bims-auttor 2026-04-19 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–04–19
forty-two papers selected by
Viktor Korolchuk, Newcastle University

Graded activation of the CLEAR network through mTORC1 suppression on cargo-harboring lysosomes.
Cutting edge: ESCRT-mediated phagophore closure in mammals.
A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.
Mitochondria power the cell's recycling center.
Unravelling chaperone-mediated microautophagy targeting KFERQ-like motif containing proteins in yeast.
TAX1BP1 targets STING1 via microautophagy and Golgiphagy to limit inflammatory signaling.
Ubiquitin ligase RCHY1 regulates autophagosome-lysosome fusion.
Poxvirus A52 protein subverts autophagy flux by blocking autophagosome-lysosome fusion to promote viral replication.
Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.
Golgi-derived phosphatidylinositol 4-phosphate is crucial for organization of the pre-autophagosomal structure.
Fine-Tuning Autophagy in Skeletal Muscle: From Homeostasis to Muscle Wasting Disorders.
The ATG14: multi-layer autophagy control and an emerging therapeutic target in cancer.
A tRNA epitranscriptomic checkpoint coordinates sperm mitochondrial load with embryonic allophagic clearance.
Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
Autophagy selectively clears ER in TNF-α-induced muscle atrophy.
Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.
Estrogen Regulates Microtubule-Associated Protein 1 Light Chain 3 in Mouse Uterine Endometrial Epithelium.
Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6.
Viral-host interactions mediated by the mTOR signaling pathway.
CORO1C (coronin 1C) promotes autophagosome formation by coordinating branched actin network dynamics.
Nrf1 coordinates proteasome activity and autophagy to maintain cardiac proteostasis.
Structural basis for TORC2 activation.
GRASP55 maintains lysosome function by controlling sorting of lysosomal enzymes at the Golgi.
Nuclear Microautophagy Drives Vacuolar Targeting of Yeast Iron-Regulated Proteins During Lipid and Iron Limitation.
Clock and the Cleaner: Circadian Rhythms and Autophagy Coupling in Alzheimer's Disease.
Autophagy: Bridging the brain-periphery connection.
Mitochondrial Fission and Fusion Disorders and Autophagy Abnormalities in Parkinson's Disease.
Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast accumulation by inhibiting Parkin-dependent mitophagy.
The autophagy switch: A critical determinant of arsenic-induced carcinogenesis and cancer therapy.
Independent roles of autophagy and apoptosis in post-apocrine-secretion cell death of salivary glands during Drosophila metamorphosis.
BNIP3/BNIP3L-Dependent Mitophagy Protects Against Hippocampal Neuronal Damage and Apoptosis in a Model of Vascular Dementia.
FTMT-mediated suppression of mitophagy links iron accumulation to osteoporosis.
Nutrition, Cell Signalling, Mitochondrial Function, and Chronic Non-Communicable Disease.
mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway.
A stress-induced PI3P complex controls autophagy in erythroid precursors.
VPS34 in Autophagy, Cancer, and Cancer Therapy.
Allyl-substituted ALT001 promotes alternative mitophagy and improves therapeutic outcomes in Alzheimer's disease models.
WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease.
SQSTM1/p62 at the Crossroads of Autophagy, Inflammation, and Lethal Infection.
GPR176 represses mitophagy to promote the progression of osteosarcoma by facilitating mTORC1 activity via PI3K-AKT pathway.
Nitroalkenes Exploit Dependence on Autophagy-Lysosome Pathway in PARPi-Resistant Triple Negative Breast Cancer.
Impaired mitochondrial stress signaling mediates bone loss in male mice in the absence of BNIP3.

Cell Rep. 2026 Apr 09. pii: S2211-1247(26)00306-2. [Epub ahead of print]45(4): 117228

Graded activation of the CLEAR network through mTORC1 suppression on cargo-harboring lysosomes.

Cheng-Wei Hsieh, Guang-Chao Chen, Wei Yuan Yang.

  Cellular lysosomal capacity is tightly controlled to match catabolic demands and sustain lysosomal signaling pathways. Here, we report that cells can adjust their lysosomal capacity in response to varying autophagy loads. Manipulating the number of mitochondria targeted for mitophagy leads to a proportional upregulation of transcription factor EB (TFEB)-mediated lysosome adaptation programs. This quantitative control is exerted through Rag GTPase-driven mTORC1 suppression. GATOR1 is selectively recruited to lysosomes containing autophagic cargo, initiating local Rag GTPase-dependent suppression of mTORC1 activities. This mitophagy-induced mTORC1 suppression leads to TFEB activation and dephosphorylation of TOS-motif-containing substrates (S6K and 4EBP) under nutrient-rich conditions. This phenomenon similarly occurs during aggrephagy. These findings suggest that autophagic cargo-harboring lysosomes exhibit consistently low mTORC1 activity. Lysosomes can, therefore, sense the magnitude of autophagy loads and quantitatively translate this signal into TFEB activation to support self-regulated homeostasis.

Keywords:  CP: molecular biology; GATOR1; TFEB; aggregate autophagy; folliculin; lysosome; mTORC1; mitophagy

DOI:  https://doi.org/10.1016/j.celrep.2026.117228
Biochem J. 2026 May 06. 483(5): 741-759

Cutting edge: ESCRT-mediated phagophore closure in mammals.

Yoshinori Takahashi, David M Opozda, Hong-Gang Wang.

  Autophagy delivers cytoplasmic materials to lysosomes, supporting protein and organelle quality control as well as nutrient recycling to maintain cellular homeostasis. A defining feature of macroautophagy, the major form of autophagy, is the formation of double-membrane autophagosomes that encapsulate cargo either non-selectively or through selective recognition mechanisms. Completion of autophagosome biogenesis requires closure of the phagophore, a step that ensures full cargo sequestration and enables efficient degradation following lysosomal fusion. Recent studies have uncovered a critical role for the endosomal sorting complex required for transport (ESCRT) machinery in mediating phagophore closure, revealing that this event contributes to cellular functions beyond cargo degradation. In the present review, we summarize current advances in defining the molecular mechanisms and physiological significance of phagophore closure in mammals and highlight emerging concepts and future directions for the field.

Keywords:  autophagosome; autophagy; endosomal sorting; phagophore closure

DOI:  https://doi.org/10.1042/BCJ20250148
J Cell Sci. 2026 Apr 13. pii: jcs.264577. [Epub ahead of print]

A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.

Riccardo Babic, Leon Lucya, Christoph Reiter, Franziska Kriegenburg, Ramón Castellanos-Martínez, David M Hollenstein, Florian Becker, Carola Hunte, Claudine Kraft.

  Mitophagy, the selective degradation of damaged mitochondria, preserves mitochondrial quality, yet how mitochondrial fission is coordinated with autophagy initiation remains unclear. Here we identify the mitochondrial outer membrane protein MTFR1L as a key component of mitophagy initiation hubs after using a synthetic FKBP-FRB system to tether ULK1 kinase to mitochondria independently of damage. We find that MTFR1L is enriched at ULK1 foci together with additional fission factors and constitutive mitochondrial targeting of MTFR1L shifts mitochondrial morphology towards fragmentation. MTFR1L depletion decreases respiratory capacity, elevates apoptosis, and impairs mitophagy flux. Upon mitophagy induction, MTFR1L is phosphorylated in a ULK1 kinase-dependent manner, and reciprocally modulates ULK1 activity, establishing a feedback loop. Moreover, MTFR1L is required for proper ATG13 stability. These findings position MTFR1L as a critical link between mitochondrial fission and the autophagy machinery, coordinating mitophagy initiation and cell survival.

Keywords:  ATG13; Autophagy; MTFR1L; Mitophagy; ULK1

DOI:  https://doi.org/10.1242/jcs.264577
Autophagy. 2026 Apr 16. 1-2

Mitochondria power the cell's recycling center.

Zhiqi Tian, Jun-Lin Guan, Jiajie Diao.

  The lysosome has long been understood as an organelle defined by its acidity. The steep proton gradient maintained within its lumen, a pH of 4.5 to 5.0, is prerequisite for the activation of resident hydrolases and, by extension, for all lysosome-dependent degradation, including autophagy. This acidic luminal pH is maintained by the V-type ATPase (V-ATPase), which hydrolyzes ATP to actively pump protons into the lumen. Yet a fundamental question has lingered: where do all these protons ultimately come from? Most recently, we found a striking answer - the mitochondrion.

Keywords:  Lysosome; acidification; membrane contact; mitochondria; proton flux

DOI:  https://doi.org/10.1080/15548627.2026.2659293
Autophagy. 2026 Apr 13. 1-22

Unravelling chaperone-mediated microautophagy targeting KFERQ-like motif containing proteins in yeast.

Krishna Upadhayay, Pushpender Bhardwaj, Namra Farooqi, Bhagyashree Rabha, Adarsh Mishra, Kamalesh Verma, Ramandeep Singh, Deepak Sharma.

