bims-raghud 2026-10-18 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–10–18
seven papers selected by
Irene Sambri, TIGEM

Revisiting Inherited Metabolic Diseases (IMDs) Through the Lens of Selective Autophagy.
Autophagy-lysosome flux failure in diabetic kidney disease: tubular vulnerability and cell-state remodeling.
BNIP3/NIX-mediated mitophagy versus Parkin-mediated mitophagy: mechanistic differences and functional implications.
Combined Loss of VHL and TSC1 Drives Clear Cell Renal Cell Carcinoma with Metabolic and Redox Reprogramming that Creates an NRF2 Dependency.
Podocyte Metabolic Flexibility Under Stress Conditions: From Metabolic Adaptation to Maladaptive Responses.
Targeting lysosomal ion channels to overcome cancer treatment resistance: emerging mechanisms and therapeutic opportunities.
Cyclophilin D deficiency exacerbates diet-induced obesity and selectively enhances skeletal muscle mitochondrial respiration in male mice.

J Inherit Metab Dis. 2026 Nov;49(6): e70259

Revisiting Inherited Metabolic Diseases (IMDs) Through the Lens of Selective Autophagy.

Marianna Maddaluno, Laura Cinque, Viviana Cetrangolo, Chiara De Leonibus.

  Selective autophagy is increasingly recognized as a fundamental quality-control mechanism that complements bulk autophagy by enabling the targeted degradation of specific intracellular cargos, including mitochondria, endoplasmic reticulum (ER), lipid droplets, glycogen, peroxisomes, ferritin, ribosomes, and protein aggregates. Cargo selectivity is mediated by selective autophagy receptors (SARs), which link damaged or superfluous substrates to the autophagic machinery through LC3/GABARAP interactions, thereby coordinating cargo sequestration. Recent studies have revealed substantial mechanistic differences between bulk and selective autophagy, highlighting the specialized signaling pathways, receptor networks, and transcriptional programs that regulate selective cargo clearance. Dysregulation of these pathways has emerged as a key contributor to the pathogenesis of inherited metabolic diseases (IMDs), a heterogeneous group of genetic disorders characterized by defective metabolism and multisystem involvement. This review summarizes the molecular mechanisms underlying major forms of selective autophagy, including mitophagy, pexophagy, glycophagy, lipophagy, ER-phagy, and ferritinophagy. It also discusses their relevance across IMD classes, such as mitochondrial disorders, lysosomal storage disorders, and peroxisomal diseases, among many others. Furthermore, selective autophagy is highlighted as a potential therapeutic target, with modulation of autophagy receptors and signaling pathways offering promising strategies to restore cellular homeostasis and improve disease manifestations in IMDs.

Keywords:  bulk autophagy; inherited metabolic diseases (IMDs); selective autophagy; selective autophagy cargos (SACs); selective autophagy receptors (SARs)

DOI:  https://doi.org/10.1002/jimd.70259
Front Endocrinol (Lausanne). 2026 ;17 1957312

Autophagy-lysosome flux failure in diabetic kidney disease: tubular vulnerability and cell-state remodeling.

Kaili Hu, Kaini Zhou, Aihua Fei, Cangwu Dong.

  Diabetic kidney disease (DKD) is conventionally framed as a glomerular microvascular complication but may also involve tubular degradative maladaptation, in which tubular cells progressively fail to clear damaged organelles, lipid droplets, and stress-related cargo through the autophagy-lysosome system. Among tubular compartments, proximal tubular epithelial cells depend particularly heavily on mitochondrial metabolism, endocytic trafficking, vesicular transport, and lysosome-supported proteostasis, making them especially vulnerable to diabetic metabolic stress. This review examines whether autophagy-lysosome failure, encompassing both initiation-level and flux-completion defects, provides a candidate link between adaptive tubular stress responses and maladaptive tubular cell-state remodeling. We appraise therapeutic opportunities for restoring degradative capacity, including standard metabolic and hemodynamic therapies, transcription factor EB (TFEB)- and AMP-activated protein kinase (AMPK)-centered interventions, selective autophagy modulation, and mechanism-guided integrative strategies. We propose a testable, stage-dependent reversibility framework, rather than an established DKD staging system: restoration of autophagy-lysosome flux and lysosomal capacity may be most effective before persistent senescence, ferroptotic vulnerability, and fibrosis become difficult to reverse. Accordingly, we distinguish initiation defects from completion defects using flux-competent criteria and identify the stage-dependent reversibility window as the principal conceptual contribution of this review, rather than a validated clinical staging construct.

