bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–02–01
thirty-one papers selected by
Viktor Korolchuk, Newcastle University
  1. Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.
  2. Identification of KHS-101 as a Transcription Factor EB Activator to Promote α-Synuclein Degradation.
  3. UBE4B Mediates Mitophagy via NIPSNAP1 Ubiquitination and NDP52 Recruitment.
  4. SNX16 functions as a nutrient-sensitive regulator of autophagosomal components recycling.
  5. Lysosomes as hubs of metabolic sensing and cellular homeostasis.
  6. Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
  7. MFN2 interacts with phosphorylated AMPK to mediate mitophagy in MCF-7 cells.
  8. Enhanced Retinal Ganglion Cell Survival via Autophagy Activation in a Novel Retinal Ischemia/Reperfusion Rat Model.
  9. Ectopically overexpressed glycine transporter 2 contributes to epileptogenesis in DEPDC5-related epilepsy.
  10. ER-phagy receptors: structural mechanisms in selective ER degradation and disease implications.
  11. Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.
  12. Role of lysosomal morphology in aging and age-related diseases.
  13. RICTOR-mediated GPX4 downregulation regulates chondrocyte ferroptosis in osteoarthritis progression.
  14. Vectorized ULK1/2 and VPS34 Inhibitors for Tissue-Selective Autophagy Inhibition in Oncology.
  15. Atg5/Autophagy inactivation in mouse bone microenvironment promotes tumor development.
  16. Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus.
  17. Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
  18. Hyperglycemia Differentially Regulates Osteoblast and Osteoclast Autophagy via AMPK/mTOR/p70 S6K Signaling in Diabetic Osteoporosis.
  19. From Hero to Hijacker: Autophagy's Double Life in Immune Patrols and Cancer Escape.
  20. Development of capsaicin-derived prohibitin ligands to modulate the Aurora kinase A/PHB2 interaction and mitophagy in cancer cells.
  21. p62 limits Salmonella Typhimurium in macrophages through its role in cell signalling.
  22. Novel tRNA Synthetase Inhibitors Increase Healthspan, Lifespan, and Autophagic Flux in C. elegans.
  23. Autophagy, Cellular Senescence and Oxidative Stress in Ageing and Age-Related Diseases.
  24. Reduced Proteasome Degradation of HSF-1 Shifts Protein Stress Management With Age in Caenorhabditis elegans.
  25. SIRT1 activation by SRT2104 enhances mitophagy and reduces senescence in auditory cells.
  26. ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
  27. Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
  28. Mitocytosis, mitophagy, and apoptosis coordinately drive mitochondrial clearance to regulate myogenic differentiation.
  29. NCOR1 alleviates myocardial infarction by improving lipid peroxidation through PPARG/PINK1-mediated mitophagy.
  30. Opposing effects of Gα12 and Gα13 loss on myotube size regulation via mTORC1 signaling.
  31. Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
  1. Int J Mol Sci. 2026 Jan 08. pii: 630. [Epub ahead of print]27(2):
    Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.
    Francesco Bellomo, Domenico De Rasmo.
      Cystinosis is a rare lysosomal storage disorder characterized by defective cystine transport and progressive multi-organ damage, with the kidney being the primary site of pathology. In addition to the traditional perspective on lysosomal dysfunction, recent studies have demonstrated that cystinosis exerts a substantial impact on cellular energy metabolism, with a particular emphasis on oxidative pathways. Mitochondria, the central hub of ATP production, exhibit structural abnormalities, impaired oxidative phosphorylation, and increased reactive oxygen species. These factors contribute to proximal tubular cell failure and systemic complications. This review highlights the critical role of energy metabolism in cystinosis and supports the emerging idea of organelle communication. A mounting body of evidence points to a robust functional and physical association between lysosomes and mitochondria, facilitated by membrane contact sites, vesicular trafficking, and signaling networks that modulate nutrient sensing, autophagy, and redox balance. Disruption of these interactions in cystinosis leads to defective mitophagy, accumulation of damaged mitochondria, and exacerbation of oxidative stress, creating a vicious cycle of energy failure and cellular injury. A comprehensive understanding of these mechanisms has the potential to reveal novel therapeutic avenues that extend beyond the scope of cysteamine, encompassing strategies that target mitochondrial health, enhance autophagy, and restore lysosome-mitochondria communication.
    Keywords:  bioenergetics; cAMP; cysteamine; cystinosis; flavonoids; ketogenic diet; lysosomal storage diseases; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/ijms27020630
  2. Int J Mol Sci. 2026 Jan 16. pii: 905. [Epub ahead of print]27(2):
    Identification of KHS-101 as a Transcription Factor EB Activator to Promote α-Synuclein Degradation.
    Haizhen Zhu, Anqi Ren, Ting Li, Tao Zhou, Ailing Li, Xin Pan, Liang Chen, Jiayi Chen.
      Neurodegenerative disorders are increasingly linked to a progressive decline in lysosomal function. Activating Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, has therefore emerged as a promising therapeutic strategy to enhance cellular clearance in these conditions. In this study, we identified KHS-101 as a novel TFEB activator through a high-throughput screen of blood-brain-barrier-permeable small molecules. We demonstrated that KHS-101 promotes TFEB nuclear translocation, enhances lysosomal biogenesis and proteolytic activity, and increases autophagic flux. Furthermore, KHS-101 significantly accelerates the degradation of pathogenic A53T mutant α-synuclein in a cellular model of Parkinson's disease, suggesting its potential to mitigate α-synuclein-mediated proteotoxicity and hold neuroprotective potential. Our findings identify KHS-101 as a potent TFEB activator and highlight the therapeutic potential of modulating the autophagy-lysosomal pathway for treating Parkinson's disease and related disorders.
