bims-auttor 2025-08-24 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–08–24
eighteen papers selected by
Viktor Korolchuk, Newcastle University

Cardiovascular diseases in the elderly: possibilities for modulating autophagy using non-coding RNAs.
Mitochondrial Quality Control in Health and Disease.
High-fat diet impairs intermediate-term memory by autophagic-lysosomal dysfunction in Drosophila.
Interleukin-33 in the Regulation of Autophagy and Apoptosis in Macrophages During Infection.
Mitophagy in Hypertensive Cardiac Hypertrophy: Mechanisms and Therapeutic Implications.
Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.
Targeting mTOR and Its Associated Signaling to Induce Cell Death in Breast Cancer Stem Cells.
A role for the autophagy receptor NBR1 in the degradation of tau aggregates.
UQCRC1 downregulation impairs cognitive function in mice via AMPK inactivation.
Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.
Reverse transcriptase inhibitors induce autophagy in a LINE-1 ORF1p-dependent manner.
Engineered RGD-Treg-Exos Targeted Delivery of miR-218-5p to Activate Mitophagy and Attenuate Podocyte Injury in Diabetic Kidney Disease.
NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy.
Unc-51 Like Kinase 3 (ULK3) is essential for autophagy and cell survival in multiple myeloma.
HIF1A overexpression promotes osteoblast differentiation through activation of autophagy to alleviate osteoporosis.
STING inhibits LINE-1 retrotransposition through sorting ORF1p to lysosomes for degradation.
P62/Sequestosome1 deficiency disrupts antioxidant and stress homeostasis during acute pancreatitis without exacerbating inflammation.
Inhibition of UBE2N promotes the clearance of mutant HTT (huntingtin) in HD knock-in mice.

Front Cell Dev Biol. 2025 ;13 1520850

Cardiovascular diseases in the elderly: possibilities for modulating autophagy using non-coding RNAs.

Silvia Scalabrin, Stefano Cagnin.

  Autophagy is a crucial mechanism implicated in both aging and cardiovascular disease, which are two closely interconnected conditions. Modulation of autophagy is expected to have profound impacts on cellular aging and maintenance of cardiovascular functions under physiological or pathological conditions. Consequently, modulation of autophagy could be an effective strategy for counteracting age-induced vascular and cardiac remodelling as well as alleviating cardiovascular disease. The present review comprehensively elucidates the multifaceted impacts of autophagy on aging of the cardiovascular system. We comprehensively analyse both vascular and cardiac tissues, including vascular and cardiac malignancies, in distinct contexts. We also emphasize the significance of non-coding RNAs (ncRNAs) in the epigenetic regulation of gene expression and their roles as biomarkers of cardiovascular pathologies while maintaining clear distinctions between the vascular and cardiac tissues. Preclinical and clinical models are described herein to highlight the importance of ncRNAs in disease treatment by considering their involvement in the modulation of autophagy within the cardiocirculatory system. Finally, we conducted a comprehensive meta-analysis of transcriptomic data to underscore the paramount importance of autophagy while demonstrating it as a process that is frequently dysregulated in both cardiac and vascular cells under pathological conditions. The findings presented herein emphasize the importance of investigating novel strategies for modulating autophagy as a potential therapeutic approach to the management of age-related cardiovascular disorders.

Keywords:  aging; autophagy; cardiovascular disease; meta-analysis; non-coding RNAs

DOI:  https://doi.org/10.3389/fcell.2025.1520850
MedComm (2020). 2025 Aug;6(8): e70319

Mitochondrial Quality Control in Health and Disease.

Lin Ye, Xinzhi Fu, Qi Li.

  Mitochondria are central regulators of cellular energy metabolism, and their functional integrity is essential for maintaining cellular homeostasis. Mitochondrial quality control (MQC) encompasses a coordinated network of mitochondrial biogenesis, dynamics (fusion and fission), and selective autophagy (mitophagy), which together sustain mitochondrial structure and function. Under physiological conditions, MQC ensures the removal of dysfunctional mitochondria, restricts excessive reactive oxygen species production, and modulates apoptosis, thereby supporting the high energy demands of organs such as the heart and brain. Disruption of MQC contributes to the onset and progression of various diseases, including neurodegenerative disorders, cardiovascular pathologies, and metabolic syndromes, largely through accumulation of damaged mitochondria and impaired metabolic signaling. While the core components of MQC have been characterized, the mechanistic interplay among its modules and their disease-specific alterations remain incompletely defined. This review provides an integrated overview of the molecular pathways governing mitochondrial biogenesis, dynamics, and mitophagy, with a focus on their cross-talk in maintaining mitochondrial homeostasis. We further discuss how MQC dysfunction contributes to disease pathogenesis and examine emerging therapeutic approaches aimed at restoring mitochondrial quality. Understanding the regulatory logic of MQC not only elucidates fundamental principles of cellular stress adaptation but also informs novel strategies for disease intervention.