  Under prolonged starvation, mammalian cells activate chaperone-mediated autophagy (CMA) that degrades cellular proteins containing KFERQ-like motifs via lysosomes. During CMA, the lysosomal membrane protein LAMP2A acts as an essential receptor for the HSPA8/HSC70-CMA substrate complex. Thus, the evidence of CMA in organisms lacking LAMP2A on lysosomes/vacuoles is still lacking. Here, we examined the fate of proteins containing such motifs in S. cerevisiae that lack the CMA receptor on vacuoles. Intriguingly, we found that even in the absence of LAMP2A, proteins containing such motifs translocate into vacuoles upon prolonged starvation. We report for the first time that phosphatidylserine acts as an Hsp70-family protein-substrate receptor on the vacuolar membrane to facilitate the substrate translocation into vacuoles. As the newly discovered degradation pathway is dependent upon cytosolic Hsp70 (as in CMA) as well as the ESCRT complex, and involves invagination of the vacuolar membrane, we refer to it as chaperone-mediated microautophagy. Taken together, this study has led to the identification of a novel cellular pathway in S. cerevisiae that facilitates the clearance of cellular proteins under chronic stress.Abbreviations: CMA: chaperone-mediated autophagy; CMA-tag: KFERQ motif; ESCRT: endosomal sorting complexes required for transport; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HSPA8: heat shock protein 8; LAMP2A: lysosomal-associated membrane protein type 2A; Lact-C2: lactadherin C2 domain; PAmCherry: photoactivatable mCherry; PBS: phosphate-buffered saline; PS: phosphatidylserine; PtdIns4P: phosphatidylinositol-4-phosphate; RFP: red fluorescent protein; TBST: Tris-buffered saline with Tween 20.

Keywords:  CMA; Chaperones; KFERQ motifs; microautophagy; phosphatidylserine; protein degradation

DOI:  https://doi.org/10.1080/15548627.2026.2654191
Autophagy. 2026 Apr 16. 1-3

TAX1BP1 targets STING1 via microautophagy and Golgiphagy to limit inflammatory signaling.

Sujit Suklabaidya, Suchitra Mohanty, Edward W Harhaj.

  The CGAS-STING1 pathway plays a key role in detecting cytosolic DNA and initiating immune responses. Excessive STING1 activation can lead to aberrant inflammation and autoinflammatory diseases; therefore, the STING1 degradation pathway is tightly regulated by several negative regulatory mechanisms. In our recent study, we show that the selective autophagy receptor TAX1BP1 functions as a negative regulator of STING1 signaling. TAX1BP1 promotes the degradation of activated STING1 through microautophagy by facilitating the interaction of STING1 with the ESCRT-0 protein HGS, and selective autophagy of the Golgi apparatus in a process known as Golgiphagy. In TAX1BP1-deficient macrophages, STING1 aggregates accumulate at the trans-Golgi network, leading to stronger antiviral and inflammatory responses. These findings support a novel mechanism linking organelle quality control and innate immune regulation, highlighting Golgiphagy as an important feedback mechanism that limits STING1 signaling.Abbreviations: cGAMP: cyclic guanosine monophosphate-adenosine monophosphate; CGAS: Cyclic GMP-AMP synthase; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; ECTV: ectromelia virus; HGS: hepatocyte growth factor-regulated tyrosine kinase substrate; IKK: IκB kinase; IRF3: interferon regulatory factor 3; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TAX1BP1: Tax1 binding protein 1.

Keywords:  CGAS; Golgiphagy; SQSTM1/p62; STING1; TAX1BP1; microautophagy

DOI:  https://doi.org/10.1080/15548627.2026.2658230
Cell Death Discov. 2026 Apr 15.

Ubiquitin ligase RCHY1 regulates autophagosome-lysosome fusion.

Ruchi Umargamwala, Jantina Manning, Julian M Carosi, Donna Denton, Sharad Kumar.

Autophagy is a fundamental cellular recycling process that maintains homeostasis during animal development and under nutrient-limiting conditions. In our previous work, we employed autophagy-dependent cell death (ADCD) in the obsolete Drosophila larval midgut as a model to identify the enzymes involved in protein modification via ubiquitination with potential roles in autophagy regulation. From a genetic screen we identified RING E3 ligase RCHY1 as a candidate regulator. Here, we demonstrate that RCHY1 is essential for autophagy regulation during larval midgut ADCD in Drosophila and promotes autophagic flux in HeLa cells. Loss of Rchy1 impaired autophagosome-lysosome fusion and led to the accumulation of amphisomes in larval midgut cells. Similarly, depletion of RCHY1 in HeLa cells disrupted autophagic flux and reduced autolysosome formation, indicating evolutionary conservation of its function. Collectively, our findings identify RCHY1 as a putative regulator of autophagy that facilitates autophagosome-lysosome fusion.

DOI: https://doi.org/10.1038/s41420-026-03088-w
PLoS Pathog. 2026 Apr;22(4): e1014137

Poxvirus A52 protein subverts autophagy flux by blocking autophagosome-lysosome fusion to promote viral replication.

Kang Niu, Yongxiang Fang, Yining Deng, Ziyue Wang, Shijie Xie, Junda Zhu, Baifen Song, Wenxue Wu, Zhizhong Jing, Chen Peng.

Many poxviruses are significant zoonotic pathogens threatening public health. Autophagy, a regulated process vital for cellular homeostasis, can participate in defense against virus invasion. However, the relationship between poxviruses and host cell autophagy is not fully understood. This study shows that vaccinia virus (VACV) induces autophagy but blocks autophagosome-lysosome fusion. Modified vaccinia virus Ankara (MVA), an attenuated VACV strain that cannot replicate in most mammalian cells, fails to do so. Both pharmacological inhibition of early autophagy via 3-MA treatment and genetic ablation of ATG3 and ATG7 led to a significant enhancement of MVA replication. The VACV protein A52 inhibits autolysosome formation by disrupting interactions between SNAP29, STX17, and VAMP8, which is crucial for autophagic flux. Importantly, A52 also promotes the degradation of SNAP29, thereby aiding viral replication. Furthermore, SNAP29 is a newly identified host restriction factor for MVA, as its suppression enables MVA replication in human cells. These findings elucidate how poxviruses modulate autophagy for their own replication and further explain MVA's restriction in human cells.

DOI: https://doi.org/10.1371/journal.ppat.1014137
Neural Regen Res. 2026 Apr 14.

Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.

Valentina Tedeschi, Raffaella Ciancio, Silvia Piccirillo, Alessandra Preziuso, Tiziano Serfilippi, Valentina Terenzi, Simona Magi, Vincenzo Lariccia, Pasqualina Castaldo, Antonio Vinciguerra, Ilaria Piccialli, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Agnese Secondo.

  Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.

Keywords:  ; autophagy; channels; endoplasmic reticulum; endoplasmic reticulum stress; lysosome; mitochondria; mitochondria-associated membranes; neurodegenerative diseases

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01754
J Biol Chem. 2026 Apr 09. pii: S0021-9258(26)00315-7. [Epub ahead of print] 111445

Golgi-derived phosphatidylinositol 4-phosphate is crucial for organization of the pre-autophagosomal structure.

Huichao Lang, Kuninori Suzuki.

  Macroautophagy (hereafter autophagy) is a conserved intracellular degradation pathway that is essential for maintaining cellular homeostasis. Autophagosome (AP) formation involves pre-autophagosomal structure (PAS) organization and expansion of the isolation membrane (IM). Although phosphatidylinositol 4-phosphate (PtdIns4P) localizes to the IM and is required for autophagy, the specific functional role it plays in AP formation remains unclear. Pik1, a PtdIns 4-kinase localized to the Golgi, plays a critical role in this process. We used temperature-sensitive pik1 mutant cells and found that PAS localization of Atg9, Atg17, Atg1 and Atg13 remained normal at the restrictive temperature, indicating that PAS scaffold formation was unaffected. In contrast, the recruitment of downstream Atg proteins, the PtdIns 3-kinase complex I including Atg14, the Atg2-Atg18 complex, and Atg8, was impaired under the same condition. These findings demonstrate that Pik1-generated PtdIns4P is essential for PAS organization. Since Atg9 vesicles are derived from the Golgi, we hypothesized that PtdIns4P is transported to the PAS on Atg9 vesicles to mediate recruitment of downstream Atg proteins. To test this, we performed immunoprecipitation analysis using a PtdIns4P-binding protein and found that Atg9 was co-immunoprecipitated at the permissive temperature, but not at the restrictive temperature. This result indicates that PtdIns4P is enriched on Atg9 vesicles through Pik1 activity. Moreover, our assessment in pik1 mutant cells showed that IM expansion is impaired at the restrictive temperature. Collectively, these results identify PtdIns4P as a key component of PAS organization.

Keywords:  Atg9; Pik1; Saccharomyces cerevisiae; autophagosome biogenesis; isolation membrane; lipid transfer; phosphatidylinositol 4-phosphate

DOI:  https://doi.org/10.1016/j.jbc.2026.111445
Aging Dis. 2026 Apr 03.

Fine-Tuning Autophagy in Skeletal Muscle: From Homeostasis to Muscle Wasting Disorders.

Qian Gou, Shi Chee Ong, Wen Xing Lee, Priya D Gopal Krishnan, Hong-Wen Tang.