    Keywords:  KHS-101; Parkinson’s disease; TFEB; autophagy–lysosome pathway; lysosome degradation; α-synuclein
    DOI:  https://doi.org/10.3390/ijms27020905
  3. Int J Mol Sci. 2026 Jan 22. pii: 1119. [Epub ahead of print]27(2):
    UBE4B Mediates Mitophagy via NIPSNAP1 Ubiquitination and NDP52 Recruitment.
    Bo Jin, Junyao Qu, Ke Xu, Yufei Zhang, Peng Xu, Xin Wang, Bo Zhao, Xianting Jiao.
      Mitophagy, as a critical form of selective autophagy, plays a central role in maintaining cellular homeostasis. While the canonical PTEN-Induced Kinase 1 (PINK1)-Parkin pathway is well established, mitophagy can still be effectively induced in Parkin-deficient cells such as HeLa, indicating the existence of Parkin-independent alternative pathways. The mitochondrial matrix proteins 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) acts as a key effector in such pathways, yet its regulatory mechanisms remain incompletely understood. Here, we identify Ubiquitination Factor E4B (UBE4B) as an E3 ubiquitin ligase for NIPSNAP1 and demonstrate that it catalyzes NIPSNAP1 ubiquitination in both Human Embryonic Kidney 293 cells (HEK293T) and HeLa cells. Under mitochondrial depolarization, UBE4B not only promotes NIPSNAP1 ubiquitination and subsequent lysosome-dependent degradation, but also significantly enhances its interaction with the autophagy adaptors Nuclear Dot Protein 52 kDa (NDP52) and Sequestosome 1 (p62/SQSTM1). Notably, while Parkin does not ubiquitinate NIPSNAP1, UBE4B-mediated ubiquitination facilitates mitophagy in Parkin-null HeLa cells by strengthening the binding between NIPSNAP1 and NDP52. Collectively, this study unveils a novel mitophagy pathway regulated by the UBE4B-NIPSNAP1 axis, offering new insights into mitochondrial quality control.
    Keywords:  HeLa cell; NIPSNAP1; UBE4B; mitophagy; parkin; ubiquitination
    DOI:  https://doi.org/10.3390/ijms27021119
  4. Autophagy. 2026 Jan 27.
    SNX16 functions as a nutrient-sensitive regulator of autophagosomal components recycling.
    Yueguang Que, Huilin Rong.
      In macroautophagy/autophagy, the inner membrane of the autophagosome and its contents are degraded within the autolysosome, while outer membrane proteins are recycled via a process known as autophagosomal components recycling (ACR). ACR is mediated by the recycler complex, powered by dynein-dynactin complexes, and regulated by RAB32-family small GTPases. However, it remains unknown whether ACR is subject to nutrient signal regulation or whether additional molecular components participate in the recycler complex. Our latest research identifies SNX16 as a new component of the recycler complex and reveals that MTORC1 phosphorylates SNX16, enabling SNX16 to function as a nutrient sensor that regulates ACR.
    Keywords:  ACR; MTOR; SNX; STX17; autophagy; lysosome
    DOI:  https://doi.org/10.1080/15548627.2026.2622466
  5. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]
    Lysosomes as hubs of metabolic sensing and cellular homeostasis.
    Aakriti Jain, Roberto Zoncu.
      Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.
    Keywords:  amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.011
  6. Elife. 2026 Jan 26. pii: RP95576. [Epub ahead of print]13
    Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
    Kanako Shinno, Yuri Miura, Koichi M Iijima, Emiko Suzuki, Kanae Ando.
      Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.
    Keywords:  D. melanogaster; aging; autophagy; cell biology; mitochondria; neuronal proteostasis; protein aggregation; proteome
    DOI:  https://doi.org/10.7554/eLife.95576
  7. Int J Biochem Cell Biol. 2026 Jan 23. pii: S1357-2725(26)00010-5. [Epub ahead of print] 106906
    MFN2 interacts with phosphorylated AMPK to mediate mitophagy in MCF-7 cells.
    Shixian Zhai, Zihong Huang, Chunchun An, Lu Gao, Tongsheng Chen.
      Mitofusin 2 (MFN2) has been reported to play an important role in mitophagy, but how MFN2 mediates mitophagy remains incompletely understood. Here, we establish that MFN2 upregulation is a key driver of mitophagy in MCF-7 cells. MFN2 overexpression triggers mitochondrial degradation, as verified by multiple mitophagy markers, whereas MFN2 knockdown abolishes the mitophagic response induced by Leflunomide (Lef), a compound that promotes mitophagy by upregulating MFN2. To elucidate the underlying mechanism, fluorescence imaging and subcellular fractionation reveal that MFN2 promotes AMP-activated protein kinase (AMPK) phosphorylation at Thr172 and facilitates translocation of AMPK from the cytoplasm to mitochondria. Quantitative Förster resonance energy transfer (FRET) analysis supports phosphorylation-dependent formation of an MFN2-AMPK complex in cells, and site-directed mutagenesis supports Thr172 phosphorylation dependence, as the phosphomimetic AMPK (T172D) mutant exhibits enhanced complex formation with MFN2, while the phosphodeficient AMPK (T172A) mutant shows little or no complex formation with MFN2. Co-immunoprecipitation further supports an MFN2-AMPK complex in cells. The MFN2-AMPK complex is essential for mitophagy: Compound C, a pharmacological inhibitor of AMPK, prevents both MFN2-AMPK complex formation and mitophagy, even in cells overexpressing MFN2. Notably, AMPK activation through Acadesine (AICAR) treatment is insufficient to induce mitophagy, but it markedly enhances mitophagy markers when combined with MFN2 overexpression. In conclusion, MFN2 mediates efficient mitophagy by recruiting Thr172-phosphorylated AMPK to mitochondria through a phosphorylation-dependent MFN2-AMPK complex.
    Keywords:  AMPK phosphorylation; Autophagy; FRET; Interaction; Leflunomide; MFN2; Mitochondrial
    DOI:  https://doi.org/10.1016/j.biocel.2026.106906
  8. Int J Mol Sci. 2026 Jan 20. pii: 1031. [Epub ahead of print]27(2):
    Enhanced Retinal Ganglion Cell Survival via Autophagy Activation in a Novel Retinal Ischemia/Reperfusion Rat Model.