Keywords:  disease intervention; mitochondria; mitochondrial quality control; therapeutic strategies

DOI:  https://doi.org/10.1002/mco2.70319
PLoS Genet. 2025 Aug;21(8): e1011818

High-fat diet impairs intermediate-term memory by autophagic-lysosomal dysfunction in Drosophila.

Tong Yue, Minrui Jiang, Kotomi Onuki, Motoyuki Itoh, Ayako Tonoki.

High-fat diet (HFD) is considered a risk factor for age-related memory impairments such as Alzheimer's disease. However, how HFD affects memory formation remains unclear. In this study, we established a model of memory defects caused by HFD in Drosophila. Our results revealed that the HFD impaired intermediate-term memory (ITM), but not short-term memory (STM), produced by classical aversive olfactory conditioning, and decreased autophagic activity in the heads of the HFD-fed flies. Transient reduction in autophagic activity also impaired ITM, but not STM. Genetic enhancement of autophagic activity in neurons effectively restored ITM performance in the HFD-fed flies. Mechanistically, HFD impairs lysosomal function by downregulating the expression of lysosome-related genes, leading to impaired fusion of autophagosomes with lysosomes. These findings suggest that HFD impairs ITM by reducing autophagic activity and lysosomal dysfunction in the neurons.

DOI: https://doi.org/10.1371/journal.pgen.1011818
Immunol Invest. 2025 Aug 18. 1-17

Interleukin-33 in the Regulation of Autophagy and Apoptosis in Macrophages During Infection.

Ahmet Alperen Palabiyik, Esra Palabiyik.

  Introduction: Interleukin-33 (IL-33) is a multifunctional cytokine from the interleukin-1 family that plays a pivotal role in modulating macrophage responses during infection. Functioning both as an extracellular alarmin and as a nuclear transcriptional regulator, IL-33 orchestrates a dynamic balance between autophagy and apoptosis, crucial for immune homeostasis.Methods: A systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published between January 2010 and April 2025. Search terms combined "Interleukin-33" with keywords related to autophagy, apoptosis, macrophages, and infection.Results: It enhances autophagy by activating AMP-activated protein kinase (AMPK), inhibiting mechanistic target of rapamycin (mTOR), and interacting with Beclin-1 to promote autophagosome formation and LC3 lipidation. Concurrently, IL-33 suppresses apoptosis by upregulating Bcl-2 and Mcl-1, inhibiting Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), and blocking caspase activation. Recent studies also highlight the importance of post-translational modifications (PTMs) and the nuclear domain of IL-33 in fine-tuning these responses. Furthermore, IL-33-based combination therapies with immune checkpoint inhibitors (ICIs) are emerging as promising immunotherapeutic strategies.Discussion: This review synthesizes current insights into IL-33-mediated regulation of macrophage fate and identifies key research gaps. A better understanding of the context-dependent roles of IL-33 will be critical for translating these mechanisms into effective, targeted therapies for infectious and inflammatory diseases.

Keywords:  Apoptosis; Interleukin-33; ST2; autophagy; combination immunotherapy; immune modulation; macrophages

DOI:  https://doi.org/10.1080/08820139.2025.2547691
J Clin Hypertens (Greenwich). 2025 Aug;27(8): e70127

Mitophagy in Hypertensive Cardiac Hypertrophy: Mechanisms and Therapeutic Implications.

Shijun Li, Xiaoying Li.

  Hypertensive cardiac hypertrophy (HCH) is a compensatory response to chronic pressure overload, ultimately progressing to heart failure if left unmanaged. Emerging evidence highlights the critical role of mitochondrial dysfunction in HCH pathogenesis, with impaired mitophagy-a selective autophagic process that removes damaged mitochondria-contributing to cardiomyocyte death, oxidative stress, and fibrosis. Protective mitophagy eliminates damaged mitochondria, averting reactive oxygen species (ROS)/calcium overload in HCH. Conversely, its dysregulation-either insufficient clearance or excessive removal-exacerbates mitochondrial dysfunction, driving pathological hypertrophy, fibrosis, and bioenergetic crisis. This dual nature presents a therapeutic paradox demanding contextual modulation. This review comprehensively examines the molecular mechanisms underlying mitophagy dysregulation in HCH, focusing on key pathways such as PINK1/Parkin, BNIP3/NIX, and FUNDC1. We also discuss the interplay between mitophagy and other cellular processes, including mitochondrial biogenesis, inflammasome activation, and metabolic remodeling. Furthermore, we explore potential therapeutic strategies targeting mitophagy to ameliorate HCH, including pharmacological agents, lifestyle interventions, and gene therapy approaches. Understanding the dual role of mitophagy in HCH-both protective and detrimental-may pave the way for novel precision medicine strategies in cardiovascular disease.

