bims-auttor 2026-03-08 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–03–08
33 papers selected by
Viktor Korolchuk, Newcastle University

SLC29A1/ENT1 and SLC29A3/ENT3 differentially regulate autophagy.
Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
Chaperone-mediated autophagy: the Achilles heel of the retinal pigment epithelium during age-related macular degeneration.
SLC4A1 mutations that cause distal renal tubular acidosis alter cytoplasmic pH and cellular autophagy.
Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.
Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele.
Delayed forebrain excitatory and inhibitory neurogenesis in STRADA-related megalencephaly via mTOR hyperactivity.
Epigallocatechin-3-gallate suppresses Hepatitis B virus replication through activating the AMPK/TFEB pathway to promote autophagic degradation of viral core protein.
Structural and mechanistic basis of mTORC2 activation of protein kinase AKT/PKB.
Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.
The TBCK-PPP1R21-FERRY3/C12orf4 complex: a RAB5-GAP brake essential for endo-lysosomal homeostasis.
Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.
α-hemolysin targets LGALS3 (galectin 3) to promote intracellular survival of Staphylococcus aureus via lysosomal disruption and autophagy inhibition.
GCN2 in proteostasis: structural logic, signalling networks and disease.
Autocrine SFRP2 (secreted frizzled related protein 2) enhances lung myofibroblast fibrogenic activity by suppressing PINK1-mediated mitophagy initiation.
Duloxetine ameliorates cerebral ischemic injury by inhibiting autophagy.
Dietary restriction in aging and longevity.
Integration of metabolomics and transcriptomics to reveal metabolic characteristics and the role of mTORC1 in β-cell proliferation induced by a short-term high-fat diet.
UBA1 promotes cardiac hypertrophy by suppressing autophagy via targeting ATG5 for ubiquitination.
Increased Smoothened signaling promotes kidney fibrosis through inhibiting autophagy in fibroblasts.
STING1 exacerbates iodinated contrast-induced acute kidney injury by promoting ferroptosis through chaperone-mediated autophagic degradation of FTH1.
USP24 inhibits autophagy in diabetic myocardial disorder by regulating TRAF6-mediated ubiquitination of Beclin-1.
Association of mitochondrial genetic background with pS65-Ub in Lewy body disease.
A compound enhancing lysosomal function reduces tau pathology, microglial reactivity and rescues working memory in 3xTg AD mice.
Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.
Proteostasis, disease and the ageing neuron: Compartmental complexity in non-renewing cells.
Overproduction of 42 Amino Acids Long Amyloid Beta Leads to Activation of Secretory Autophagy and Development of Drusen-Like Structures Originating From Retinal Pigment Epithelium.
ANKFY1 suppresses PDCoV replication by degrading viral nsp8 protein via p62-dependent selective autophagy.
Mitochondrial deficits and activation of autophagy in human iPSC-derived midbrain dopaminergic progenitors from patients with Wilson's disease.
Escitalopram accelerated aging via impaired IIS/autophagy signaling pathway.
Senescence-related myocardial dysfunction: keeping a young heart.
Genistein alleviates Osteoporosis by inhibiting the differentiation and autophagy of osteoclasts via regulating the CYLD/p62/RANKL axis.
USP30 alleviates intestinal ischemia-reperfusion injury by deubiquitinating MFN2 mediating the mitochondrial endoplasmic reticulum pathway.

Autophagy. 2026 Mar 05. 1-21

SLC29A1/ENT1 and SLC29A3/ENT3 differentially regulate autophagy.

Bhawana Bissa, Tejinder Kaur, Arnav Joshi, Rajgopal Govindarajan.