    Si Hyung Lee, Jung Woo Han, Su-Ah Yoon, Hun Soo Chang, Tae Kwann Park.
      Autophagy is a fundamental catabolic process that degrades and recycles intracellular components, serving as a key survival mechanism in neurons. In glaucomatous optic neuropathy, autophagy has been linked to both protection of retinal ganglion cells (RGCs) and their accelerated loss, yet its precise impact remains unresolved. In this study, we established and validated a straightforward rat model of retinal ischemia/reperfusion (I/R) using double circumlimbal sutures, which reliably produced RGC apoptosis, retinal thinning, and axonal degeneration compared with controls. Early after reperfusion (1-6 h), robust induction of the autophagy marker LC3B was observed, but this activation diminished within 48 h. Other autophagy-related proteins, including ATG4, ATG7, Beclin-1, and p62, followed similar temporal patterns, while components of the mammalian target of rapamycin (mTOR) pathway displayed an inverse time course. Pharmacologic suppression of mTOR with intravitreal rapamycin administered prior to ischemia provided the most significant neuroprotection, whereas post-injury treatment yielded minimal benefit. Collectively, these findings indicate that timely stimulation of autophagy before retinal ischemic injury can enhance RGC survival and may represent a therapeutic potential for glaucoma management.
    Keywords:  autophagy; circumlimbal suture; glaucoma; retinal ischemia/reperfusion
    DOI:  https://doi.org/10.3390/ijms27021031
  9. Exp Neurol. 2026 Jan 24. pii: S0014-4886(26)00031-2. [Epub ahead of print] 115668
    Ectopically overexpressed glycine transporter 2 contributes to epileptogenesis in DEPDC5-related epilepsy.
    Tao Yang, Rajat Benerjee, Mirte Scheper, Mi Jiang, Eleonora Aronica, Yu Wang.
      Loss-of-function mutations in DEPDC5 (DEP domain-containing protein 5), a critical negative regulator of mTORC1 (mechanistic Target of Rapamycin Complex 1), are often identified in patients with refractory epilepsy. To understand its underlying pathogenesis and develop novel therapeutics, we used a highly clinically relevant rat model of DEPDC5-related epilepsy and resected human patient tissues to profile the molecular architecture in the dysplastic cortex. We report here that Slc6a5 (solute carrier family 6 member 5 gene), a marker gene for glycinergic inhibitory neurons, is ectopically overexpressed in mutant excitatory neurons in both experimental animal and human tissues. Using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) in utero electroporation (IUE) to simultaneously knock out Depdc5 and Slc6a5 in forebrain excitatory neurons reduces seizure frequency and duration. These data suggest that SLC6A5 plays an important role in the epileptogenesis of DEPDC5-related epilepsy, although the underlying mechanisms remain unclear.
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115668
  10. Acta Pharmacol Sin. 2026 Jan 27.
    ER-phagy receptors: structural mechanisms in selective ER degradation and disease implications.
    Wen-Jing Yang, Rui Sheng.
      The endoplasmic reticulum (ER) is a central organelle for protein synthesis and folding, lipid metabolism and calcium signaling, etc. To maintain ER homeostasis, cells employ a specific autophagy process termed ER-phagy (reticulophagy), which depredates ER components via three forms: macro-ER-phagy (involving bulk ER sequestration), micro-ER-phagy (lysosome-direct), and ER-to-lysosome-associated degradation (ERLAD). The identification of specific ER-phagy receptors including FAM134A, FAM134B, FAM134C, TEX264, SEC62, RTN3L, CCPG1, ATL3, CALCOCO1 and others has significantly advanced our understanding of ER quality control mechanisms. In this review we summarize the current knowledge on ER-phagy receptors, and emerging evidence linking ER-phagy dysfunction to various disease pathologies including neurological disorders, cancer, metabolic diseases, cardiovascular diseases, infections and immune disorders. Recent evidence shows that ER-phagy receptors can form novel ER-derived structures, such as ER-tubular bodies (ER-TBs) consisted of ATL3 and RTN3L, which mediate Golgi-bypassing unconventional protein secretion under stress conditions, revealing non-degradative functions of these receptors beyond quality control. Targeting ER-phagy receptors may provide insights into potential therapeutic strategies for diseases associated with this fundamental cellular process.
    Keywords:  ER-phagy; ER-phagy receptors; FAM134B; TEX264; endoplasmic reticulum; human diseases
    DOI:  https://doi.org/10.1038/s41401-025-01724-2
  11. Acta Pharm Sin B. 2026 Jan;16(1): 1-12
    Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.
    Joshua Kramer, Eric Rohwer, Palaniappan Sethu, Min Xie, Timmy Lee, Victor Darley-Usmar, Jianhua Zhang.
      Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia-reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell-cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.
    Keywords:  Cardiomyocytes; Exophers; Fibroblasts; Macrophages; Migrasomes; Mitophagy; TNTs; Transmitophagy
    DOI:  https://doi.org/10.1016/j.apsb.2025.11.030
  12. Ageing Res Rev. 2026 Jan 23. pii: S1568-1637(26)00025-5. [Epub ahead of print]115 103033
    Role of lysosomal morphology in aging and age-related diseases.
    Huimin Liu, Haiqing Tang, Shanshan Pang.