Keywords:  hypertensive cardiac hypertrophy; mitochondrial dysfunction; mitophagy; oxidative stress; therapeutic targets

DOI:  https://doi.org/10.1111/jch.70127
Biochem Soc Trans. 2025 Aug 18. pii: BST20253050. [Epub ahead of print]

Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.

Nicoletta T Basilone, Viveka M Pimenta, Gary S Shaw.

  Parkin, a Ring-InBetweenRING-Rcat E3 ubiquitin ligase, plays a vital role in the clearance of damaged mitochondria (mitophagy) by ubiquitylating a broad spectrum of mitochondrial proteins. Mutations in the PRKN gene alter parkin ubiquitylation activity and are a leading cause of early-onset Parkinsonism, underlining its critical function in maintaining mitochondrial homeostasis. The structures, substrates, and ubiquitylation mechanisms used by parkin in mitophagy are well established. Yet, early studies as well as more recent proteomics studies identify alternative substrates that reside in the cytosol or other cellular compartments, suggesting potential roles for parkin beyond mitophagy. In addition to its well-documented activation via S65 phosphorylation, numerous other post-translational modifications (PTMs) have been identified in parkin. Some of these modifications have the potential to serve key regulatory mechanisms, perhaps fine-tuning parkin activity or potentially signaling the involvement in alternative cellular pathways beyond mitochondrial quality control. This review examines the canonical mechanism of parkin-mediated ubiquitylation while also exploring alternative regulatory influences that may modulate its enzyme activity. By analyzing emerging evidence on PTMs including phosphorylation, acetylation, ubiquitylation, oxidation, and interaction with alternative activating molecules, we highlight the broader functional landscape of parkin and its implications for cellular stress response.

Keywords:  Parkinson's disease; mitochondrial dysfunction; parkin; protein structure; ubiquitin ligases

DOI:  https://doi.org/10.1042/BST20253050
Cell Biol Int. 2025 Aug 20.

Targeting mTOR and Its Associated Signaling to Induce Cell Death in Breast Cancer Stem Cells.

Kirti S Prabhu, Zahwa Mariyam, Syed A Rahman, Shilpa Kuttikrishnan, Fareed Ahmad, Ummu Habeeba, Abdul Q Khan, Afsheen Raza, Said Dermime, Salahddin A Gehani, Kulsoom Junejo, Shahab Uddin.

Breast cancer (BC) is a frequently diagnosed neoplasm in women and the second major cause of cancer-related deaths. Many BC patients develop metastasis and advanced tumors, increasing morbidity and mortality. There is substantial evidence that tumor relapses in BC patients are driven by a unique population of cells called cancer stem cells (CSCs). Breast CSCs confer stemness to BC and survive through the maintenance of several mechanisms, among which is the involvement of the mTOR signaling pathway. mTOR and its associated AKT signaling play a crucial role in regulating CSCsin various human cancers, including breast cancer. This study investigated the role of targeting mTOR/AKT signaling in the modulation of cell death in 2D and 3D breast cancer models. Torin-2, a dual mTOR inhibitor, effectively suppressed cell proliferation by inducing mitochondrial apoptosis. The inhibition of mTOR led to a decrease in AKT activity and downregulation of key translational machinery components, including 4EBP1, eIF4E, and p70S6K. Torin-2 treatment activated autophagy signaling in both 2D and 3D cell models. The induction of autophagy was evidenced by an increase in the autophagy protein LC3II/I in response to Torin-2 treatment. In addition, Torin-2 treatment of spheroids derived from breast cancer cells suppressed the expression of stem cell marker ALDH. Altogether, the dual inhibition of mTORC1 and mTORC2 by Torin-2 resulted in a more profound antitumor activity. This broader and more potent inhibition of the mTOR pathway contributes to effectiveness in suppressing 2D and 3D breast cancer cell growth and survival.