  Despite the well-established role of equilibrative nucleoside transporters (ENTs) in salvaging nucleosides for DNA synthesis, the presence of multiple ENT subfamilies within a single genome suggests putative, non-redundant functions in maintaining cellular homeostasis. In this study, we demonstrate that, in contrast to endolysosomal SLC29A3/ENT3, which promotes macroautophagy/autophagy, cell surface-localized SLC29A1/ENT1 is capable of inhibiting autophagy by suppressing PRKAA/AMPK phosphorylation. Consistent with this, silencing SLC29A1 induces autophagy, whereas silencing SLC29A3 suppresses it. Treatment with adenosine (Ado), a shared substrate of SLC29A1 and SLC29A3, triggers PRKAA/AMPK phosphorylation and autophagy in a concentration-dependent manner. This effect is PRKAA-dependent, as Ado fails to induce autophagy in prkaa-null cells. Mechanistically, elevated SLC29A1 expression promotes increased efflux and decreased intracellular retention of Ado, thereby attenuating PRKAA/AMPK activation and autophagic flux. However, this effect is contingent upon the metabolic state of the cells. Importantly, SLC29A1's regulatory effect is tied to its transport function, as pharmacological inhibition of SLC29A1 transport enhances intracellular Ado accumulation, PRKAA/AMPK phosphorylation, and autophagy. Unlike SLC29A3, which modulates the MTOR pathway, SLC29A1 does not affect MTOR signaling. Instead, it promotes BECN1-BCL2 interaction, thereby inhibiting autophagosome formation. Notably, autophagy itself differentially regulates SLC29A1 and SLC29A3 expression, with compensatory upregulation observed when either is modulated. Finally, slc29a1-/- and slc29a3-/- mice display autophagic proficiency and deficiency, respectively. These findings underscore a dynamic and reciprocal regulatory relationship between SLC29A1 and SLC29A3 in autophagy, offering new avenues for therapeutic modulation in autophagy-related disorders.

Keywords:  AMPK; Adenosine; ENT; autophagy; nucleoside; transporter

DOI:  https://doi.org/10.1080/15548627.2026.2639407
Autophagy Rep. 2026 ;5(1): 2635914

Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.

Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Nobuo N Noda, Tomotake Kanki.

  Mitophagy selectively eliminates damaged or excess mitochondria to maintain mitochondrial homeostasis. During this process, mitochondria need to be fragmented to allow their sequestration within autophagosomes. However, the well-known dynamin-related fission factors, Dnm1 in yeasts and DNM1L/DRP1 in mammals, are dispensable for mitophagy, leaving the underlying mechanism unresolved. In the yeast Saccharomyces cerevisiae, the identification of the mitochondrial intermembrane space protein Atg44 (autophagy-related 44) uncovered the existence of a new class of proteins, mitofissin, involved in mitochondrial fission during mitophagy. Whether Atg44 alone is sufficient for mitophagy-associated fission remained unclear. Our recent study identified Mfi2 (mitofissin 2) as a mitochondrial outer membrane-resident mitofissin that is required for efficient mitophagy and acts independently of Dnm1. Our findings indicate that mitophagy-associated mitochondrial fission is driven by mitofissins acting from both the inner and outer mitochondrial membranes. Here, we discuss remaining issues, including how mitofissin activities are regulated and how their function is modulated by mitochondrial lipids such as cardiolipin.

Keywords:  Atg44; Dnm1; Mfi2; mitochondrial fission; mitofissin; mitophagy

DOI:  https://doi.org/10.1080/27694127.2026.2635914
Autophagy. 2026 Mar 04. 1-3

Chaperone-mediated autophagy: the Achilles heel of the retinal pigment epithelium during age-related macular degeneration.

Juan Ignacio Jiménez-Loygorri, Ana Maria Cuervo, Deborah A Ferrington, Patricia Boya.