Skeletal muscle homeostasis and regenerative capacity depend on efficient protein turnover, organelle quality control, and metabolic adaptation. Disruption of these processes contributes to muscle atrophy and functional decline during aging and various pathological conditions. Autophagy, a lysosome-dependent degradative pathway, maintains muscle integrity by clearing damaged proteins and organelles, preserving mitochondrial quality, and supporting muscle stem cell (MuSC) function. Both insufficient and excessive autophagy are detrimental: reduced flux impairs proteostasis, mitochondrial function, and regeneration, whereas hyperactivation drives excessive protein degradation, mitochondrial loss, and muscle wasting under stress. This review discusses molecular mechanisms regulating autophagy in skeletal muscle, including nutrient- and energy-sensing pathways (AMPK and mTORC1), transcriptional control of autophagy and lysosomal genes, and mitochondrial modulators. Evidence from genetic models and disease contexts indicates that both insufficient and excessive autophagy are associated with muscle degeneration, highlighting the need for balanced autophagic control rather than simple activation or inhibition. Together, these observations support a conceptual framework in which skeletal muscle health depends on maintaining autophagic activity within a context-dependent functional range, although this range is not yet quantitatively defined. This framework provides a useful basis for considering therapeutic strategies targeting muscle wasting.

DOI: https://doi.org/10.14336/AD.2026.0170
Apoptosis. 2026 Apr 17. pii: 129. [Epub ahead of print]31(4):

The ATG14: multi-layer autophagy control and an emerging therapeutic target in cancer.

Wenbo Wang, Chujuan Yu, Fulin Sun, Ruofeng Wang, Weikai Xia, Qinghang Song, Huhu Zhang, Zhenzhen Jia, Min Zhang, Haoran Wang, Zhenxiang Wang, Rong Fu, Lina Yang.

  ATG14 (ATG14L/Barkor) is the autophagy-specific subunit of class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) and functions as a pivotal node linking autophagosome formation to autophagosome-lysosome fusion. Functionally, ATG14 regulates cell fate through multiple mechanisms. Under hypoxic or nutrient-deprived conditions, ATG14 maintains tumor cell survival and drug resistance, remodels cellular metabolism via lipophagy and mitophagy, and can either suppress or promote programmed cell death depending on the cellular context. Moreover, ATG14 plays protective roles in maintaining neuronal and hepatic homeostasis and is involved in the development of inflammatory and metabolic disorders. Here, we discuss the multi-layered regulation of ATG14, including post-translational modifications (phosphorylation, ubiquitination, palmitoylation), epitranscriptomic and non-coding RNA regulation, and competitive complex interactions, all of which fine-tune its autophagic output and functional plasticity. We further highlight the central roles of ATG14 during the autophagic process, summarize recent advances in cancer-related ATG14 research, and review ongoing drug development efforts as well as potential therapeutic strategies targeting ATG14. Our goal is to provide a comprehensive understanding of the physiological and pathological functions of ATG14 and to explore its potential as a druggable signaling hub. Given its bidirectional regulatory capacity to either suppress cytoprotective autophagy or enforce lethal autophagy-ATG14-targeted interventions must be strategically designed based on the disease stage and autophagy dependence.

Keywords:  ATG14; ATG14L; Autophagy; Cancer; Disease; PI3KC3-C1

DOI:  https://doi.org/10.1007/s10495-026-02302-5
Autophagy. 2026 Apr 16. 1-3

A tRNA epitranscriptomic checkpoint coordinates sperm mitochondrial load with embryonic allophagic clearance.

Zhenhuan Luo, Qin-Li Wan, Dan Wu, Chenyang He, Tristan Argeo Rodriguez, Qinghua Zhou, Hao Wang.

  The strict maternal inheritance of mitochondrial DNA is enforced by the efficient elimination of paternal mitochondria, yet the role of epigenetic regulation in this process remains unclear. In our recent study, we identify the demethylase ALKB‑1 as an essential factor for paternal mitochondrial elimination (PME) in Caenorhabditis elegans (C. elegans), functioning through tRNA m1A demethylation. ALKB‑1 deficiency leads to tRNA hypermethylation, which disrupts mitochondrial proteostasis and increases ROS production, thereby activating SKN‑1-ATFS‑1 stress signaling. This cascade compromises mitochondrial reduction during spermatogenesis, resulting in an increased burden of paternal mitochondria transmitted to the embryo. Concurrently, ALKB‑1 is required in the embryo to sustain autophagic clearance, evidenced by impaired autophagic flux and delayed PME upon maternal loss. Thus, delayed clearance stems dually from an excessive mitochondrial load in sperm and a compromised autophagic degradation capacity in the embryo. Our work establishes ALKB‑1‑dependent tRNA demethylation as a dual‑germline epitranscriptomic checkpoint that ensures intergenerational mitochondrial quality control.

Keywords:  Allophagy; Caenorhabditis elegans; demethylase ALKB‑1; paternal mitochondrial elimination; tRNA m1A

DOI:  https://doi.org/10.1080/15548627.2026.2659294
Trends Biochem Sci. 2026 Apr 16. pii: S0968-0004(26)00061-7. [Epub ahead of print]

Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.

Andrew N Bayne, Jean-François Trempe.

  PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration into broader cellular signaling networks. This review synthesizes these insights, focusing on the molecular determinants of PINK1/Parkin activation and the regulatory crosstalk that integrates mitophagy with other cellular stress responses. These mechanistic advances position the PINK1/Parkin pathway as a promising, tractable therapeutic target for Parkinson's disease and related pathologies.

Keywords:  PINK1; Parkin; Parkinson’s disease; mitochondrial quality control (MQC); mitophagy; stress response; therapeutic development

DOI:  https://doi.org/10.1016/j.tibs.2026.02.014
Autophagy Rep. 2026 ;5(1): 2649064

Autophagy selectively clears ER in TNF-α-induced muscle atrophy.

Ursula K Dueren, Alan An Jung Wei, A Elisabeth Gressler, Simon Rapp, Oliver Popp, Robert Kerridge, Viviana Buonomo, Paolo Grumati, Philipp Mertins, Matthias Selbach, Anna Katharina Simon, Thomas Sommer.

  Skeletal muscle atrophy is a pathological condition characterized by the progressive loss of muscle mass and function, driven by factors such as disuse, inflammation, and aging. While the ubiquitin-proteasome system is established as the central mediator of myofibrillar protein degradation, the role of selective autophagy and the degradation of organelles remains underexplored in this context. To address this, we employed a quantitative, time-resolved in vitro analysis of protein synthesis and degradation in C2C12 myotubes undergoing TNF-α-induced atrophy, using dynamic Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) coupled with LC-MS/MS. Our data challenges the classical view of atrophy as a uniform, degradation-centric process. Instead, we reveal temporally distinct patterns of selective protein turnover, including differential degradation of myofibrillar, ribosomal, and endoplasmic reticulum (ER)-resident proteins. Early atrophy is characterized by suppressed short-term protein synthesis, increased ubiquitin-ligase expression, proteasomal activation, and ribosome turnover. In contrast, late atrophy features proteasome-dependent myofibrillar protein degradation, selective synthesis, and degradation of mitochondrial and cytoplasmic ribosomes, indicative of metabolic adaptation. Moreover, we identify a temporal shift in autophagic selectivity: from ER homeostasis to a stress-induced ER-degradation program. Notably, autophagy inhibition during atrophy leads to the accumulation of ER-phagy receptors Tex264 and Calcoco1, implicating ER-phagy as a key contributor to atrophic remodeling and highlighting receptor-mediated selective autophagy as a regulatory axis in muscle proteostasis. By elucidating the role of ER-phagy, this study opens avenues for therapeutic interventions targeting proteostasis in inflammation-induced muscle-wasting, contributing to a refined understanding of muscle atrophy beyond proteasomal degradation, particularly in acute inflammatory conditions such as sepsis.

Keywords:  Dynamic SILAC; ER-phagy; TNF-α; autophagy; inflammation; muscle atrophy; proteostasis

DOI:  https://doi.org/10.1080/27694127.2026.2649064
Autophagy. 2026 Apr 12.

Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.

Ang Li, Xianglu Xiao, Dajiang Qin, Huanxing Su.

  Lysosomal dysfunction is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), yet effective pharmacological strategies to restore lysosomal homeostasis remain limited. Transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis, has emerged as an attractive therapeutic target. In our recent study published in Pharmacological Research, we established a robust artificial intelligence (AI) - driven virtual screening pipeline and identified isoginkgetin (ISO) as a potent TFEB activator that effectively promotes lysosomal biogenesis and enhances lysosomal function. Importantly, ISO exhibits potent neuroprotective effects against motor neuron degeneration in ALS models. Using this AI-driven strategy, we identified a previously unrecognized neuroprotective mechanism by which ISO protects motor neurons through TFEB-dependent restoration of lysosomal function, validating lysosomal function as a promising therapeutic target for ALS. Collectively, this work establishes that AI-powered screening to identify mTORC1-independent TFEB agonists is a valuable paradigm for the discovery and development of therapeutic agents against ALS and other neurodegenerative diseases.

Keywords:  Amyotrophic lateral sclerosis; Isoginkgetin; Lysosome; artificial intelligence; transcription factor EB

DOI:  https://doi.org/10.1080/15548627.2026.2659295
Dev Reprod. 2026 Mar;30(1): 25-38

Estrogen Regulates Microtubule-Associated Protein 1 Light Chain 3 in Mouse Uterine Endometrial Epithelium.