DOI: https://doi.org/10.1002/cbin.70071
Neurobiol Dis. 2025 Aug 14. pii: S0969-9961(25)00276-1. [Epub ahead of print]214 107060

A role for the autophagy receptor NBR1 in the degradation of tau aggregates.

Marie Neu, Iwan Parfentev, Gregory K Potts, Nina Stöberl, Jürgen Korffmann, Andreas Striebinger, Daniela Geist, Dimitris Papageorgiou, Hanna Tarhonskaya, Nicholas McKitterick, Jeroen van Bergeijk, Christopher Untucht, Peter Reinhardt, Jon D Williams, Michaela J Heimann, Laura Gasparini, Dagmar E Ehrnhoefer.

  Neurofibrillary tangles (NFTs), comprising hyperphosphorylated and aggregated Tau protein, are a primary neuropathological feature of Alzheimer's Disease (AD). In patients, the formation and spread of NFTs across the brain correlate with cognitive decline. However, the mechanisms driving Tau aggregation and leading to the subsequent neuronal dysfunction are not fully understood. In this study, we explored proteomic and phosphoproteomic changes resulting from the seed-induced aggregation of endogenous Tau in human neurons, derived from induced pluripotent stem cells (iPSCs). We discovered previously undescribed phosphorylation sites on NBR1, an autophagy receptor, which were significantly altered by Tau aggregation in vitro. We further show that NBR1 directly interacts with phosphorylated Tau and Tau aggregates in various cellular models. This interaction is associated with autophagic Tau degradation in HEK biosensor cells, and siRNA-mediated knockdown of NBR1 significantly increases Tau aggregate levels in iPSC-derived neurons. Additionally, we find that NBR1 expression is significantly increased in AD patients, and it specifically interacts with Tau in human AD brain, underscoring the relevance of our findings to the human disease. These insights provide a deeper understanding of the molecular interactions between autophagy receptors and Tau pathology in AD and reveal a role for NBR1 as an important receptor for pathological forms of Tau.

Keywords:  Alzheimer's disease; Autophagy receptor; Mass spectrometry; Phosphoproteomics; Proteomics; Tau aggregation; iPSC-derived neurons

DOI:  https://doi.org/10.1016/j.nbd.2025.107060
PeerJ. 2025 ;13 e19873

UQCRC1 downregulation impairs cognitive function in mice via AMPK inactivation.

Jing Zhang, Zuoxi Wu, Zonghong Long, Feng Ceng, Fuhai Bai, Hong Li.

   Background: Ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) is an essential subunit of complex III in the mitochondrial respiratory chain. Although earlier studies have indicated that UQCRC1 downregulation causes cognitive impairment, the underlying mechanisms remain unclear.
Methods: To investigate its pathophysiological effects, we developed a mouse model with downregulated UQCRC1 expression. Hippocampus-dependent cognitive performance was evaluated using a series of behavioral paradigms. Mitochondrial bioenergetic status was assessed by measuring adenosine triphosphate (ATP) levels, while oxidative stress was quantified through detection of reactive oxygen species (ROS). Molecular analyses were performed to assess AMP-activated protein kinase (AMPK) signaling dynamics and autophagic flux. Additionally, pharmacological interventions aimed at activating AMPK and enhancing lysosomal function were employed to elucidate mechanistic pathways.
Results: Downregulation of UQCRC1 resulted in significant deficits in hippocampus-dependent cognitive performance, accompanied by impaired mitochondrial bioenergetics (lower ATP synthesis) and elevated oxidative stress (increased ROS levels). Mechanistically, these phenotypes were associated with diminished AMPK activation and disrupted autophagic flux. Importantly, pharmacological activation of AMPK or enhancement of lysosomal activity in UQCRC1-deficient mice effectively ameliorated cognitive deficits and restored mitochondrial redox homeostasis .
Conclusions: This study identifies AMPK as a pivotal metabolic orchestrator of mitochondrial-lysosomal functional crosstalk and reveals its non-canonical function in maintaining neuronal homeostasis via coordinated regulation of autophagic flux and redox balance. Our findings propose AMPK-driven interorganelle communication as a modifiable therapeutic target for addressing cognitive decline resulting from mitochondrial dysfunction.

Keywords:  Autophagy; Cognition; Hippocampus; Mitochondria; ROS; Respiratory chain; UQCRC1

DOI:  https://doi.org/10.7717/peerj.19873
J Biomed Sci. 2025 Aug 19. 32(1): 77

Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.

Fasih A Rahman, Mackenzie Q Graham, Alex Truong, Joe Quadrilatero.