      Lysosomes are responsible for clearing cellular waste and facilitating material recycling, thus playing a crucial role in maintaining cellular homeostasis and even in resisting the development of various diseases. Lysosomes are highly dynamic organelles. While typically exhibiting a vesicular morphology, lysosomes can remodel into tubular structures under specific conditions; this morphological plasticity underpins their functional complexity. Aging triggers significant lysosomal morphological remodeling and functional decline, contributing to the development of age-related diseases, notably neurodegenerative disorders. Although lysosomal function has been extensively studied in age-related diseases, the mechanisms driving aging-associated morphological alterations and their pathophysiological significance remain elusive. This review synthesizes current knowledge on the regulation of lysosomal morphology and its changes and functions during aging and in age-related diseases. We propose that altered lysosomal morphology represents not merely a hallmark of aging, but also a significant determinant of lysosomal and cellular functions during aging. Targeting lysosomal morphology holds promise as an emerging strategy for counteracting functional deterioration in aged lysosomes and mitigating associated disease pathogenesis.
    Keywords:  Aging; Lysosomes; Morphology; Tubulation; Vesicular enlargement
    DOI:  https://doi.org/10.1016/j.arr.2026.103033
  13. Int Immunopharmacol. 2026 Jan 26. pii: S1567-5769(26)00117-7. [Epub ahead of print]173 116274
    RICTOR-mediated GPX4 downregulation regulates chondrocyte ferroptosis in osteoarthritis progression.
    Jingting Xu, Zehang Zheng, Fei Xin, Xiong Zhang, Liangcai Hou, Wenxin Zhong, Eryou Feng, Genchun Wang, Fengjing Guo.
      Osteoarthritis (OA) is the most common degenerative joint disease worldwide and the leading cause of chronic pain and mobility limitation in the elderly. Numerous studies have demonstrated that ferroptosis plays a crucial role in the development and progression of OA; however, the precise mechanisms remain to be elucidated. RICTOR (Rapamycin-Insensitive Companion of mTOR) is a key protein in cellular signal transduction and an essential component of mTORC2 (mammalian target of rapamycin complex 2), vital for the stability and activity of the complex. Our previous work established that RICTOR regulates autophagy to influence OA, yet whether RICTOR affects ferroptosis is unclear. This study aims to investigate the role of RICTOR in chondrocyte ferroptosis and to explore the RICTOR-ferroptosis axis as a potential therapeutic target.First, we observed elevated RICTOR expression in cartilage from OA patients and destabilization of the medial meniscus (DMM) mice, as well as in erastin-treated OA chondrocytes. RICTOR knockdown attenuated erastin-induced reduction of Col2a1 and promoted down-regulation of MMP13. Moreover, the RICTOR inhibitor JR-AB2 ameliorated cartilage degradation in the DMM-induced OA mouse model and mitigated the decline of GPX4 in vivo. Overall, our results indicate that RICTOR induces ferroptosis in OA by regulating GPX4 expression.
    Keywords:  Chondrocyte; Ferroptosis; GPX4; Osteoarthritis; RICTOR
    DOI:  https://doi.org/10.1016/j.intimp.2026.116274
  14. J Med Chem. 2026 Jan 26.
    Vectorized ULK1/2 and VPS34 Inhibitors for Tissue-Selective Autophagy Inhibition in Oncology.
    Lorenzo Cianni, Kathryn Jacobs, Sergei Grintsevich, Sophie Lyssens, Eline Roeyen, Koen Augustyns, Maya Berg, Hans De Winter, Guido R Y de Meyer, Wim Martinet, Patrizia Agostinis, Gabriele Bergers, Pieter Van der Veken.
      Autophagy, the primary lysosomal degradation pathway, plays a key role in cell survival and homeostasis. In tumors, it is upregulated to support cancer cell plasticity, adaptation to the microenvironment, and therapy resistance, making its inhibition an attractive therapeutic strategy. However, since autophagy is essential in healthy tissues, selective inhibition in tumors is critical. To address this, we designed inhibitors of two autophagy initiation factors (ULK1/2 and VPS34) equipped with tumor-targeting vectors. Our most promising candidates combine a low-nanomolar ULK1/2 inhibitory scaffold with an RGR-sequence targeting peptide. These compounds were validated across in vitro, in cellulo, and in vivo models, demonstrating selective activity and preserved efficacy. As the first examples of tumor-targeted autophagy inhibitors, they open new avenues for developing tissue-specific modulators of autophagy, with potential applications in oncology and beyond.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c00997
  15. Autophagy. 2026 Jan 29.
    Atg5/Autophagy inactivation in mouse bone microenvironment promotes tumor development.
    Marie-Charlotte Trojani, Marie Nollet, Olivier Camuzard, Sabine Santucci-Darmanin, Véronique Breuil, Fanny Burel-Vandenbos, Laurie Fradet, Morgane Le Gall, Virginie Salnot, Dominique Heymann, Georges F Carle, Valérie Pierrefite-Carle.
      Bone is an attractive site for cancer colonization, both for primary tumors such as osteosarcoma and for metastases of various malignancies. Preventing bone metastasis, which is associated with a poor prognosis, is a major challenge and identifying the factors involved in skeletal tumoral development is crucial to improve survival. In the present work, we showed that inactivation of the macroautophagy/autophagy-essential gene Atg5 in osteoblasts, the cells in charge of bone formation, stimulates osteosarcoma and breastbone metastasis growth as well as metastatic dissemination. We determined that Atg5 inactivation leads to systemic inflammation and bone proteome modifications including translation downregulation, stress granule formation, and upregulation of fatty acid beta-oxidation. In addition, Atg5 inactivation triggered lysosomal exocytosis through an autophagy-independent effect. Thus, our findings indicated that autophagy/ATG5 deficiency in the bone microenvironment generates a favorable environment for tumor development through several mechanisms and suggested that a bone-targeted autophagy inducer could be used to delay bone metastasis appearance.
    Keywords:  Autophagy; bone metastasis; bone microenvironment; breast cancer; osteoblast; osteosarcoma
    DOI:  https://doi.org/10.1080/15548627.2026.2624756
  16. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00027-4. [Epub ahead of print]
    Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus.
    Isabella R Lawrence, Emily C Sutton, Shivang Bhaskar, Susan J Baserga.