Sohyeon Moon, Soohyung Lee, Youngsok Choi.

  Microtubule-associated protein 1 light chain 3 (LC3) belongs to the ATG8 family and plays a crucial role in regulating the induction of autophagy. Autophagy proceeds via the conversion of LC3B-I to LC3B-II, which is degraded during the fusion of autophagosomes and lysosomes. Uterine autophagy is regulated by ovarian steroid hormones. However, the mechanism governing late-stage autophagic maturation (autophagosome-lysosome fusion) in the uterus remains unclear. We have previously reported that the activity and expression of serine/threonine protein kinase 4 (STK4) are regulated by estrogen (E2) in the uterine epithelium. In the present study, we investigated the regulatory role of STK4 in autolysosome formation via LC3. We found that estrogen treatment reduced LC3B-II within three hours, but not LC3B-I, suggesting regulation at the late-stage autophagic maturation step, without evidence of suppressed autophagosome formation. Treatment with the estrogen receptor antagonist ICI 182,780 clearly reversed the reduction in LC3B-II caused by E2. Furthermore, we discovered that STK4 knockdown decreased the phosphorylation of threonine at the 50th position of the LC3B protein. Finally, we observed that LC3B phosphorylation plays a role in autolysosome formation rather than in autophagosome formation. These findings imply that late-stage autophagic maturation in the uterine epithelium is regulated by LC3B phosphorylation via estrogen and STK4. This will improve our understanding of uterine dynamics via the regulation of autophagy during the estrous cycle.

Keywords:  Endometrium; Estrogen; Microtubule-associated protein 1 light chain 3; Serine/threonine protein kinase 4

DOI:  https://doi.org/10.12717/DR.2026.30.1.25
Nat Commun. 2026 Apr 11. pii: 3436. [Epub ahead of print]17(1):

Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6.

Kerstin Filippi, Kathrin Graf-Riesen, Maithreyan Kuppusamy, Andreas Unger, Kenichi Kimura, Martin Matijass, Henrique Baeta, Magdalena Podlacha, Daniel Haertter, Alexei P Kudin, Martin Wiemann, Grzegorz Węgrzyn, Cornelia Kornblum, Jens Reimann, Wolfgang A Linke, Pitter F Huesgen, Wolfram S Kunz, Bernd K Fleischmann, Michael Hesse.

Myofibrillar myopathy 6 is a rare, autosomal-dominant neuromuscular disorder caused by an amino acid exchange Pro209Leu in the co-chaperone BAG3, which disrupts muscle protein turnover and causes severe muscle weakness and shortened lifespan. We generated transgenic mice overexpressing the human mutant BAG3P209L-GFP, which rapidly develop skeletal muscle weakness unlike controls expressing BAG3WT-GFP. Here we show that mutant mice exhibit sarcomere breakdown, inflammation, protein aggregates, centralized nuclei and mitochondrial defects in their skeletal muscles, thereby reducing contraction force by ~90%. Omics profiling uncovered impaired protein synthesis, blocked autophagy, impaired mitophagy and loss of sarcomere proteins. Pathway modulation in vitro and in vivo showed autophagy dysfunction as the primary driver for the pathology, while BAG3 knockdown gene therapy markedly restored muscle function in vivo. In summary, this model recapitulates core disease features, revealing how BAG3 aggregates and loss of BAG3 function impair autophagy to drive muscle degeneration.

DOI: https://doi.org/10.1038/s41467-026-71749-6
Cell Insight. 2026 Apr;5(2): 100311

Viral-host interactions mediated by the mTOR signaling pathway.

Zizhen Ming, Bing Su, Qiming Liang.

  The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that regulates multiple key cellular processes. It assembles into two major multi-protein complexes, called mTOR complex (mTORC)1 and mTORC2, to integrate cues from cellular nutrient status, energy levels, and growth factors. mTOR plays crucial roles in key physiological processes such as protein synthesis, autophagy initiation, lipid metabolism, and cell survival. As obligate intracellular parasites, viruses rely heavily on the host's biosynthetic machinery, making viral propagation dependent on host-derived metabolic resources. Consequently, the metabolic networks and cellular functions governed by the mTOR pathway directly support the viral life cycle, establishing it as a critical regulatory node in virus-host interactions. To fulfil their replication demands, viruses have evolved diverse strategies to manipulate the mTOR signaling: sustained activation of host anabolic metabolism, selectively inhibition the mTOR-mediated autophagy to generate membranous structures, and dynamically tuning mTORC1 and mTORC2 activities to meet stage-specific replication needs. This review systematically elucidates the structural basis and regulatory landscape of the mTOR signaling pathway, highlighting the specific mechanisms used by various viruses to modulate the mTOR function. It also examines the central role of mTOR in antiviral immunity and provides preclinical and clinical evidence supporting mTOR-targeted antiviral strategies. Ultimately, this review aims to outline a comprehensive theoretical framework for understanding virus-host interactions through mTOR modulation and offers novel perspectives on the development of mTOR-based antiviral interventions.

Keywords:  Antiviral therapy; Autophagy; Immune evasion; Viral infection; mTOR signaling

DOI:  https://doi.org/10.1016/j.cellin.2026.100311
Autophagy. 2026 Apr 12.

CORO1C (coronin 1C) promotes autophagosome formation by coordinating branched actin network dynamics.

Guozhong Zhang, Ningqing Yu, Yi Sun, Xiaowen Li, Lihong Sun, Guang Liu, Yue Huang.

  Macroautophagy/autophagy is a critical cellular process that maintains the cellular homeostasis by degrading and recycling cytotoxic material. Despite its importance, the intricate mechanisms governing this process remain partially elusive. Here, we designed and performed a genome-wide loss-of-function screen on a mouse haploid ESC mutant library and identified the actin-binding protein CORO1C (coronin 1C) as a previously unrecognized regulator of mammalian autophagy. Interactions between CORO1C and the ACTR2/ARP2 (actin related protein 2)-ACTR3/ARP3 complex are essential for branched actin network assembly, SQSTM1/p62 body formation, and maintaining autophagosome structural integrity. Unlike CORO1A and CORO1B, CORO1C possesses a unique second actin-binding site involved in regulating the branched actin network and autophagic process. Notably, coro1c-/- newborn mice died earlier in starvation than wild-type littermates and multiple tissues showed autophagy-deficient phenotypes. Moreover, the adult coro1c-deficient mice exhibit severe spatial learning memory impairment. Collectively, our research uncovered the surprising role of CORO1C in promoting the formation of branched actin network and its central role in the assembly of structures vital to autophagy.

Keywords:  ARP2/3 complex; SQSTM1/p62 body formation; autophagy; branched actin network; coronin 1C; genetic screen

DOI:  https://doi.org/10.1080/15548627.2026.2658234
Commun Biol. 2026 Apr 17.

Nrf1 coordinates proteasome activity and autophagy to maintain cardiac proteostasis.

Lakindu P Kankanamge, Hyunji An, Qin Guo, Maksymillian Prondzynski, Soon Ho Kwon, Durgesh Anil Bonde, William T Pu, Eric N Olson, Miao Cui.

Proteolytic stress frequently arises during disease and aging, particularly in long-lived, post-mitotic cells such as cardiomyocytes. To maintain proteostasis, cardiomyocytes depend on coordinated protein quality control pathways, including the ubiquitin-proteasome system and autophagy. Mechanisms that activate these pathways hold therapeutic potential for heart disease. Here, we demonstrate that transient activation of nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1), a transcriptional regulator of proteasome activity, in cardiomyocytes during ischemia/reperfusion injury improves cardiac function. In addition to regulating the proteasome, we identify a critical role for Nrf1 in activating autophagy, which is essential for its cardioprotective effects. Through multi-omics analyses, we define both transcriptional and post-transcriptional functions of Nrf1 that underlie its cardioprotective activity. Loss-of-function studies in mice demonstrate that Nrf1, but not its homolog Nrf2, is required for autophagy and baseline cardiac function. Together, our findings establish a dual function of Nrf1 in promoting cardiac proteostasis by regulating both proteasomal and autophagic protein quality control pathways. Activating Nrf1 thus offers a therapeutic strategy for treating ischemic heart disease.

DOI: https://doi.org/10.1038/s42003-026-10067-5
Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00198-X. [Epub ahead of print]86(8): 1560-1573.e5

Structural basis for TORC2 activation.

Luoming Zou, Maria G Tettamanti, Caroline Gabus, Ariane Bergmann, Robbie Loewith, Lucas Tafur.

  The target of rapamycin complex 2 (TORC2) is a central node in signaling feedback loops, serving to maintain the biophysical homeostasis of the plasma membrane (PM). How TORC2 is regulated by mechanical perturbation of the PM is not well understood. To address this, we determined the cryo-electron microscopy structure of endogenous yeast TORC2 at up to 2.2 Å resolution. Our model refines the position and interactions of TORC2-specific subunits, providing a structural basis for the differential assembly of Tor2 into TORC2. Furthermore, we observe the insertion of the pleckstrin-homology domain of the Avo1 subunit into the Tor2 active site, providing a regulatory mechanism mediated by phosphoinositides. Structure-guided functional experiments reveal a potential TORC2 membrane-binding surface and a positively charged pocket in the Avo3 subunit that is necessary for TORC2 activation. Collectively, our data suggest that signaling phosphoinositides activate TORC2 by membrane-induced structural rearrangements via the concerted action of conserved regulatory subunits.