   BACKGROUND: Postnatal skeletal muscle development leads to increased muscle mass, strength, and mitochondrial function, but the role of mitochondrial remodeling during this period is unclear. This study investigates mitochondrial remodeling during postnatal muscle development and examines how constitutive autophagy deficiency impacts these processes.
METHODS: We initially performed a broad RNA-Seq analysis using a publicly available GEO database of skeletal muscle from postnatal day 7 (P7) to postnatal day 112 (P112) to identify differentially expressed genes. This was followed by investigation of postnatal skeletal muscle development using the mitophagy report mouse line (mt-Kiema mice), as well as conditional skeletal muscle knockout (Atg7f/f:Acta1-Cre) mice.
RESULTS: Our study observed rapid growth of body and skeletal muscle mass, along with increased fiber cross-sectional area and grip strength. Mitochondrial maturation was indicated by enhanced maximal respiration, reduced electron leak, and elevated mitophagic flux, as well as increased mitochondrial localization of autophagy and mitophagy proteins. Anabolic signaling was also upregulated, coinciding with increased mitophagy and fusion signaling, and decreased biogenesis signaling. Despite the loss of mitophagic flux in skeletal muscle-specific Atg7 knockout mice, there were no changes in body or skeletal muscle mass; however, hypertrophy was observed in type IIX fibers. This lack of Atg7 and loss of mitophagy was associated with the activation of mitochondrial apoptotic signaling as well as ubiquitin-proteasome signaling, suggesting a shift in degradation mechanisms. Inhibition of the ubiquitin-proteasome system (UPS) in autophagy-deficient skeletal muscle led to significant atrophy, increased reactive oxygen species production, and mitochondrial apoptotic signaling.
CONCLUSION: These results highlight the role of mitophagy in postnatal skeletal muscle development and suggest that autophagy-deficiency triggers compensatory degradative pathways (i.e., UPS) to prevent mitochondrial apoptotic signaling and thus preserve skeletal muscle integrity in developing mice.

Keywords:  Apoptosis; Autophagy; BNIP3; Development; Mitochondria; Mitophagy; Skeletal muscle; UPS

DOI:  https://doi.org/10.1186/s12929-025-01153-7
bioRxiv. 2025 Aug 12. pii: 2025.08.07.669170. [Epub ahead of print]

Reverse transcriptase inhibitors induce autophagy in a LINE-1 ORF1p-dependent manner.

Michela Damizia, Mirko Baranzini, Ilaria Sciamanna, Ludovica Altieri, Paola Rovella, Omar G Rosas Bringa, Samira Hozeifi, Leila J Saba, Apostolos Mourtzinos, Anna O'Shea, Mohammad Salik Zeya Ansari, Federica Andreola, Roberto Cirilli, Gianluca Sbardella, Annalucia Serafino, Gerald G Schumann, Daniela Trisciuoglio, John LaCava, Patrizia Lavia, Corrado Spadafora.

Human L ong Interspersed N uclear E lement-1 (LINE-1) retrotransposons propagate throughout the genome via reverse-transcribed RNA intermediates. LINE-1 expression is pervasive in cancer. Functional LINE-1s encode two proteins: ORF1p, an RNA-binding protein, and ORF2p, harboring reverse transcriptase and endonuclease activities. Reverse transcriptase inhibitors, including non-nucleoside (NNRTI) and nucleoside (NRTI) inhibitors, inhibit cancer cell proliferation and antagonize cancer progression. We previously found that two NNRTIs induced DNA damage, nuclear lamin rupture, micronuclei formation, and autophagy in prostate cancer cells. We now find that two different RTIs up-regulate LINE-1 mRNA expression and ORF1p abundance in nuclei, triggering ORF1p interactions with lamin B1 and with DNA damage factors. ORF1p accumulates within micronuclei with damaged DNA and with the autophagy receptor p62. We further demonstrate that inhibiting autophagy, or decreasing ORF1p levels, prevent DNA damage and preserve lamin B1 integrity, uncoverig a role of LINE-1-ORF1p in the autophagy response of cancer cells, independent on retrotranscription events.

DOI: https://doi.org/10.1101/2025.08.07.669170
Adv Sci (Weinh). 2025 Aug 19. e12034

Engineered RGD-Treg-Exos Targeted Delivery of miR-218-5p to Activate Mitophagy and Attenuate Podocyte Injury in Diabetic Kidney Disease.