      Ribosome biogenesis is a complex, multi-step cellular process that begins in the nucleolus and produces ribosomes that translate mRNA into proteins in the cytoplasm. This process is essential for cellular growth yet is resource intensive. It is therefore tightly coordinated with cytoplasmic requirements, energy availability, and the cell cycle through several kinase signaling pathways. Increasing evidence indicates that proteins shared between the cytoplasm and nucleolus may enhance this coordination. Here, we evaluate the interplay between the cytoplasm and nucleolus in human cells, presenting an intricate bidirectional regulatory network with emerging clinical relevance. We describe the phosphorylation events that promote ribosome biogenesis during interphase, focusing on mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase (ERK), and casein kinase II (CK2). By contrast, protein phosphorylation inactivates ribosome biogenesis during mitosis. We further summarize several factors shared among the mitotic machinery, cytoplasmic organelles, and the nucleolus. Moreover, we highlight the mounting evidence that dysregulated cytoplasmic-nucleolar feedback contributes to the progression of several diseases.
    Keywords:  cancer; endoplasmic reticulum; lysosome; mTOR; mitochondria; mitosis; muscle atrophy; rRNA; ribosome biogenesis; ribosomopathies
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.007
  17. Autophagy. 2026 Jan 28.
    Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
    Fasih A Rahman, Mackenzie Q Graham, Joe Quadrilatero.
      Skeletal muscle is a heterogeneous tissue consisting of fibers with distinct contractile speeds, metabolic profiles, and cellular signaling. This heterogeneity may extend to mitochondrial quality control processes such as mitophagy. Using mt-Keima mice, we found that mitophagic activity was greater in the fast-twitch, glycolytic extensor digitorum longus (EDL) compared to the slow-twitch, oxidative soleus (SOL) muscle. Live imaging of quadriceps (QUAD) muscle revealed two distinct fiber populations: those with high total mt-Keima signal but low mitophagic activity, and others with low signal but higher mitophagic activity. Additionally, we observed skeletal muscle type and regional differences in autophagic and mitophagic protein content. Further, select mitophagic proteins strongly correlated with mitochondrial proteins across different regions of the gastrocnemius, while others did not. These findings highlight the complexity of mitophagy regulation in skeletal muscle and emphasize the importance of considering muscle phenotype, including fiber type, region, and mitochondrial content when studying mitophagy.
    Keywords:  Fibers; metabolism; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1080/15548627.2026.2623988
  18. Mol Cell Endocrinol. 2026 Jan 27. pii: S0303-7207(26)00016-X. [Epub ahead of print] 112739
    Hyperglycemia Differentially Regulates Osteoblast and Osteoclast Autophagy via AMPK/mTOR/p70 S6K Signaling in Diabetic Osteoporosis.
    Bin Zhou, Fen Feng, Cila Zhou, Kuang Yao, Ping Huang.
      Type 2 diabetes mellitus (T2DM) often induces diabetic osteoporosis (DOP) with impaired bone remodeling, yet its underlying mechanism remains elusive. This study identified the differential regulatory role of the AMPK/mTOR/p70 S6K signaling axis in bone cell function. In vivo, diabetes reduced AMPK phosphorylation, enhanced mTOR/p70 S6K activation, and diminished autophagy in rat femoral tissue. In vitro, HG exerted cell-type-specific effects via the AMPK signaling pathway: in osteoblasts, HG inhibited AMPK phosphorylation, activated mTOR/p70 S6K, suppressed autophagy, and impaired mineralization as well as alkaline phosphatase (ALP) activity; conversely, in osteoclasts, HG enhanced autophagy through the inverse regulatory pathway and accelerated osteoclast differentiation and bone resorption. Collectively, these findings illustrate that hyperglycemia disrupts bone homeostasis via cell-type-specific regulation of AMPK, suggesting that AMPK-mediated autophagy serves as a potential critical therapeutic target for diabetes-related bone diseases.
    Keywords:  AMPK; autophagy; diabetic osteoporosis; osteoblast; osteoclast
    DOI:  https://doi.org/10.1016/j.mce.2026.112739
  19. Cells. 2026 Jan 06. pii: 102. [Epub ahead of print]15(2):
    From Hero to Hijacker: Autophagy's Double Life in Immune Patrols and Cancer Escape.
    Flavie Garampon, Aurore Claude-Taupin.
      Cells are constantly exposed to mechanical forces that shape their behavior, survival, and fate. The autophagy machinery emerges as a central adaptive pathway in these processes, acting not only as a metabolic and quality control mechanism but also as a key regulator of membrane dynamics and mechanotransduction. Here, we review how mechanical stress influences autophagy initiation, autophagosome maturation, and lysosomal function across different cell types. We discuss parallels between leukocyte diapedesis and circulating tumor cell (CTC) extravasation, two processes that involve profound mechanical challenges and rely on autophagy-related pathways to maintain cell integrity and enable transendothelial migration. Special attention is given to the dual role of autophagy-related proteins (ATGs) in these contexts, ranging from cytoplasmic degradation dependent on lysosomal fusion to secretory functions. Understanding how mechanical forces modulate autophagy and ATG-dependent pathways may reveal novel insights into immune regulation, tumor dissemination, and potential therapeutic targets aimed at controlling inflammation and metastasis.
    Keywords:  autophagy; cancer; diapedesis; extravasation; immunology; mechanobiology; migration; shear stress
    DOI:  https://doi.org/10.3390/cells15020102
  20. Commun Biol. 2026 Jan 24.
    Development of capsaicin-derived prohibitin ligands to modulate the Aurora kinase A/PHB2 interaction and mitophagy in cancer cells.
    Amel Djehal, Claire Caron, Deborah Giordano, Valentina Pizza, Kimberley Farin, Angelo Facchiano, Laurent Désaubry, Giulia Bertolin.