Keywords:  TOR signaling; cell growth; cryo-electron microscopy; membrane mechanotransduction; phosphoinositides; target of rapamycin complex 2

DOI:  https://doi.org/10.1016/j.molcel.2026.03.022
EMBO Rep. 2026 Apr 16.

GRASP55 maintains lysosome function by controlling sorting of lysosomal enzymes at the Golgi.

Julian Nüchel, Maryam Omidi, Stephanie A Fernandes, Marina Tauber, Sandra Pohl, Markus Plomann, Constantinos Demetriades.

Lysosomes are multifunctional organelles that play important roles in cellular recycling, signaling, and homeostasis, relying on precise trafficking and activation of lysosomal enzymes. While the Golgi apparatus plays a central role in lysosomal enzyme sorting, the mechanisms linking Golgi function to lysosomal activity remain incompletely understood. Here, we identify the Golgi-resident protein GRASP55, but not its paralog GRASP65, as necessary for lysosome function. Loss of GRASP55 expression leads to missorting and secretion of lysosomal enzymes, lysosomal dysfunction and bloating. GRASP55 deficiency also disrupts lysosomal mTORC1 signaling, reducing the phosphorylation of its lysosomal substrates TFEB/TFE3, while sparing its non-lysosomal targets. Mechanistically, GRASP55 binds and maintains the COPI adaptor GOLPH3 protein at the Golgi, thereby controlling the Golgi localization and stability of LYSET and GNPTAB that are required for mannose 6-phosphate (M6P) tagging of lysosomal enzymes. These findings reveal an essential role for GRASP55 in Golgi-lysosome communication and lysosomal enzyme trafficking and underscore the importance of Golgi-mediated protein sorting in lysosome function and lysosomal mTORC1 signaling.

DOI: https://doi.org/10.1038/s44319-026-00773-w
Microbiologyopen. 2026 Apr;15(2): e70278

Nuclear Microautophagy Drives Vacuolar Targeting of Yeast Iron-Regulated Proteins During Lipid and Iron Limitation.

Tania Jordá, Sergi Puig.

  Iron is an essential cofactor involved in cellular processes, including energy generation and the biosynthesis of DNA, proteins, and lipids. The limited solubility of iron at physiological pH frequently results in iron deficiency, thus necessitating sophisticated regulatory mechanisms to maintain iron homeostasis. In Saccharomyces cerevisiae, the transcription factor Aft1 mediates the early response to iron limitation by accumulating in the nucleus and activating the iron regulon, a set of genes involved in iron uptake, utilization and sparing. One of Aft1 targets, CTH2, encodes for a protein that promotes iron economy by post-transcriptionally downregulating non-essential iron-dependent pathways. Yeast cells that exhibit defects in unsaturated fatty acid (UFA) biosynthesis, such as mga2Δ mutants, mislocalize Aft1 to the vacuole under iron-deficient conditions, which impairs activation of the iron regulon. In this study, we show that Cth2, but not other nucleo-cytoplasmic shuttling proteins, also accumulates in the vacuole under simultaneous UFA and iron deficiencies. The deletion of autophagy- and piecemeal microautophagy of the nucleus (PMN)-related genes, including ATG1 and NVJ1, prevents Aft1 vacuolar mislocalization. Furthermore, the subcellular distribution of Nvj1 supports PMN activation under these conditions. Despite preventing vacuolar accumulation, these mutations do not restore the regulatory functions of Aft1 and Cth2, nor do they rescue growth in low-iron conditions. These findings suggest that PMN selectively targets non-functional iron-regulated proteins for degradation when both iron and UFA levels are limiting, serving as a quality control mechanism rather than a pathway for functional recovery. These findings underscore a regulatory layer coordinating nutrient sensing and protein turnover.

Keywords:  Aft1; Cth2; autophagy; iron deficiency; unsaturated fatty acids; yeast

DOI:  https://doi.org/10.1002/mbo3.70278
Aging Dis. 2026 Apr 02.

Clock and the Cleaner: Circadian Rhythms and Autophagy Coupling in Alzheimer's Disease.

Liyun Ma, Zhenxiang Gong, Rong Gao, Lina Zhu, Liru Wu, Min Zhang, Li Ba.

Alzheimer's disease (AD) continues to progress despite decades of research on protein aggregation, highlighting the need to understand upstream homeostatic failures. Among the earliest alterations in AD are disruptions of circadian rhythms and autophagy, which are mechanistically intertwined. Although circadian dysfunction and autophagic failure have been studied separately, the stage-dependent, region-specific, and cell-type-specific interplay between these systems remains poorly integrated, limiting the development of targeted interventions. In a healthy brain, the circadian clock and autophagy mutually interact, maintaining proteostasis, neuronal function, and rhythmic metabolic and immune processes. In early-stage AD, circadian rhythms show mild disruption and autophagy initiation remains active, but downstream autophagosome-lysosome fusion and lysosomal degradation are impaired, leading to the accumulation of AD pathological proteins. Dysregulation is cell-type-specific: neuronal clocks remain relatively intact, whereas astrocytic and microglial clocks exhibit altered metabolic and immune rhythms, contributing to early pathogenic events. In late-stage AD, severe circadian disruption likely uncouples circadian control from autophagy, and these dysfunctions mutually exacerbate each other, driving neuroinflammation, neuronal dysfunction, and further accumulation of pathological proteins. This review synthesizes current evidence on the circadian-autophagy axis, highlighting mechanistic insights and therapeutic opportunities, and emphasizes the importance of integrating stage-, region-, and cell-type-specific dynamics for the development of precise interventions in AD.

DOI: https://doi.org/10.14336/AD.2025.1496
Neural Regen Res. 2026 Apr 14.

Autophagy: Bridging the brain-periphery connection.

Camila Sandoval-Valenzuela, Diego Acuña-Catalán, Daniela Pinto-Núñez, Patricia Rivera-Reyes, Yorka Cheuquemilla-Mellado, Alfredo Torres, Flavia Lambertucci, Guido Kroemer, Maria Chiara Maiuri, Alfredo Criollo, Eugenia Morselli.

  Autophagy, a fundamental cellular degradation and recycling process, has emerged as a central regulator of systemic physiology by orchestrating communication between the brain and peripheral organs. Beyond its traditional role in maintaining intracellular homeostasis, autophagy coordinates immune responses, metabolic balance, and inter-organ signaling through mechanisms including selective degradation and secretory pathways. In this review, we explore how autophagy in neurons, glial cells, immune cells, and metabolic tissues modulates both local and systemic functions, impacting processes such as neuroinflammation, energy homeostasis, and gut-brain axis communication. We highlight the dual role of autophagy in promoting tissue health and facilitating the transfer of metabolic and inflammatory cues across organ systems. Additionally, we discuss how autophagy dysfunction disrupts brain-periphery communication, contributing to the development of neurodegenerative and metabolic diseases. Understanding the mechanisms underlying autophagy-dependent inter-organ signaling will help identify therapeutic avenues for restoring systemic homeostasis and prevent the development of chronic diseases.

Keywords:  brain; glucose homeostasis; hypothalamus; neurodegenerative diseases; neuroinflammation; neuropeptides; obesity; secretory autophagy

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00650
Neurochem Res. 2026 Apr 11. pii: 136. [Epub ahead of print]51(2):

Mitochondrial Fission and Fusion Disorders and Autophagy Abnormalities in Parkinson's Disease.

Yufei Liu, Haoran Li, Jie Bai.



Keywords:  Mitochondria; Mitochondrial autophagy; Mitochondrial fission and fusion; Parkinson’s disease

DOI:  https://doi.org/10.1007/s11064-026-04752-4
Nat Commun. 2026 Apr 17.

Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast accumulation by inhibiting Parkin-dependent mitophagy.

Yunjuan Nie, Li Xu, Yanyan Liu, Jiao Li, Zhixu Wang, Xiaorun Zhai, Xiaoru Sun, Chunxiao Hu, Bo Xu, Yaxian Wu, Haitao Yu, Manjula Karpurapu, Huaqi Guo, Gaoshang Chai.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease where macrophages drive fibrogenesis, yet Hdac11's role is unclear. We first identify pronounced Hdac11 upregulation in IPF lungs, which is associated with an enrichment in alveolar macrophages (AMs). Genetic ablation of Hdac11 or adoptive transfer of Hdac11-deficient macrophages markedly attenuates fibrosis. Specifically, Hdac11 deficiency significantly reduces M2 macrophage polarization in vivo and vitro and is associated with reduced macrophage-myofibroblast transition (MMT) like phenotypic reprogramming, thereby decreasing myofibroblast accumulation and profibrotic gene expression. Mechanistically, impaired mitophagy mediates Hdac11-mediated M2 macrophage polarization and is associated with MMT-like changes. Hdac11 regulates mitochondrial quality control by deacetylating Parkin at lysine 76, promoting its ubiquitination and degradation, which impairs mitophagy and drives profibrotic macrophage activation. Pharmacological Hdac11 inhibition effectively reverses bleomycin-induced fibrosis. Taken together, our work identifies Hdac11 as a target of Parkin-mediated mitophagy in macrophages, establishing Hdac11-Parkin axis disruption as an important mechanism in IPF and highlighting Hdac11 inhibition as a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41467-026-71639-x
Toxicol Rep. 2026 Jun;16 102229

The autophagy switch: A critical determinant of arsenic-induced carcinogenesis and cancer therapy.