Zhaochen Guo, Shaohui Gao, Ziyue Wang, Zige Chen, Jinglei Chen, Aiping Duan, Feng Xu, Qinger Wang, Weisong Qin, Caihong Zeng, Zhihong Liu, Hao Bao.

  Diabetic kidney disease (DKD) is the main cause of end-stage kidney disease, and podocyte injury is an important factor in the development of DKD. Mitophagy is severely inhibited in the podocytes of patients. Damaged mitochondria aggregate in the cytoplasm and can not be removed effectively. Restoring mitophagy may be a novel strategy for the treatment of DKD. In this study, Regulatory T cells (Tregs) are found to reduce podocyte injury in DKD through exosomes. Sequencing and cross-sectional analysis revealed that exosomes from Tregs delivered miR-218-5p to increase mitophagy in podocytes by inhibiting the TNC/TLR4/SRC/FUNDC1 pathway. Treg-Exos are engineered to express RGD peptides on the membrane surface. RGD-Treg-Exos bind to integrins on the surface of podocytes and effectively target podocytes for the delivery of miR-218-5p, thus increasing mitophagy in podocytes, reducing cell apoptosis, and alleviating podocyte injury. In summary, this study revealed that engineered RGD-Treg-Exos effectively ameliorated podocyte injury in DKD, thus constituting a novel method for DKD treatment.

Keywords:  diabetic kidney disease; exosome; miRNA; mitophagy; treg

DOI:  https://doi.org/10.1002/advs.202412034
Transl Psychiatry. 2025 Aug 18. 15(1): 292

NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy.

Ye Sun, Liya Li, Xianglong Yang, Shengming Yin, Zhaoyang Xiao.

Major depressive disorder (MDD) is characterized by persistent low mood and anhedonia. Mitochondrial dysfunction is linked to MDD, but the mechanisms are unclear. In this study, transcriptomic analysis of MDD patients' peripheral blood found three key genes: TFAM, SURF1, and NDUFB9. Single-cell transcriptomic analysis of the prefrontal cortex (PFC) in MDD patients identified seven cell types. Analysis showed strong interactions between excitatory and inhibitory neurons in the PFC, with the three genes mainly in inhibitory neurons and NDUFB9 having the highest expression. We then established a chronic unpredictable mild stress (CUMS) mouse model. CUMS exposure induced depressive-like behaviors in mice, as evidenced by decreased sucrose preference, increased immobility time in the forced swim, and reduced activity and frequency of entries into the central area in the open field. Moreover, CUMS-exposed mice exhibited mitochondrial dysfunction in the prefrontal cortex (PFC). Notably, the expressions of TFAM, SURF1, and NDUFB9 were decreased in the PFC of CUMS mice, with the most significant decrease observed in NDUFB9. Subsequently, the overexpression of NDUFB9 in CUMS-treated mice significantly alleviated depressive-like behaviors, restored mitochondrial function and reduced the death of inhibitory neurons. It also enhanced mitophagy by PINK1/Parkin pathway. Inhibiting autophagy and mitophagy confirmed mitophagy's pivotal role in NDUFB9-mediated restoration. Co-IP and protein half-life assays revealed that NDUFB9 stabilizes PINK1, thereby promoting mitophagy. In conclusion, our findings reveal a novel role of NDUFB9 on alleviating depression-like behavior by enhancing mitophagy, suggesting that targeting NDUFB9 could offer a promising therapeutic strategy for MDD.

DOI: https://doi.org/10.1038/s41398-025-03502-4
Res Sq. 2025 Aug 12. pii: rs.3.rs-7160521. [Epub ahead of print]

Unc-51 Like Kinase 3 (ULK3) is essential for autophagy and cell survival in multiple myeloma.

Conor Lynch, Marilena Tauro, Tao Li, Praneeth Sudalagunta, Mark Meads, Rafael Canevarolo, Niveditha Nerlakanti, Raghunandan Alugubelli, Harshani Lawrence, Steven Gunawan, Mohammad Ayaz, Pradeep Nareddy, Sang Yun, Gemma Shay, Kathy Yang, Timothy Tran, Ryan Bishop, Mostafa Nasr, Nicholas Lawrence, Ernst Schonbrnn, John L Cleveland, Ariosto Siqueira Silva, Kenneth Shain.