      Aurora kinase A/AURKA is a serine/threonine kinase frequently overexpressed in cancer. Recent discoveries pointed to subcellular pools of AURKA, including at mitochondria. There, AURKA induces organelle clearance by mitophagy together with the autophagy mediator LC3, and its receptor PHB2.Here, we show that the natural product capsaicin modifies the AURKA/PHB2 interaction. We synthesize 16 capsaicin analogs, and Förster's Resonance Energy Transfer/Fluorescence Lifetime Imaging Microscopy (FRET/FLIM) in breast cancer cells reveals that compounds 12 and 13 increase the AURKA/PHB2 interaction. Molecular docking shows that they bind to the inhibitory pocket of PHB2 and to the AURKA active site. We demonstrate that compound 13 specifically inhibits mitophagy while leaving AURKA activation unaltered at centrosomes. Our results demonstrate that compound 13 is a PHB ligand acting on the AURKA/PHB2 interaction. Thanks to its specificity, it may lead to the development of anticancer drugs targeting the mitochondrial functions of AURKA.
    DOI:  https://doi.org/10.1038/s42003-026-09573-3
  21. Access Microbiol. 2026 ;pii: 001102.v3. [Epub ahead of print]8(1):
    p62 limits Salmonella Typhimurium in macrophages through its role in cell signalling.
    Daniel Underwood, Arda Balci, Virtu Solano-Collado, Heather M Wilson, Massimiliano Baldassarre, Stefania Spanò.
      The intracellular autophagy receptor p62 (also known as Sequestosome-1) plays a dual role in autophagic flux and downstream Toll-like receptor signalling and has been implicated in modulating immune responses. However, its specific function in controlling intracellular bacterial survival, particularly in macrophages, remains less well characterized. Salmonella enterica serovar Typhimurium (S. Tm) is a major global pathogen and a leading cause of gastroenteritis-associated morbidity. We have previously demonstrated that host restriction of S. Tm in macrophages involves the GTPase Rab32 and the BLOC-3 complex. In the present study, we identify a novel interaction between p62 and Rab32. Notably, p62 restricts Salmonella survival independently of the Rab32/BLOC-3 pathway. Indeed, p62-knockdown in macrophages resulted in significantly increased intracellular bacterial survival, an effect that did not correlate with altered recruitment of canonical autophagy-related proteins, as assessed by fluorescence microscopy. Through real-time polymerase chain reaction (RT-qPCR) and infection assays, we further show that p62-depleted macrophages exhibit a dampened pro-inflammatory response, which corresponds with the increased bacterial burden. These findings provide new mechanistic insight into the role of p62 in modulating the macrophage inflammatory response during Salmonella infection, highlighting its contribution to host defence beyond its canonical functions in autophagy.
    Keywords:  NFkB; Salmonella Typhimurium; autophagy; macrophages; p62
    DOI:  https://doi.org/10.1099/acmi.0.001102.v3
  22. Biomolecules. 2026 Jan 01. pii: 73. [Epub ahead of print]16(1):
    Novel tRNA Synthetase Inhibitors Increase Healthspan, Lifespan, and Autophagic Flux in C. elegans.
    Olivia C Heath, Madison P Otero, Alexander T Achusim, Dorothy S Karr, Antonio W Leger, Mark A McCormick.
      We previously demonstrated that the tRNA synthetase inhibitors mupirocin and borrelidin extend lifespan in C. elegans and S. cerevisiae and that tRNA synthetase inhibition enhances autophagy in mammalian cells. In this study, we identify four additional tRNA synthetase inhibitors, REP8839, REP3123, LysRS-In-2, and halofuginone, that extend both healthspan and lifespan in C. elegans. These compounds also trigger a significant upregulation of autophagy, specifically at their lifespan-extending doses. These phenotypes partially depend on the conserved transcription factor ATF-4. Our findings further establish tRNA synthetase inhibition as a conserved mechanism for promoting increased lifespan and now healthspan, with potential implications for therapeutic interventions targeting age-related decline in humans.
    Keywords:  ATF-4; ATF4; Gcn4; autophagy; healthspan; tRNA synthetase
    DOI:  https://doi.org/10.3390/biom16010073
  23. Int J Mol Sci. 2026 Jan 18. pii: 957. [Epub ahead of print]27(2):
    Autophagy, Cellular Senescence and Oxidative Stress in Ageing and Age-Related Diseases.
    Varvara Trachana.
      As our understanding of ageing improves, it is becoming increasingly clear that it is the consequence of systematically interconnected cellular and molecular processes that govern damage management and resilience to acute and chronic stress [...].
    DOI:  https://doi.org/10.3390/ijms27020957
  24. Aging Cell. 2026 Feb;25(2): e70399
    Reduced Proteasome Degradation of HSF-1 Shifts Protein Stress Management With Age in Caenorhabditis elegans.
    Hongwei Wang, Fengzhen Sun, Zhidong He, Xiaojie Wang, Hao Liu, Mengjiao Song, Qingxia Chen, Zhixue Li, Ligang Wu, Xiumin Yan, Xueliang Zhu, Yidong Shen.
      To maintain protein homeostasis, which is essential for health, animals have developed complex protective mechanisms against various acute and chronic stresses. However, the coordination of responses to these protein stresses, especially their age-dependent changes, is not well understood. HSF-1 is a key regulator of protein homeostasis. Our study identifies PBS-7, a proteasome subunit, as its crucial regulator. In aged C. elegans, decreased PBS-7 binding reduces proteasome-mediated degradation of HSF-1. The increase in HSF-1 enhances responses to chronic stresses, like accumulating protein aggregates, by upregulating heat shock proteins (HSPs) and autophagy genes. Meanwhile, the upregulated HSPs suppress the activation of HSF-1 upon acute stress, such as heat shock. Our findings reveal a mechanism that coordinates responses to acute and chronic protein stresses and highlights an adaptation prioritising protection against increasing protein aggregates in ageing.