  Chaperone-mediated autophagy (CMA) is a selective autophagy pathway that targets specific proteins containing a KFERQ-like motif for lysosomal degradation. It has been shown by us and others that CMA decreases during physiological aging in most tissues, and its impairment is associated with increased incidence of age-related pathologies, such as cardiovascular disease, neurodegenerative disorders or sarcopenia. However, its involvement in age-related macular degeneration (AMD), a prevalent progressive maculopathy that leads to bilateral central vision loss, had not been explored. In the early stages of AMD, the retinal pigment epithelium (RPE), a monolayer of cells that provides trophic support to photoreceptors, already presents major morphological and functional alterations but the cause of this cell type-specific vulnerability is unknown. In our latest work, we analyzed human donor RPE samples and found that CMA is selectively impaired in the RPE of AMD patients compared to healthy donors. These alterations lead to the accumulation of undegraded CMA substrates and untimely recycling of other proteins. Crucially, these findings are conserved in donor-derived iPSC-RPE models. We used this clinically relevant model to assess the consequences of dysfunctional CMA in AMD and found that it caused proteotoxicity, increased oxidative damage, and altered metabolism. Most importantly, using the new-generation CMA activator CA77.1, we restored proteostasis in AMD iPSC-RPE. Our findings shed light on the selective vulnerability of the RPE in AMD and provide evidence in support of CMA as a novel druggable target against AMD.

Keywords:  Age-related macular degeneration; chaperone-mediated autophagy; oxidative stress; proteostasis; retinal pigment epithelium

DOI:  https://doi.org/10.1080/15548627.2026.2636093
Elife. 2026 Mar 04. pii: RP108253. [Epub ahead of print]14

SLC4A1 mutations that cause distal renal tubular acidosis alter cytoplasmic pH and cellular autophagy.

Grace Essuman, Midhat Rizvi, Ensaf Almomani, Shahid A K M Ullah, Sarder M A Hasib, Forough Chelangarimiyandoab, Priyanka Mungara, Manfred J Schmitt, Marguerite Hureaux, Rosa Vargas-Poussou, Nicolas Touret, Emmanuelle Cordat.

  Distal renal tubular acidosis (dRTA) is a disorder characterized by the inability of the collecting duct system to secrete acids during metabolic acidosis. The pathophysiology of dominant or recessive SLC4A1 variant-related dRTA has been linked with the mis-trafficking defect of mutant kAE1 protein. However, in vivo studies in kAE1 R607H dRTA mice and humans have revealed a complex pathophysiology implicating a loss of kAE1-expressing intercalated cells and intracellular relocation of the H+-ATPase in the remaining type-A intercalated cells. These cells also displayed accumulation of ubiquitin and p62 autophagy markers. The highly active transport properties of collecting duct cells require the maintenance of cellular energy and homeostasis, a process dependent on intracellular pH. Therefore, we hypothesized that the expression of dRTA variants affects intracellular pH and autophagy pathways. In this study, we report the characterization of newly identified dRTA variants and provide evidence of abnormal autophagy and degradative pathways in mouse inner medullary collecting duct cells and kidneys from mice expressing kAE1 R607H dRTA mutant protein. We show that reduced transport activity of the kAE1 variants correlated with increased cytosolic pH, reduced ATP synthesis, attenuated downstream autophagic pathways pertaining to the fusion of autophagosomes and lysosomes and/or lysosomal degradative activity. Our study elucidated a close relationship between the expression of defective kAE1 proteins, reduced mitochondrial activity, and decreased autophagy and protein degradative flux.

Keywords:  cell biology; kidney; mouse; transgenic animals

DOI:  https://doi.org/10.7554/eLife.108253
Mol Biol Cell. 2026 Mar 04. mbcE25110560

Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.

Yingying Sun, Xudong Fu, Yi Li, Mengfan Peng, Lei Yang.

Aging is a complex biological process that heightens susceptibility to age-related diseases, often driven by declining mitochondrial function. Mitophagy, the selective removal of damaged mitochondria, is a key quality-control mechanism essential for maintaining cellular health, and its decline has been closely linked to aging. However, the specific role of mitophagy in cellular senescence, a hallmark of aging, remains insufficiently understood, largely due to the lack of methods to manipulate mitophagy. In this study, we employed UMI-77, a new potent mitophagy activator, to evaluate its effects on senescence in mouse mesenchymal stem cells (MSCs). Our results show that UMI-77 preserves mitochondrial integrity and effectively delays cellular senescence through mitophagy. Mechanistically, UMI-77 markedly suppressed the senescence-associated secretory phenotype (SASP). Together, our findings reveal a new anti-aging therapeutic application for UMI-77 by targeting senescence-associated chronic inflammation through mitophagy induction and SASP reduction.