Despite the availability of effective therapies such as proteasome inhibitors, multiple myeloma (MM) patients relapse with refractory disease. To identify new therapeutic targets, we assessed RNA sequencing data from CD138+ MM patient cells (n = 813) across disease stages and found that an autophagy gene signature, and particularly ULK3 expression, was strongly associated with disease progression. Functional studies revealed that ULK3 contributes to MM cell survival as part of the ULK-ATG13-FIP200 complex. We generated inhibitors (SG3-014/MA9-060) with nanomolar potency and confirmed their binding mode through co-crystallization with ULK3. In vivo, ULK3 inhibition reduced MM burden, improved survival, and protected against cancer-induced bone disease. MA9-060 also restored sensitivity to proteasome inhibitors in resistant MM cells. This synergy was validated ex vivo in patient samples, especially those with high ULK3 expression. These findings indicate a new role for ULK3-mediated autophagy in cancer and suggest that ULK3 inhibition is an effective treatment strategy for both newly diagnosed and refractory MM disease.

DOI: https://doi.org/10.21203/rs.3.rs-7160521/v1
Sci Rep. 2025 Aug 19. 15(1): 30370

HIF1A overexpression promotes osteoblast differentiation through activation of autophagy to alleviate osteoporosis.

Jiutao Qiao, Aiyun Liu, Chongyi Sun, Qingpeng Liu.

  Objective Osteoporosis (OP) is a systemic skeletal disease that increases the risk of fractures by weaking bone. Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in osteogenesis and osteoblastic differentiation. The purpose of this study is to examine the underlying mechanism of HIF-1α overexpression and its impact on osteoblast development. Methods First, we used the autophagy inhibitor 3-MA in conjunction with either a control lentivirus or an HIF-1α overexpression lentivirus to transfect rat osteoblasts in osteogenic induction media for 3, 7, 14, and 21 days. The effects of HIF-1α overexpression on osteogenic differentiation were evaluated using CCK-8, alkaline phosphatase (ALP) staining, and Alizarin Red staining. Furthermore, we investigated the mechanism by which HIF-1α overexpression mediates autophagy to regulate osteogenic differentiation through immunofluorescence, western blot, and transmission electron microscopy. Ovariectomy (OVX) was performed to establish an osteoporotic rat model. The impact of HIF-1α overexpression on autophagy and bone metabolism was evaluated by locally injecting HIF-1α overexpression lentivirus or control lentivirus, in combination with HE staining, micro-CT, immunohistochemistry, ELISA, western blot, and transmission electron microscopy. Results Overexpression of HIF-1a promotes osteoblast proliferation and enhances ALP staining as well as calcium nodule formation. In addition, the overexpression of HIF-1a significantly increases the relative protein expression levels of osteocalcin (OCN), osteoprotegerin (OPG), HIF-1a, BNIP3, Beclin1, ATG5, and LC3 II/I. This indicates that HIF-1a may facilitate osteoblast differentiation by promoting autophagy. These findings were further corroborated by in vivo experiments, which demonstrated improved pathological morphology in rat femurs, alongside increased bone mineral density (BMD), trabecular thickness (Tb. Th), bone volume/total volume ratio (BV/TV), and trabecular number (Tb. N). Additionally, there was a decrease in trabecular separation (Tb. Sp) and structural model index (SMI), along with upregulated expression of OCN, OPG, HIF-1α, BNIP3, Beclin1, ATG5, and LC3 II. Conclusion HIF-1a overexpression can promote osteogenic differentiation and ameliorate osteoporosis through the induction of autophagy. These insights provide a valuable reference for its potential application in targeted therapy.

Keywords:  Autophagy; Bone metabolism; HIF-1a; Osteogenic differentiation; Osteoporosis

DOI:  https://doi.org/10.1038/s41598-025-16046-w
EMBO Rep. 2025 Aug 18.

STING inhibits LINE-1 retrotransposition through sorting ORF1p to lysosomes for degradation.

Yu Huang, Fengwen Xu, Lingwa Wang, Shan Mei, Fei Zhao, Liming Wang, Yu Xie, Liang Wei, Yamei Hu, Zhao Gao, Tiffany Xue, Jugao Fang, Fei Guo.

  The cyclic dinucleotide sensor stimulator of interferon (IFN) genes (STING) is known for its critical role in interferon and inflammatory responses. In addition, STING also has functions independent of interferon induction. In this study, we report that STING restricts the mobilization of the cellular retrotransposon long interspersed nuclear element 1 (LINE-1) independent of cGAS and interferon induction. LINE-1 is the only active autonomous retrotransposable element in the human genome and its transposition can cause genetic and autoimmune diseases. STING inhibition of LINE-1 requires its dimerization. Mechanistically, STING interacts with LINE-1 ORF1p, then the complex translocates to the ER-Golgi intermediate compartment (ERGIC) and the Golgi followed by sorting to Rab7-positive lysosomes for degradation. Our data unveil a function of STING in maintaining host genome integrity by restricting LINE-1 retrotransposition via an IFN-independent mechanism.