Keywords:  ER-phagy; TFEB; autophagic flux; autophagy-lysosome axis; diabetic kidney disease; lipophagy; mitophagy; renal tubule epithelial cells

DOI:  https://doi.org/10.3389/fendo.2026.1957312
Adv Biol Regul. 2026 Oct 07. pii: S2212-4926(26)00043-6. [Epub ahead of print] 101186

BNIP3/NIX-mediated mitophagy versus Parkin-mediated mitophagy: mechanistic differences and functional implications.

Satoshi Waguri, Shun-Ichi Yamashita, Ritsuko Arai, Tomotake Kanki.

  Mitophagy is a form of selective autophagy in which an isolation membrane (IM or phagophore) sequesters damaged or superfluous mitochondria for lysosomal degradation. Recent advances in receptor-mediated mitophagy, particularly the BNIP3/NIX-mediated mitophagy, have highlighted the importance of this pathway in mitochondrial regulation across various biological settings, along with the well-established Parkin-mediated pathway. Parkin-mediated mitophagy senses mitochondrial damage through loss of membrane potential, whereas BNIP3/NIX-mediated mitophagy plays an important role in basal or physiologically induced mitochondrial turnover, thereby contributing to mitochondrial quality control and remodeling. These two pathways employ distinct sets of molecules to recruit the autophagy machinery to the mitochondria and exhibit different IM dynamics that are closely linked to mitochondrial fission and segregation. In this review, we first provide an updated overview of the autophagy process and then compare these two major forms of mitophagy, with particular emphasis on the molecular mechanisms of mitophagy initiation and IM dynamics. We also discuss the functional implications of these mechanistic differences in physiological and pathological context.

Keywords:  BNIP3; Mitophagy; NIX/BNIP3L; PINK1; Parkin; Phagophore

DOI:  https://doi.org/10.1016/j.jbior.2026.101186
bioRxiv. 2026 Sep 28. pii: 2026.09.24.754188. [Epub ahead of print]

Combined Loss of VHL and TSC1 Drives Clear Cell Renal Cell Carcinoma with Metabolic and Redox Reprogramming that Creates an NRF2 Dependency.

Jianing Xu, Xiaoqing Cheng, Omran A Aboud, Yingbei Chen, Ann Bialik, Ed Reznik, Toshinao Oyama, Satish Tickoo, Robert H Weiss, Emily H Cheng, James J Hsieh.

Cancer genomics studies have implicated combined loss of VHL and TSC1 as sufficient to initiate clear cell renal cell carcinoma (ccRCC) in humans. Here, we engineered a mouse model with kidney-specific deletion of Vhl and Tsc1. VhlF/FTsc1F/FKsp-Cre+ mice developed multifocal renal cell carcinomas starting at 7 weeks of age with 100% penetrance, and the resulting Vhl-/-Tsc1-/- tumors recapitulated the histopathology of human VHL-/-TSC1-/- ccRCC. Integrated transcriptomic and metabolomic analyses of 4-week-old preneoplastic renal cortices deficient for Vhl and Tsc1 demonstrated heightened HIF and mTORC1 signaling and unexpectedly revealed activation of an antioxidant response regulated by NRF2 (NFE2L2). Biochemical, cell biological, multi-omic, and xenograft studies identified an NRF2 dependency in human VHL-/-TSC1-/- ccRCC cells. Altogether, we report a mouse model that recapitulates human VHL-/-TSC1-/- ccRCC, delineate metabolic and redox reprogramming driven by unrestrained HIF and mTORC1 activation in the renal cortex, and identify NRF2 as a potential therapeutic vulnerability.

DOI: https://doi.org/10.64898/2026.09.24.754188
Cells. 2026 Sep 26. pii: 1751. [Epub ahead of print]15(19):

Podocyte Metabolic Flexibility Under Stress Conditions: From Metabolic Adaptation to Maladaptive Responses.

Marine Thirion, Emmanuel Esteve, Vanessa Tagliatti, Anne-Emilie Declèves.