Marzieh Zeinvand-Lorestani, Fakher Rahim, Hamed Zeinvand-Lorestani.

  Arsenic, a widespread environmental toxicant and unexpectedly effective chemotherapeutic agent, has complex and significant effects on cellular homeostasis. Autophagy, a conserved lysosomal degradation process, plays a key role in arsenic's dual functions as a carcinogen and a treatment. While current reviews have documented interactions between arsenic and autophagy, this review introduces a new conceptual model: the "Autophagy Switch." We propose that the cellular choice between autophagy-assisted survival and autophagy-dependent death is not simply black and white but exists within a dynamic balance called the Arsenic Contextual Triad-comprising chemical form, exposure pattern (dose and duration), and the cell's oncogenic background. We compile evidence showing how this switch influences outcomes across the cancer spectrum, from promoting skin cancer through p62/Nrf2 feedback loops to breaking down oncogenic factors like PML-RARα and BCR-ABL in leukemia. Additionally, we critically assess the therapeutic potential of targeting this switch, emphasizing how drugs that either inhibit or promote autophagy can work together with arsenic trioxide (ATO) to combat drug resistance in solid tumors such as glioblastoma and ovarian cancer. By shifting from simple descriptions to a detailed mechanistic and contextual understanding, this review offers a valuable guide for future research aiming to harness the autophagy switch for cancer prevention and personalized treatment.

Keywords:  Arsenic exposure; Autophagy; Autophagy switch; Carcinogenesis; Oxidative stress

DOI:  https://doi.org/10.1016/j.toxrep.2026.102229
Sci Rep. 2026 Apr 11.

Independent roles of autophagy and apoptosis in post-apocrine-secretion cell death of salivary glands during Drosophila metamorphosis.

Lucia Mentelová, Denisa Beňová-Liszeková, Milan Beňo, Bruce A Chase, Robert Farkaš.

  The Drosophila larval salivary glands (SGs) serve as an outstanding model to understand developmental transitions in secretory epithelial cells. They have been instrumental in understanding the regulatory mechanisms that lead to the exocytosis of SG glue (Sgs) just prior to pupariation during the late larval period, and gaining insights into apocrine secretion (AS), a non-canonical, non-vesicular transport and secretion, which occurs later in the late prepupal period to provide the immunoprotective exuvial fluid that surrounds the pupae during its metamorphosis into an adult fly. AS is the SGs major, evolutionarily conserved secretory function, as unlike Sgs exocytosis, AS is found across the Diptera. Since the SGs undergo hormonally controlled programmed cell death (PCD) shortly after they complete AS, a key question is how the regulation of AS and PCD are related. To address this, it is essential to clarify the mechanism of PCD. Earlier proposals that it occurs via autophagic cell death (ACD) or autophagy dependent cell death (ADCD) did not incorporate or explain any of the dynamic post-Sgs cellular processes that are associated with AS. Here we present three lines of evidence that the SGs die using an apoptosis-prone mechanism during which the endoplasmic reticulum (ER) becomes fragmented into vesicles that wholly fill the cytoplasm. First, although a low level of autophagy can be seen in the SGs, inducing autophagy with rapamycin does not accelerate PCD. Second, while the genetic removal of Atg1 or RNAi silencing of the Atg3, Atg5, Atg6, Atg7, and Atg12 genes inhibits the development of autophagy, this does not prevent vesiculation and subsequent SG-cell death. Third, the Drosophila SGs exhibit externalization of phosphatidylserine and attract phagocytic macrophages, both of which are pivotal hallmarks of apoptosis. Therefore, we propose that the entire Drosophila SG organ dies using a non-autophagic mechanism which utilizes key features of the apoptotic pathway.

Keywords:   Drosophila ; Apocrine secretion; Metamorphosis; Programmed cell death; Salivary glands; Secretory epithelium

DOI:  https://doi.org/10.1038/s41598-026-46472-3
Cells. 2026 Mar 25. pii: 585. [Epub ahead of print]15(7):

BNIP3/BNIP3L-Dependent Mitophagy Protects Against Hippocampal Neuronal Damage and Apoptosis in a Model of Vascular Dementia.

Yujiao Wang, Daojun Xie, Shijia Ma, Yuhe Wang, Chengcheng Zhang, Zhuyue Chen.

  Mitophagy serves as an essential quality control mechanism that maintains mitochondrial homeostasis through selective autophagic clearance of damaged organelles. Vascular dementia (VD) has been increasingly associated with mitophagy dysregulation in recent studies. However, the precise molecular mechanisms underlying mitophagy's involvement in VD pathogenesis remain poorly characterized. To elucidate the role of mitophagy in VD, we systematically examined the expression of key mitophagy pathways in hippocampal neurons of bilateral common carotid artery occlusion (BCCAO) rats and in oxygen-glucose deprivation (OGD)-treated HT22 cells. Intriguingly, under autophagy-deficient conditions, both BNIP3 and BNIP3L were markedly downregulated, whereas FUNDC1 expression increased; PINK1/Parkin levels remained unaltered. To further dissect the functional contributions of BNIP3 and BNIP3L, we administered the mitochondrial fission inhibitor Mdivi-1 to BCCAO model rats. Histopathological analysis revealed pronounced neuronal damage and apoptosis in the hippocampal region, which was further exacerbated upon Mdivi-1 treatment. In vitro, BNIP3 silencing significantly compromised cell viability, elevated reactive oxygen species (ROS) accumulation, disrupted mitochondrial membrane potential (ΔΨm), suppressed mitophagy, and increased apoptotic rates. Conversely, BNIP3 overexpression reversed these detrimental effects. Notably, treatment with the autophagy inhibitor 3-methyladenine (3-MA) diminished LC3B-Tomm20 colocalization and intensified apoptosis, reinforcing the critical role of BNIP3-mediated mitophagy in neuronal survival. Similarly, BNIP3L overexpression enhanced cell viability, attenuated ROS production, restored ΔΨm, and mitigated apoptosis, while 3-MA treatment again impaired mitophagic flux and worsened cell death. Collectively, these findings underscore the critical and distinct roles of BNIP3 and BNIP3L in maintaining mitochondrial homeostasis and neuronal survival under ischemic conditions.

Keywords:  BNIP3; BNIP3L; ROS; apoptosis; mitophagy; vascular dementia

DOI:  https://doi.org/10.3390/cells15070585
Redox Biol. 2026 Apr 06. pii: S2213-2317(26)00155-2. [Epub ahead of print]93 104157

FTMT-mediated suppression of mitophagy links iron accumulation to osteoporosis.

Ruizhi Zhang, Yike Wang, Lei Li, Junjie Li, Guangchen Feng, Yutong Hu, Gongwen Liu, Xiongyi Wang, Jiajun Zhang, Peng Wei, Houfu Lai, Keyu Zhu, Xiao Wang, Xueqin Gao, Wen Wei, Yixuan Fang, Jianrong Wang, Na Yuan, Youjia Xu.

  Primary osteoporosis is a major age-related disease with a significant global health burden. While iron accumulation is a known risk factor, the mechanisms linking it to bone loss remain unclear. Here, we report that impaired mitophagy in bone marrow mesenchymal stem cells (BMSCs) is a hallmark of osteoporosis and is critically exacerbated by iron accumulation. We found that iron accumulation in BMSCs inhibits mitophagy, leading to mitochondrial dysfunction, increased oxidative stress, and cellular senescence, ultimately impairing osteogenic differentiation. Importantly, targeted activation of mitophagy, either pharmacologically or genetically, restored mitochondrial health, reduced senescence, and rescued bone formation. Conversely, Pink1 deficiency in BMSCs was sufficient to induce osteoporosis. Mechanistically, we identified that the mitochondrial ferritin FTMT is upregulated under iron-loading conditions and binds to PINK1, suppressing its phosphorylation and thereby preventing mitophagy initiation. This pathway is clinically relevant, as BMSCs from osteoporotic patients with high ferritin levels showed elevated FTMT and reduced PINK1 phosphorylation. Therefore, we identify a novel pathway in which FTMT-mediated disruption of mitophagy drives iron-induced osteoporosis. Our findings highlight mitophagy activation as a therapeutic strategy to prevent and treat bone loss under iron accumulation.

Keywords:  Bone marrow mesenchymal stem cells; Iron accumulation; Mitochondrial ferritin; Mitophagy; Osteoporosis

DOI:  https://doi.org/10.1016/j.redox.2026.104157
Int J Mol Sci. 2026 Apr 05. pii: 3303. [Epub ahead of print]27(7):

Nutrition, Cell Signalling, Mitochondrial Function, and Chronic Non-Communicable Disease.

Russell Phillips.