DOI: https://doi.org/10.1091/mbc.E25-11-0560
Biochim Biophys Acta Mol Basis Dis. 2026 Mar 03. pii: S0925-4439(26)00060-8. [Epub ahead of print] 168211

Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele.

Sandra A Niño, Oskar Barrios-Camus, Eduardo Silva-Pavez, J César Cárdenas, Christian González-Billault.

  The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (sAD), yet its cell-autonomous effects remain poorly understood. While young, asymptomatic APOE4 carriers exhibit abnormal brain metabolism, the mechanistic link between mitochondrial dysfunction and lysosomal-autophagic failure remains unclear. In this study, we conducted a comprehensive analysis of primary human fibroblasts from APOE3 controls, APOE4, and sAD donors to assess mitochondrial bioenergetics, oxidative stress, autophagy, and lysosomal function. APOE4 fibroblasts displayed increased mitochondrial content-associated markers (PGC1α, mtDNA) accompanied by reduced respiratory capacity, elevated proton leak, and excessive mitochondrial ROS. In parallel, APOE4 fibroblasts showed impaired autophagic flux and reduced LC3-TOMM20 colocalization, indicating defective mitophagy. Lysosomal proteolytic activity, assessed using DQ-BSA, was significantly reduced and remained unresponsive under to starvation, in contrast to the partial recovery observed in sAD cells. Pharmacological targeting of mitochondrial ROS with site-specific inhibitors revealed that complex III-derived ROS is the predominant driver of redox stress in APOE4 fibroblasts, while complex I contributes primarily in sAD. Notably, selective inhibition of complex III-derived ROS with S3QEL restored lysosomal degradation, autophagic flux, and mitochondrial respiration in APOE4 cells. Together, these findings demonstrate that mitochondrial oxidative stress disrupts the mitochondria-lysosome axis in an APOE4-specific manner, revealing early and mechanistically distinct vulnerabilities that may precede neurodegeneration. Our results challenge the notion that APOE4 merely amplifies AD pathology and instead identity site-specific redox signaling as a promising target for allele-informed interventions.

Keywords:  APOE4; Autophagy; Human fibroblasts; Lysosome; Mitochondria; Mitochondrial complex III; S3QEL

DOI:  https://doi.org/10.1016/j.bbadis.2026.168211
Stem Cell Reports. 2026 Mar 05. pii: S2213-6711(26)00044-5. [Epub ahead of print] 102833

Delayed forebrain excitatory and inhibitory neurogenesis in STRADA-related megalencephaly via mTOR hyperactivity.

Tong Pan, Grace Lin, Xuan Li, Debora VanHeyningen, John C Walker, Sahej Kohli, Aiswarya Saravanan, Amrita Kondur, Daniel C Jaklic, Saul Pantoja-Gutierrez, Shivanshi Vaid, Julie Sturza, Ken Inoki, Tomozumi Imamichi, Weizhong Chang, Louis T Dang.

  Biallelic pathogenic variants in STRADA (STE20-related adaptor alpha), an upstream regulator of the mechanistic target of rapamycin (mTOR) pathway, result in megalencephaly, drug-resistant epilepsy, and severe intellectual disability. This study explores how mTOR pathway hyperactivity alters cell fate specification in dorsal and ventral forebrain development using STRADA knockout human stem cell-derived brain organoids. In both dorsal and ventral forebrain STRADA knockout organoids, neurogenesis is delayed, with a predilection for progenitor renewal, increased proliferation and an expanded outer radial glia population. Ventrally, interneuron subtypes shift to an increase in neuropeptide Y-expressing cells. Inhibition of the mTOR pathway with rapamycin rescues most phenotypes. When mTOR pathway variants are present in all cells of the developing brain, overproduction of interneurons and altered interneuron cell fate may underlie mechanisms of megalencephaly, epilepsy, and cognitive impairment. Our findings suggest that mTOR inhibition during fetal brain development could be a potential therapeutic strategy in STRADA deficiency.