    Keywords:  HSF‐1; proteasome; stress resistance
    DOI:  https://doi.org/10.1111/acel.70399
  25. Sci Rep. 2026 Jan 27.
    SIRT1 activation by SRT2104 enhances mitophagy and reduces senescence in auditory cells.
    Sung Il Cho, Eu-Ri Jo, Hee Sun Jang.
      Age-related hearing loss is characterized by the progressive degeneration of cochlear hair cells and neurons, with mitochondrial dysfunction and impaired mitophagy implicated as molecular mechanisms. Sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, plays a critical role in the regulation of mitochondrial quality control and mitophagy. SRT2104, a synthetic SIRT1 activator with improved bioavailability compared to resveratrol, has shown neuroprotective effects in age-related neurodegeneration. However, the role of SIRT1 in auditory cell senescence remains unclear. In this study, we investigated the effects of SRT2104 on cellular senescence and mitophagy in HEI-OC1 auditory cells and organotypic cochlear explants. Senescence was induced using low-dose H₂O₂, and SRT2104 was used as a pre-treatment. SRT2104 significantly enhanced SIRT1 activity, upregulated mitophagy-related proteins (PINK1, Parkin, BNIP3, and LC3-II), and downregulated senescence markers (p53 and p21) in cellular and explant models. β-galactosidase staining confirmed reduced senescence in SRT2104-treated groups. Pre-treatment with SRT2104 preserved mitochondrial function, as indicated by enhanced mitochondrial membrane potential, improved mitochondrial DNA integrity, and increased ATP production. SIRT1 knockdown abolished these protective effects, confirming that SRT2104 mediated its anti-senescence and pro-mitophagy activities via SIRT1. Our findings demonstrated that SRT2104 alleviates premature senescence and promotes mitophagy in auditory cells via SIRT1 activation. The pharmacological activation of SIRT1 may represent a promising therapeutic strategy to counteract age-related degeneration in the auditory system.
    DOI:  https://doi.org/10.1038/s41598-026-37606-8
  26. Nat Commun. 2026 Jan 29.
    ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
    Zhenhuan Luo, Yimin Li, Chenyang He, Dan Wu, Wenyu Dai, Liubing Hu, Jing Yang, Brian L Harry, Zhenyu Ju, Nektarios Tavernarakis, Hao Wang, Qin-Li Wan, Qinghua Zhou.
      Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans (C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded protein response (UPRmt) through ATFS-1, causing accumulation of mitochondria and mtDNA in sperm, which ultimately impedes efficient paternal mitochondrial removal and negatively impacts male fertility and embryonic development. Our findings describe a mechanism whereby ALKB-1-mediated tRNA m1A epitranscriptomic modifications are necessary for maintaining mitochondrial quality control, thereby influencing PME efficiency, underscoring the importance of this epitranscriptomic stress checkpoint in upholding proper mitochondrial inheritance during reproduction.
    DOI:  https://doi.org/10.1038/s41467-026-68813-6
  27. J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):
    Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
    Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.
      Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.
    DOI:  https://doi.org/10.1083/jcb.202501023
  28. J Adv Res. 2026 Jan 26. pii: S2090-1232(26)00090-1. [Epub ahead of print]
    Mitocytosis, mitophagy, and apoptosis coordinately drive mitochondrial clearance to regulate myogenic differentiation.
    Dandan Wang, Mei Li, Jun Ma, Guocheng Du, Jingwen Zhou, Jian Chen, Xin Guan.
       INTRODUCTION: Skeletal muscle is a high-energy-consuming tissue whose development and function critically depend on mitochondrial homeostasis. Mitochondrial quality control involves multiple clearance mechanisms, including mitocytosis, mitophagy, and apoptosis. However, how these pathways are coordinated during myogenic differentiation remains systematically unexplained.
    OBJECTIVES: This study aimed to investigate the sequential activation and coordination of mitocytosis, mitophagy, and apoptosis inresponse to gradient mitochondrial damage, and to explore their impact on myogenesis.
    METHODS: We established a gradient mitochondrial damage model in myoblasts using different concentrations of CCCP. Through fluorescence imaging, western blotting, genetic interventions, and small-molecule inhibitors, we investigated the activation sequence and crosstalk among different clearance pathways, and explored their effects on myotube formation and function.
    RESULTS: Escalating mitochondrial damage triggered a sequential activation of clearance mechanisms: KIF5B-mediated mitocytosis was first induced, followed by PINK1-dependent mitophagy, and ultimately Caspase 3-mediated apoptosis. When mitocytosis was inhibited, mitophagy dominated mitochondrial clearance, whereas enhanced mitocytosis suppressed both mitophagy and apoptosis. When mitophagy was impaired, cellular homeostasis could be maintained by upregulating mitocytosis under mild mitochondrial damage, but this led to premature apoptosis under severe mitochondrial damage. Myogenesis was significantly suppressed when either mitocytosis or mitophagy was impaired, whether through small-molecule inhibitors or the genetic knockdown of KIF5B or PINK1. Notably, low-dose CCCP treatment promoted myotube formation and mitochondrial function, and also attenuated the myogenic deficits resulting from KIF5B or PINK1 deficiency. Furthermore, KIF5B overexpression enhanced glycolytic metabolism and accelerated myoblast proliferation, highlighting its role beyond mitochondrial clearance.
    CONCLUSION: These findings provide new insights into the coordinated regulatory network among mitochondrial clearance mechanisms and their roles in myogenic differentiation. These insights advance the understanding of muscle biology and offer potential strategies for enhancing muscle regeneration in biomedical and cellular agriculture applications.
    Keywords:  Apoptosis; Mitochondrial clearance; Mitocytosis; Mitophagy; Myogenic differentiation
    DOI:  https://doi.org/10.1016/j.jare.2026.01.065
  29. Biochem Cell Biol. 2026 Jan 01. 104 1-15
    NCOR1 alleviates myocardial infarction by improving lipid peroxidation through PPARG/PINK1-mediated mitophagy.
    Zhenzhen Liu, Yanru He, Wenjing Zhu.