  Cellular homeostasis is a dynamic process which balances anabolic processes with catabolic and recycling processes. These processes require nutrients, which are converted to energy to fuel the complex interactions of intracellular signalling. Cellular health requires that, on average, energy input and energy requirements are matched. Cells contain a nutrient-sensing mechanism which controls the balance between anabolism and catabolism. Normal intracellular functions generate products which regulate signalling pathways, and health at a cellular level requires a fluctuation between relative nutrient abundance and relative nutrient scarcity. This allows clearance of damaged intracellular molecules and organelles. When nutrient supply exceeds cellular requirements, adaptations to intracellular signalling occur, resulting in energy being stored as glycogen in muscle and the liver and fatty acids in adipose tissue. Overfuelling and aberrant fuelling of mitochondria result in oxidative stress, which not only disrupts cellular homeostasis but can alter epigenetic expression, with intergenerational effects. If the recycling mechanisms of the cell are insufficient to clear metabolic products, apoptosis may result or expression of Damage-Associated Molecular Patterns (DAMPs) on the cell surface may occur, activating immunity and inflammation at a systemic level. Disrupted cellular signalling affects cells with different "professional" functions in different organs, and it is the mechanism which underlies the associations between chronic non-communicable diseases such as cancer, type 2 diabetes, cardiovascular disease, neurodegenerative disease, autoimmune diseases, and macular degeneration. Mitochondria are the controllers of energy production and are pivotal in cell signalling. Mitochondrial function governs health at cellular and organismal levels. This paper reviews the influence of nutrition on mitochondrial function, nutrient sensing, autophagy, insulin signalling, and apoptosis-the key pathways in cellular homeostasis.

Keywords:  AMPK; apoptosis; autophagy; extracellular vesicles; insulin signalling; mTOR; mitochondria; nutrient sensors; nutrition; redox signalling

DOI:  https://doi.org/10.3390/ijms27073303
Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00195-4. [Epub ahead of print]86(8): 1546-1559.e8

mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway.

Thomas A O'Loughlin, John S Stiles, Pritika Acharya, Abolfazl Arab, Laine Goudy, Raymond Dai, Ashir A Borah, William A Weiss, Uche N Medoh, Luke A Gilbert.

  Aberrant activation of the PI3K/AKT/mTOR signaling pathway is a common feature of cancer, but while mTOR kinase represents an attractive drug target, mTOR inhibitors have not seen broad success as single agents. To identify strategies to enhance the utility of third-generation bi-steric mTORC1 inhibitors, we performed genome-scale CRISPR interference chemogenomics screens, which revealed that mTORC1 inhibitor-mediated cytostasis leaves cells exquisitely dependent on the lipid peroxide scavenging enzyme GPX4. Mechanistically, using unbiased CRISPR activation chemogenomics screens, we demonstrate that mTORC1-dependent control of ferroptosis occurs, in part, through regulation of SCARB1 expression. Specifically, we find that the high-density lipoprotein (HDL) can suppress ferroptosis through interaction with its receptor SCARB1 and delivery of vitamin E to target cells. Our work highlights combining mTORC1 with GPX4 inhibition as one of the most promising combinatorial approaches for mTOR-targeted cancer therapies and defines an HDL-SCARB1 ferroptosis-suppression system that is regulated by mTORC1 activity.

Keywords:  GPX4; HDL; SCARB1; antioxidant; cancer; cell biology; ferroptosis; functional genomics; lipoprotein; mTOR; tocopherol; vitamin E

DOI:  https://doi.org/10.1016/j.molcel.2026.03.019
iScience. 2026 Apr 17. 29(4): 115182

A stress-induced PI3P complex controls autophagy in erythroid precursors.

Pooja Roy, Blake A Rose, Suhita Ray, Venkatasai R Dogiparthi, Meg A Schaefer, Cheryl L Stucky, Suyong Choi, Nicholas T Woods, Kyle J Hewitt.

  Samd14 coordinates stem cell factor/Kit receptor signaling and is crucial for the survival of erythroid precursors in anemia contexts. Here, we show that Samd14 is needed to maintain balanced autophagy in erythroid precursors following acute anemia. Autophagy-associated gene signatures and protein levels are deregulated when erythropoiesis accelerates in acute anemia. Mechanistically, Samd14 interacts via its SAM domain with phosphatidylinositol 3-phosphate (PI3P), an integral component of endosomal and autophagic membranes. Pharmacologic inhibition of VPS34, the class III PI 3-kinase that generates PI3P, impaired erythroid differentiation specifically in stress contexts. Loss of Samd14 shifted the sensitivity of erythroid precursors to VPS34 inhibition, where higher doses were required to block differentiation. Given the critical roles of autophagy in normal differentiation, Samd14's stress-dependent activation and roles in autophagy suggest that this mechanism is needed to maintain progenitor levels and balance the production of healthy, mature red blood cells in anemia.

Keywords:  cell biology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.115182
Cells. 2026 Apr 01. pii: 636. [Epub ahead of print]15(7):

VPS34 in Autophagy, Cancer, and Cancer Therapy.

Elisabetta Bartolini, Bassam Janji, Ruize Gao.

  Autophagy is a fundamental lysosome-dependent degradation process that maintains cellular homeostasis in response to stress. VSP34 (Vacuolar Protein Sorting 34, PIK3C3) is the only class-III phosphatidylinositol 3-kinase and generates phosphatidylinositol 3-phosphate (PI3P) for auto-phagosome nucleation and maturation. Thus, it provides a critical adaptive survival pathway for cells that are experiencing metabolic stress. The VPS34-autophagy axis plays dual roles in cancer, which depend on the context: it can restrain early tumorigenesis, but in established tumors, it can promote survival in conditions of hypoxia, nutrient deprivation, and therapeutic pressure. Moreover, VPS34 shapes the tumor microenvironment (TME) through its influence on both immune and cancer cells by modulating autophagy, cGAS-STING (cyclic GMP-AMP synthase Stimulator of Interferon Genes), and STAT1 pathways. VPS34 inhibition has been reported to induce an interferon response that increases CD8+ T and natural killer (NK) cell infiltration and converts cold tumors into hot ones. This behavior suggests that combining VPS34 inhibitors with cancer immunotherapies could be beneficial. In this review, we summarize the molecular functions and regulations of VPS34 in autophagy and discuss recent advances linking VPS34 to tumor and cancer immunotherapy.

Keywords:  VPS34; autophagy; cancer immunity; cancer immunotherapy; cancer therapy; immunity

DOI:  https://doi.org/10.3390/cells15070636
Sci Rep. 2026 Apr 17.

Allyl-substituted ALT001 promotes alternative mitophagy and improves therapeutic outcomes in Alzheimer's disease models.

Jee-Hyun Um, Se Myeong Choi, Young Yeon Kim, Dong Jin Shin, Eunhee Yoo, Han-Joo Maeng, Alen Benhur Pravin Nathan, Jihoon Jo, Jong Hyun Cho, Jeanho Yun.

  The impairment of mitophagy plays a key role in the pathology of Alzheimer's disease (AD). We previously demonstrated that ALT001 induces mitophagy via the alternative mitophagy pathway and ameliorates mitochondrial dysfunction and cognitive deficits in AD models. In this study, we synthesized a novel derivative, namely, ALT001-4a, by introducing an allyl group at the C13 position of ALT001. Compared with ALT001, ALT001-4a exhibited an approximately fivefold lower EC50 for inducing mitophagy, while maintaining low cytotoxicity, and it exerted this effect via the alternative mitophagy pathway. Similarly, ALT001-4a induced mitophagy in the hippocampus of mice at a fourfold lower dose than ALT001. Importantly, ALT001-4a successfully restored mitochondrial and cognitive function in both a cellular AD model and a 5xFAD AD model. These findings suggest that the structural modification of ALT001 can generate derivatives with superior potency and potential for treating Alzheimer's disease and that further optimization could enable the development of ALT001-4a as a viable therapeutic agent for AD.

Keywords:  Alternative mitophagy; Alzheimer’s disease; Mitophagy inducer; Structural optimization

DOI:  https://doi.org/10.1038/s41598-026-48974-6
bioRxiv. 2026 Apr 07. pii: 2026.04.03.716340. [Epub ahead of print]

WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease.

Maxime Teixeira, Razan Sheta, Morgan Bérard, Christine Insinna, Anne-Laure Mahul-Mellier, Constantin V L Delmas, Eva Lépinay, Walid Idi, Alexandra Ricard, Esther Del Cid-Pellitero, Christine Trabolsi, Stéphane Gobeil, Marie-Hélène Canron, Erwan Bézard, Alex Rajput, Francesca Cicchetti, Martin Parent, Edward A Fon, Nagendran Ramalingam, Ulf Dettmer, Frederic Calon, Christopher Westlake, Hilal A Lashuel, Abid Oueslati.