Keywords:  PMSE syndrome; STRADA; brain organoid; cell fate specification; epilepsy; interneuron development; mTOR; mTORC1; mammalian target of rapamycin; mechanistic target of rapamycin

DOI:  https://doi.org/10.1016/j.stemcr.2026.102833
Chin J Nat Med. 2026 Mar;pii: S1875-5364(26)61105-3. [Epub ahead of print]24(3): 300-312

Epigallocatechin-3-gallate suppresses Hepatitis B virus replication through activating the AMPK/TFEB pathway to promote autophagic degradation of viral core protein.

Yuling Yang, Di Yang, Yuxuan Yang, Zhe Wang, Lianhui Li, Maolong Wang, Jiayi Xu, Bingqiang Zhang, Lin Hou, Zibin Tian, Ning Li.

  Epigallocatechin-3-gallate (EGCG), a major polyphenolic compound in green tea, exhibits anti-viral activity against multiple viruses, including hepatitis B virus (HBV). However, its role in HBV replication and the underlying mechanisms remain incompletely understood. In this study, we investigated the effects of EGCG on HBV replication and its modulation of autophagy using two established HBV cell models. Our results show that EGCG significantly reduces secreted levels of hepatitis B surface antigen (HBsAg) and HBV deoxyribonucleic acid (DNA), as well as intracellular HBV DNA replicative intermediates, encapsidated pregenomic ribonucleic acid (pgRNA), and core protein (HBc), without affecting total HBV messenger RNAs (mRNAs) or pgRNA levels. EGCG enhances autophagic flux, evidenced by increased autophagosome formation and accelerated turnover of the selective autophagy receptor p62 and LC3-Ⅱ. This enhanced autophagy promotes HBc degradation. Pharmacological inhibition of autophagy with 3-methyladenine (3-MA), chloroquine (CQ), or bafilomycin A1 (BafA1) abolished the suppressive effect of EGCG on HBV. Notably, treatment with CQ or BafA1 together with EGCG markedly increased HBV production by blocking autophagic degradation and inducing accumulation of autophagosomes-effects similar to those induced by the autophagy activator rapamycin, which facilitates HBV replication. Mechanistically, EGCG activates the adenosine 5'-monophosphate-activated protein kinase (AMPK)/transcription factor EB (TFEB) signaling axis, leading to enhanced lysosomal biogenesis and ATP production, thereby promoting autophagic clearance. Pharmacological or genetic inhibition of AMPK attenuated TFEB transcriptional activity, suppressed lysosomal biogenesis and ATP generation, impaired autophagic degradation, increased HBc levels, and ultimately enhanced HBV replication. Conversely, pharmacological activation of AMPK produced opposing effects. These findings reveal a novel mechanism by which EGCG inhibits HBV: EGCG promotes autophagic degradation of the viral core protein via activation of the AMPK/TFEB signaling pathway.

Keywords:  AMPK; Autophagy; EGCG; HBV; Lysosome biogenesis; TFEB

DOI:  https://doi.org/10.1016/S1875-5364(26)61105-3
Biochem J. 2026 Mar 04. 483(3): 375-389

Structural and mechanistic basis of mTORC2 activation of protein kinase AKT/PKB.

Nam Chu, Nhat Le, Ouada Nebie, Sammi Yang.

  The PI3K/AKT/mTOR signaling pathway is crucial for regulating essential cellular processes such as growth, survival, metabolism, and protein synthesis. Dysregulation of this pathway is strongly associated with diseases like cancer, where it drives uncontrolled cell proliferation and survival. The mTOR kinase forms two multiprotein complexes, mTORC1 and mTORC2, which govern distinct signaling pathways. mTORC1, regulated by nutrients, controls protein synthesis, cell growth, and autophagy, while mTORC2 acts as a central node in phosphoinositide 3-kinase (PI3K) and Ras signaling, often disrupted in cancer and diabetes. AKT, recruited by PIP3 to the plasma membrane, is phosphorylated by PDK1 and mTORC2, enabling it to regulate various cellular functions. Notably, mTORC2 selectively phosphorylates AKT and PKC but no other closely related kinases targeted by mTORC1, reflecting a high degree of substrate specificity. This specificity is due to structural elements in AKT that interact with the mTORC2 subunit mSin1 as revealed by recent studies using semisynthetic probes, paving the way for the design of mTORC2-specific inhibitors. Given the pathway's significant role in disease progression, particularly cancer, targeting the AKT/mTOR axis holds considerable therapeutic promise. However, challenges remain due to the complex regulation and feedback mechanisms in this pathway. Emerging combination therapies show promise in overcoming these obstacles. This review highlights the intricate regulation of the AKT/mTOR pathway and its potential for developing targeted therapies.