  Podocytes are essential for glomerular function by maintaining the integrity of the glomerular filtration barrier. As terminally differentiated, post-mitotic cells, they are highly vulnerable to injury, which represents a central event in the development of chronic kidney disease. Although podocytes have been extensively studied to elucidate their structure and function, their metabolism and the role of metabolic dysregulation in podocyte injury remain incompletely understood. This review summarizes current knowledge of podocyte metabolism and its responses to diverse stressors. We discuss the basal metabolic profile of podocytes, which remains a matter of debate in the literature, with a focus on mitochondrial function. We further examine how stress conditions such as gluco- and lipotoxicity, vasoactive stress, mechanical stress, and immune dysregulation induce metabolic adaptations that become maladaptive upon sustained exposure. Metabolic reprogramming and its consequences, including cytoskeletal disorganization, are reviewed alongside emerging therapeutic strategies aimed at restoring podocyte metabolic homeostasis. A better understanding of podocyte metabolic flexibility may provide innovative strategies to preserve podocyte integrity and prevent the progression of chronic kidney disease.

Keywords:  chronic kidney disease; glomerular disease; metabolism; mitochondria; podocyte; therapeutic target

DOI:  https://doi.org/10.3390/cells15191751
Front Pharmacol. 2026 ;17 1911117

Targeting lysosomal ion channels to overcome cancer treatment resistance: emerging mechanisms and therapeutic opportunities.

Na Luo, Qiuxiang Wang, Jun Zhang, Zhiqin Deng.

  Lysosomes are critical cellular organelles that not only regulate metabolic regulation but also play pivotal roles in cell death, signal transduction, and tumorigenesis. The various ion channels expressed on the lysosomal membrane are central to these physiological functions; they intricately maintain lysosomal pH homeostasis, calcium ion homeostasis, and membrane potential. Consequently, the dysregulation of these channels has emerged as a potential target of tumor cells, driving tumor cell proliferation, metastasis, apoptosis, and drug resistance. This review summarizes the structure and function of major lysosomal ion channels, emphasizing their central roles in regulating the tumor microenvironment, cell survival, and treatment resistance. Specifically, we highlight their involvement in mediating resistance to chemotherapy, radiotherapy, and immunotherapy, elucidating the associated molecular mechanisms. Furthermore, we explore the prospects and challenges of developing targeted therapeutic strategies towards these ion channels to overcome tumor drug resistance.

Keywords:  drug resistance; immunotherapy resistance; ion channel; lysosome; radiotherapy resistance; tumor therapy

DOI:  https://doi.org/10.3389/fphar.2026.1911117
Pflugers Arch. 2026 Oct 13. pii: 91. [Epub ahead of print]478(11):

Cyclophilin D deficiency exacerbates diet-induced obesity and selectively enhances skeletal muscle mitochondrial respiration in male mice.

Jazzmin L Hembree, William A Abplanalp, John W Elrod, Paul T Pfluger.

Mitochondrial dysfunction is a hallmark of obesity-associated metabolic disease, with the mitochondrial permeability transition pore serving as a key regulator of cellular energy homeostasis. Cyclophilin D, encoded by Ppif, is the principal regulatory component of this pore and has been implicated in insulin secretion, adipocyte survival, and whole-body energy balance. However, whether Ppif loss produces a consistent metabolic phenotype when challenged with high fat diet (HFD) exposure, and whether systemic metabolic alterations reflect tissue-specific changes in mitochondrial oxidative capacity, remains unresolved. Here, we characterized male, 21-weeks-old mice with germline Ppif deletion longitudinally over 34 weeks under standard (SD) and HFD using body composition analysis, indirect calorimetry, glucose and insulin tolerance testing and tissue-resolved, Seahorse-based mitochondrial respirometry. Under SD, knockout mice displayed elevated fat mass without differences in food intake or energy expenditure. High-fat feeding progressively amplified this adiposity, with knockout mice developing significantly greater body weight and fat mass than wild-type littermates by weeks 28 and 36. Glucose tolerance and insulin sensitivity remained comparable between genotypes under either diet. ANCOVA revealed significant effects of lean mass (p < 0.001) and genotype (p = 0.017) on energy expenditure, as well as a significant lean mass × genotype interaction (p = 0.025). Consistent with a distinct contribution of lean mass to EE in KO vs. WT mice, we found increased ADP-stimulated mitochondrial respiration in quadriceps of knockout mice under both diets, without corresponding differences in brown adipose tissue or liver, or changes in mitochondrial content across tissues. These findings establish cyclophilin D as a diet- and tissue-specific regulator of energy homeostasis, informing therapeutic strategies targeting the permeability transition pore or cyclophilin D interactome in metabolic disease.

DOI: https://doi.org/10.1007/s00424-026-03218-4