The aggregation of α-synuclein (α-SYN) into Lewy bodies (LBs) is a central event in the pathogenesis of Parkinson's disease (PD) and related synucleinopathies 1,2 . Despite significant advances in understanding α-SYN self-assembly, the precise sequence of early aggregation steps has not been directly visualized in living neurons. Here, we use an optogenetic-induced protein aggregation system with a high temporal resolution to monitor the onset of α-SYN assembly in neurons. We found that the initiation and accumulation of α-SYN aggregates occur predominantly at the lysosomal membrane, an event driven by the α-SYN N-terminus and modulated by the membrane-associated adaptor protein WD repeat-containing protein 44 (WDR44). Remarkably, we demonstrate that WDR44 knockdown markedly reduced de novo α-SYN aggregation in both neuronal cultures and in vivo, whereas WDR44 overexpression enhances α-SYN aggregation in PD patient-derived iPSC neurons. Consistent with its potential pathogenic involvement, WDR44 aberrantly accumulates in vivo and in the brains of PD patients, where it colocalizes with LB inclusions. Finally, we show that lysosome-associated α-SYN aggregates compromised lysosomal structure and function, leading to neuronal impairment, a phenotype worsened by WDR44 overexpression, linking early aggregation events to downstream toxicity. Together, these findings reveal the earliest dynamic stages of α-SYN oligomerization in living neurons and identify the WDR44-α-SYN interaction as a promising therapeutic target for reducing α-SYN pathology and enabling early intervention in PD.

DOI: https://doi.org/10.64898/2026.04.03.716340
Cells. 2026 Apr 07. pii: 652. [Epub ahead of print]15(7):

SQSTM1/p62 at the Crossroads of Autophagy, Inflammation, and Lethal Infection.

Ruoxi Zhang, Rui Kang, Daolin Tang.

  Sequestosome 1 (SQSTM1, also known as p62) has emerged as a multifunctional signaling adaptor that bridges autophagy, proteostasis, and inflammation. In this review, we discuss the molecular mechanisms by which SQSTM1 regulates selective autophagy and immune signaling pathways, and how its dynamic modulation shapes host responses during sepsis. We highlight the tissue-specific roles of SQSTM1 in sepsis-associated injury across major organs-including the liver, kidney, heart, lung, brain, and skeletal muscle-and explore its function as a damage-associated molecular pattern (DAMP) in the extracellular milieu. Recent studies implicate extracellular SQSTM1 in metabolic reprogramming and pro-inflammatory cytokine production via INSR signaling, supporting its classification as a novel DAMP and potential therapeutic target. We conclude a stage- and compartment-specific model for SQSTM1 during sepsis: its transition from a protective intracellular autophagy mediator in the early stage to a pathological extracellular DAMP in late stage. Furthermore, we discuss the translational relevance of pharmacological agents that modulate SQSTM1 levels or activity to restore immune balance and organ homeostasis. A better understanding of SQSTM1's dual roles in immune activation and resolution could open new avenues for precision therapies in sepsis.

Keywords:  SQSTM1/p62; autophagy; damage-associated molecular pattern (DAMP); inflammation; sepsis

DOI:  https://doi.org/10.3390/cells15070652
Transl Cancer Res. 2026 Mar 31. 15(3): 193

GPR176 represses mitophagy to promote the progression of osteosarcoma by facilitating mTORC1 activity via PI3K-AKT pathway.

Jiyong Jiang, Bowen Zheng, Jing Wang, Yi Fang, Lianbo Yang, Jinghang Lv, Haidong Liang.

   Background: Osteosarcoma (OS) is a common primary malignant tumor of the bone. It is reported that abnormal GPR176 expression contributes to the occurrence and subsequent progression of tumors. However, the role of GPR176 in OS has not been elucidated. Thus, the aim of this study was to evaluate the role of GPR176 in the progression of OS.
Methods: The expression level and prognosis of GPR176 were explored based on Gene Expression Omnibus (GEO), TARGET and Genotype-Tissue Expression (GTEx) databases, as well as the involved pathways. Effects of GPR176 on the proliferation, migration, invasion, and apoptosis of U2OS cells, as well as in a mouse tumor xenograft model. Multiple parameters were employed to explore the role of GPR176 in mitophagy, including mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitophagy-related proteins. The protein levels of downstream substrates of mTORC1 were analyzed by Western blot.
Results: The expression level of GPR176 was obviously elevated in OS, and increased GPR176 expression associated with poor prognosis in patients with OS. Gene Set Enrichment Analysis (GSEA) showed that GPR176 is mainly involved in the oxidative phosphorylation, retinol metabolism, and ErbB signaling pathways. GPR176 knockdown suppressed the proliferation, migration, and invasion of U2OS cells and enhanced their apoptosis. GPR176 downregulation also induced mitophagy in U2OS cells, as evidenced by an increase in ROS levels; a decrease in MMP, adenosine triphosphate (ATP), and mitochondrial DNA (mtDNA); and concomitant changes in mitophagy-related proteins. GPR176 knockdown suppresses mTORC1 activity in U2OS cells. Moreover, GPR176 knockdown represses the growth of tumor xenografts in vivo while promoting mitophagy. The levels of phosphorylated-mechanistic target of rapamycin complex 1 (p-mTORC1)/mTORC1, p-v-akt murine thymoma viral oncogene homolog 1 (AKT)/AKT, and p-phosphatidylinositol-3 kinase (PI3K)/PI3K were significantly downregulated following GPR176 knockdown.
Conclusions: GPR176 is upregulated in OS and is associated with a poor prognosis. GPR176 suppresses mitophagy to promote OS progression by facilitating mTORC1 activity via the PI3K-AKT pathway.

Keywords:  GPR176; Osteosarcoma (OS); PI3K-AKT pathway; mTORC1; mitophagy

DOI:  https://doi.org/10.21037/tcr-2025-2146
Cancer Lett. 2026 Apr 11. pii: S0304-3835(26)00267-3. [Epub ahead of print] 218504

Nitroalkenes Exploit Dependence on Autophagy-Lysosome Pathway in PARPi-Resistant Triple Negative Breast Cancer.

Lisa Hong, Sanghoon Lee, Leonard Frisbie, Yaoning Zhao, John J Skoko, Christopher Merkel, Tetsushi Kataura, Viktor I Korolchuk, Lan Coffman, Adrian V Lee, Bruce A Freeman, Francisco J Schopfer, Carola A Neumann.

Lack of DNA double-strand break repair efficiency exquisitely sensitizes cancers to poly-ADP ribose polymerase inhibitors (PARPi). Unfortunately, resistance to PARPi poses an insurmountable challenge for patients. Mechanisms that confer insensitivity to PARPi therapy include enhanced DNA damage repair and autophagy. Natural and non-natural unsaturated fatty acid nitroalkene derivatives (NFA) show anticancer actions that sensitize TNBC cells to PARPi and other DNA-damaging treatments. We reveal that nitro-oleic acid (OA-NO2) re-sensitizes PARPi-resistant TNBC cells to PARPi. RNA-seq analysis of clinically relevant mutBRCA1 PARPi-resistant TNBC cell lines exhibited upregulation in autophagy and lysosomal pathways. Bio-orthogonal analysis identified the autophagy regulator SQSTM1/p62 as a novel OA-NO2 target, alkylating two redox-sensitive Cys residues of p62 (Cys105 and Cys113). These Cys are essential for p62 regulation of autophagy and mimicked the effects of p62 Cys105 and Cys113Ala mutants and when alkylated by OA-NO2 showed impaired p62 oligomerization, degradation, and inhibition of autophagy. Combination treatment of PARPi-resistant TNBC with a PARPi and OA-NO2 identified the most synergistic HSA scores and inhibited p62-associated autophagy and lysosome function. These data underscore the clinical potential of OA-NO2 for treating PARPi-resistant TNBC patients.

DOI: https://doi.org/10.1016/j.canlet.2026.218504
bioRxiv. 2026 Apr 08. pii: 2026.04.06.710936. [Epub ahead of print]

Impaired mitochondrial stress signaling mediates bone loss in male mice in the absence of BNIP3.

Li Tian, Victoria Van Berlo, Vivin Karthik, Joshua P Passarelli, Victoria E DeMambro, Patience Mudjgiwa, Calvin Vary, Anyonya R Guntur.

Osteoblasts generate bone by secreting collagen and mineralizing it in response to various signaling cues. We have previously shown that the majority of ATP generated by differentiated osteoblasts in response to glucose is through glycolysis in contrast to undifferentiated cells that are more dependent on oxidative phosphorylation. To confirm our previous findings, metabolomics was performed for unlabeled polar metabolites, revealing elevated glycolytic metabolites at the later stages of differentiation. Krebs cycle (TCA cycle) metabolites were also changed confirming metabolic rerouting with differentiation. We hypothesized that an increase in mitophagy shifts ATP generation towards glycolysis resulting in the observed bioenergetic and metabolic changes. Utilizing calvarial osteoblasts isolated from a mitophagy reporter mouse model (MitoQC), an increase in mitophagy and the mitophagy receptor, Bnip3, was observed with osteoblast differentiation. KD of Bnip3 in osteoblasts inhibited differentiation and mineralization arising from impaired mitochondrial function. In vivo, male Bnip3 null mice exhibited a significant decrease in osteoblast numbers resulting in lower bone mass. Mechanistically we identified decreased fusion and increased fission factors, impaired stress signaling and increased proapoptotic factors in the absence of Bnip3 . These data demonstrate for the first time that BNIP3 expression and mitophagy during osteoblast differentiation are necessary for relieving mitochondrial stress to maintain optimal bone mass.

DOI: https://doi.org/10.64898/2026.04.06.710936