Keywords:  IFN-Independent; LINE-1; Lysosome; Retrotransposition; STING

DOI:  https://doi.org/10.1038/s44319-025-00551-0
Pancreatology. 2025 Aug 11. pii: S1424-3903(25)00573-3. [Epub ahead of print]

P62/Sequestosome1 deficiency disrupts antioxidant and stress homeostasis during acute pancreatitis without exacerbating inflammation.

Wenting Chen, Jingren Wang, Eiji Warabi, Mai Imasaka, Yuki Takeda, Hiroshi Nishiura, Satoru Takahashi, Masaki Ohmuraya.

   BACKGROUNDS: Acute pancreatitis (AP) is a common inflammatory disease of the pancreas, characterized by complex pathogenesis and limited specific treatment options. The selective autophagy adapter protein p62/sequestosome1 emerged as a key player in cellular stress responses, with emerging evidence suggesting its role in modulating both infection-driven and sterile inflammation. However, the role of p62 in the pathogenesis of AP remains unclear.
METHODS: To investigate the role of p62 in AP, we generated pancreas-specific conditional knockout mice (p62ff; Ptf1acre/+) and induced AP by 12 repeated intraperitoneal cerulein injections. Mice were sacrificed either 1 h or 8 h after the final injection. Pancreatic damage was assessed along with serum amylase levels, intrapancreatic trypsin activity, proinflammatory cytokines, antioxidant genes, ER stress and cell death markers using immunohistochemistry, qRT-PCR, and western blotting.
RESULTS: p62ff; Ptf1acre/+ mice showed normal growth and pancreatic development. Upon cerulein challenge, both p62 knockout and control mice developed comparable pancreatic injury, without significant differences in histological scores, amylase, or trypsin activity. However, p62-deficient mice displayed significantly impaired antioxidant responses. Notably, Nqo1 expression was reduced and Keap1 accumulated, indicating disrupted Nrf2 signaling. Ferroptosis markers also showed genotype- and time-dependent changes: GPX4 was reduced at 1 h, while FTH1 without significant differences in p62-deficient mice. Periodic acid-Schiff staining further revealed increased glycogen depletion in knockout mice, suggesting elevated metabolic stress.
CONCLUSIONS: These findings suggest that while p62 deletion does not affect overall AP severity, it compromises redox homeostasis and metabolic recovery, highlighting a protective role for p62 during pancreatic injury.

Keywords:  Autophagy; Cell death; Cerulein; Inflammation; Pancreatic acinar cell

DOI:  https://doi.org/10.1016/j.pan.2025.07.416
Autophagy. 2025 Aug 16.

Inhibition of UBE2N promotes the clearance of mutant HTT (huntingtin) in HD knock-in mice.

Kaili Ou, Xiang Wang, Mingwei Guo, Dandan Li, Chen Zhang, Laiqiang Chen, Junqi Hou, Qingqing Jia, Longhong Zhu, Su Yang, Shihua Li, Xiao-Jiang Li, Peng Yin.

  Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington disease (HD) is characterized by the accumulation of ubiquitinated mutant HTT (huntingtin) in the central nervous system. Ubiquitination of the misfolded proteins, a common feature of the neurodegenerative diseases, is mediated by the different lysine residues on ubiquitin. We previously discovered that the age-dependent increase of UBE2N (ubiquitin conjugating enzyme E2 N) exacerbated the accumulation of misfolded HTT and amyloid proteins, accompanied by the elevation of K63 ubiquitination. Pharmacological inhibition of UBE2N could ameliorate the amyloid deposition. However, the effect of UBE2N suppression on HTT aggregate clearance has remained unknown. In the current work, we demonstrate that selectively suppressing UBE2N, with antisense oligonucleotides or small-molecular inhibitors, increased removal of HTT aggregates by proteasome degradation in the striatum of HD knock-in mice. We also identified two novel ubiquitin specific peptidases, USP29 and USP49, that participated in the clearance of HTT aggregates, via accelerating K48-mediated ubiquitin-proteasome function. Our findings provide a potential pharmacological approach to treat neurodegeneration caused by mutant HTT.

Keywords:  Aggregate; HTT; K63; UBE2N; UPS; ubiquitin specific peptidases

DOI:  https://doi.org/10.1080/15548627.2025.2549109