doppler analyses revealed improved blood flow perfusion following MOTS-c treatment. Histological staining (HE, Masson, F-CHP) demonstrated enhanced angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to assess pyroptosis, macroautophagy/autophagy, LMP, and MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-κB pathway-related proteins. MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated LMP in ischemic flaps. Mechanistically, in vivo overexpression of PLA2G4A/cPLA2 (phospholipase A2, group IVA (calcium, calcium dependent)) via AAV confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, MOTS-c inhibited PLA2G4A via the MAPK1-MAPK3-NFKB signaling cascade, thereby reducing LMP and enhancing flap survival. These findings suggest that MOTS-c restores cellular homeostasis by targeting the PLA2G4A-LMP axis, representing a promising therapeutic strategy for improving outcomes in ischemic flap surgery.

Keywords: Ischemic flaps; MAPK1-MAPK3-NFKB signaling pathway; MOTS-c; lysosomal membrane permeabilization; pyroptosis

DOI: https://doi.org/10.1080/15548627.2026.2677180

Acta Diabetol. 2026 May 22.

Reversing diastolic dysfunction in diabetes: a mitochondrial quality control-centric pharmacological approach.

Wenkai Fu, Junqi Wang, Zhijiang Guo, Sang-Bing Ong, Yong Gao, Hang Zhu, Junyan Wang, Zhiyong Du, Miao Meng, Xing Chang.

Diabetic cardiomyopathy (DCM) is a major contributor to the cardiovascular complications associated with diabetes. This condition is characterized by structural and functional abnormalities of the myocardium that occur independently of factors such as hypertension or other established cardiac diseases. In this review, we focus on the mitochondrial quality control (MQC) system, a critical determinant in the pathogenesis of DCM. In the diabetic milieu, chronic hyperglycemia and lipid overload disrupt mitochondrial homeostasis, leading to oxidative stress, impaired energy metabolism, and dysregulated mitochondrial dynamics. These disturbances serve as precursors to severe pathological outcomes, including cardiomyocyte death, myocardial fibrosis, and the progression of heart failure. This paper systematically examines the four pillars of MQC regulation-mitochondrial dynamics, selective autophagy (mitophagy), mitochondrial biogenesis, and the mitochondrial unfolded protein response (UPRmt)-and discusses how dysregulation of these regulatory networks contributes to the development of DCM. We further explore the molecular mechanisms involving key regulators such as Drp1 and Parkin, emphasizing their potential as therapeutic targets. Although current research has identified promising strategies, including hypoglycemic agents, melatonin, and various natural compounds that modulate MQC in preclinical models, translating these findings into clinical practice remains challenging due to species differences and the inherent complexity of MQC regulation. Future research should prioritize multi-target combination therapies and personalized treatment strategies aimed at preserving mitochondrial homeostasis and delaying the progression of DCM.

Keywords: Diabetic cardiomyopathy; Mitochondrial homeostasis; Mitochondrial quality control; Oxidative stress

DOI: https://doi.org/10.1007/s00592-026-02706-4

Sci Adv. 2026 May 22. 12(21): eaeb8658

Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking.

Ryan M Loughran, Gurpreet K Arora, Jiachen Sun, Alicia Llorente, Sophia Crabtree, Cynthia Y Zhang, Kyanh Ly, Ren-Li Huynh, Wonhwa Cho, Brooke M Emerling.

In p53-deficient cancers, targeting cholesterol metabolism has emerged as a promising therapeutic approach, given that p53 loss dysregulates sterol regulatory element-binding protein 2 pathways, thereby enhancing cholesterol biosynthesis. While cholesterol synthesis inhibitors such as statins have shown initial success, their efficacy is often compromised by the development of acquired resistance. Consequently, strategies are being explored to disrupt cholesterol homeostasis more comprehensively by inhibiting its synthesis and intracellular transport. In this study, we investigate a previously underexplored function of PI5P4Ks, which catalyzes the conversion of PI(5)P to PI(4,5)P2 at intracellular membranes. Our findings reveal that PI5P4Ks play a key role in facilitating lysosomal cholesterol transport, regulating lysosome positioning, and sustaining growth signaling via the mechanistic target of rapamycin (mTOR) pathway. While PI5P4Ks have previously been implicated in mTOR signaling and tumor proliferation in p53-deficient contexts, this work elucidates an upstream mechanism that unifies these earlier observations.

DOI: https://doi.org/10.1126/sciadv.aeb8658