      Abnormal lipid accumulation following myocardial infarction (MI) serves as a critical pathological factor contributing to cardiomyocyte injury. The nuclear receptor corepressor 1 (NCOR1) is famous as a key regulator in atherosclerosis, fatty liver, and other metabolic diseases, and recent evidence suggested that NCOR1 exerted a protective action in damaged heart cells. In this study, in a murine MI model induced by left anterior descending coronary artery ligation, we observed a significant downregulation of NCOR1 in myocardial tissues. NCOR1 was also downregulated in oxygen-glucose deprivation (OGD)-treated H9C2 cells, in which NCOR1 overexpression improved lipid metabolic dysregulation and peroxidation. Mechanistically, NCOR1 interacted with peroxisome proliferator activated receptor gamma (PPARγ) protein, which transcriptionally activated the expression of the mitophagy marker gene PINK1. Either knockdown of PPARγ or PINK1 was able to reverse the improvement of NCOR1 overexpression on OGD-induced dysregulation of mitophagy, lipid peroxidation, and cardiomyocyte damage. Finally, we demonstrated that NCOR overexpression (mediated by lentiviral vector) reduced infarct size, attenuated myocardial damage, and significantly improved cardiac function in MI mice. These findings not only identify NCOR1 as a novel protector in hypoxic-ischemic myocardium but also delineate the "NCOR1-PPARγ-PINK1" axis as a novel mechanism for improving mitochondrial function and lipid peroxidation, offering a promising therapeutic target for MI treatment.
    Keywords:  NCOR1; PPARγ; lipid peroxidation; mitophagy; myocardial infarction
    DOI:  https://doi.org/10.1139/bcb-2025-0075
  30. Biochem Biophys Res Commun. 2026 Jan 21. pii: S0006-291X(26)00090-2. [Epub ahead of print]802 153326
    Opposing effects of Gα12 and Gα13 loss on myotube size regulation via mTORC1 signaling.
    Mai Kubota, Shuhei Fujita, Ryohei Kamata, Kazuma Tamura, Keiichiro Sugimoto, Tomoya Kitakaze, Naoki Harada, Ryoichi Yamaji.
      To reduce the risk of diseases caused by a reduction in skeletal muscle mass and quality, it is important to understand the molecular mechanisms underlying the maintenance and improvement of skeletal muscle mass and quality. Gα12 and/or Gα13 have been implicated in the regulation of myotube size through the mechanistic target of rapamycin complex 1 (mTORC1) signaling; however, their specific and potentially distinct molecular mechanisms remain unknown. Knockdown and rescue experiments revealed that the loss of Gα12 decreased myotube size, whereas the loss of Gα13 increased it. Gα12 knockdown reduced the phosphorylation levels of mTORC1 signaling components (Akt, mTOR, and p70S6K) and the levels of puromycin-labeled proteins, whereas Gα13 knockdown increased these levels. Loss of Gα12 or Gα13 suppressed SRF-RE-dependent transcriptional activity. While expression of a constitutively active form of RhoA (RhoA-CA) activated SRF-RE activity, notably, RhoA-CA expression did not affect myotube size, nor did it alter myotube atrophy induced by Gα12 knockdown or hypertrophy induced by Gα13 knockdown. Depletion of Gα12 increased the mRNA expression of oxidative myosin heavy chain (MyHC) isoforms Myh7 and Myh2 and decreased the mRNA expression of Myh1 and Myh4, whereas depletion of Gα13 increased the mRNA expression of Myh7, Myh2, Myh1, and Myh4. These results indicate that loss of Gα12 induces myotube atrophy by suppressing mTORC1 signaling and protein synthesis, whereas loss of Gα13 induces myotube hypertrophy by enhancing these processes, likely independent of SRF-RE-mediated transcription. Notably, Gα12 and Gα13 oppositely regulated the mRNA expression of MyHC isoforms, particularly Myh1 and Myh4.
    Keywords:  Atrophy; Gα12/13; Hypertrophy; Myosin heavy chain; Myotube; Serum response factor
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153326
  31. Autophagy. 2026 Jan 29.
    Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
    Yang Qu, Shanhui Ren, Ying Liao, Xusheng Qiu, Lei Tan, Cuiping Song, Yingjie Sun, Chan Ding.
      Mitochondria serve as the cellular "power plants," supplying energy and regulating metabolism, signal transduction, and other physiological processes. To successfully replicate within host cells, viruses have evolved multiple strategies to hijack mitochondrial functions. The oncolytic Newcastle disease virus (NDV) causes severe organelle damage in tumor cells; however, how it manipulates mitochondrial architecture to facilitate its own replication remains poorly understood. Here, we provide evidence that NDV infection disrupts mitochondrial spatial distribution and imbalances mitochondrial fusion and fission, leading to mitochondrial structural damage. The resulting accumulation of fragmented mitochondria is cleared via PRKN-dependent mitophagy, a process that supports NDV replication. Interestingly, although MAVS (mitochondrial antiviral signaling protein) is degraded along with mitophagy, genetic ablation of PRKN - while blocking MAVS degradation - does not restore downstream innate immune responses. This indicates that NDV exploits mitophagy to enhance replication through mechanisms not entirely dependent on the suppression of MAVS-mediated immunity. Given the central role of mitochondria, we further explored the link between amino acid metabolism and viral proliferation after NDV infection. Our results show that NDV-induced mitophagy leads to the accumulation of free amino acids in host cells, and this metabolic reprogramming promotes viral replication. In summary, we show that NDV drives its replication by remodeling mitochondrial dynamics to induce mitophagy, which in turn triggers an amino acid metabolic reprogramming that benefits the virus. This provides new insights into the mechanisms supporting efficient oncolytic NDV replication, offering potential avenues for therapeutic intervention in oncolytic virus therapy.
    Keywords:  Amino acid metabolism; MAVS; NDV, PINK1-PRKN; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2624746
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