Keywords:  AKT; cell signaling; mTOR; posttranslational modifications; protein kinase

DOI:  https://doi.org/10.1042/BCJ20253108
Front Cell Neurosci. 2026 ;20 1738415

Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.

Georgie Lines, Martin Helley, Sébastien Gillotin, Janet Brownlees, James Duce, Phillip Smethurst.

  Neurodegenerative proteinopathies are characterized by impaired protein clearance and the accumulation of misfolded or aggregated proteins, ultimately leading to neuronal death. The two principal pathways responsible for protein degradation in cells are the ubiquitin proteasome system (UPS) and autophagy. Emerging evidence indicates that these pathways share regulatory components and engage in extensive crosstalk. In this review, we summarize the mechanisms of the UPS and autophagy, highlight their points of interaction, and discuss therapeutic opportunities to modulate both systems in parallel to enhance protein clearance in neurodegenerative disease.

Keywords:  UPS—ubiquitin proteasome system; autophagy; neurodegenearation; neurodegenerative diseases; proteasome; therapeutics

DOI:  https://doi.org/10.3389/fncel.2026.1738415
Autophagy. 2026 Mar 06.

The TBCK-PPP1R21-FERRY3/C12orf4 complex: a RAB5-GAP brake essential for endo-lysosomal homeostasis.

Yingji Chen, Xiayun Xu, Yi Zheng, Hongyan Wang, Chenji Wang.

  TBCK syndrome is a severe neurodevelopmental disorder characterized by hypotonia, intellectual disability, and progressive neurodegeneration. While the TBCK gene has been implicated in MTOR signaling, its primary molecular function has remained controversial. In a recent study, we identify TBCK as the catalytic core of a heterotrimeric complex comprising TBCK, PPP1R21, and FERRY3/C12orf4. This complex functions as a specific GTPase-activating protein (GAP) for RAB5. TBCK deficiency or missense mutations of its key residues in the RABGAP-TBC domain lead to constitutive RAB5 hyperactivation, which blocks the transition from early to late endosomes and results in the formation of massively enlarged RAB5-positive endosomes. Furthermore, this RAB5 hyperactivation drives the constitutive activation of the PIK3C3/VPS34 complex. These defects culminate in a failure of lysosomal enzyme delivery and a secondary collapse of macroautophagic/autophagic flux. These findings redefine TBCK syndrome as a primary disorder of endosomal dynamics and highlight the TBCK-PPP1R21-FERRY3 axis as a critical "brake" for maintaining neuronal homeostasis.

Keywords:  Autophagic flux; CLN15; RAB5; TBCK syndrome; endosomal trafficking; lysosomal storage disease; neurodegeneration

DOI:  https://doi.org/10.1080/15548627.2026.2642337
Curr Opin Cell Biol. 2026 Mar 05. pii: S0955-0674(26)00015-3. [Epub ahead of print]100 102627

Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.

Akriti Prashar, Rosa Puertollano.

Mitochondria are highly dynamic and multifaceted organelles that perform essential cellular functions such as producing energy, regulating metabolism, and orchestrating immune responses. Lysosomes are crucial signaling hubs that are important for nutrient sensing, signal transduction, and regulation of cellular degradation and recycling processes including the removal of damaged mitochondrial components or entire mitochondria. Together, these two organelles perform critical cellular functions. Emerging evidence links defects in both organelles to multiple diseases, underscoring how their functions are intricately linked. To coordinate their activities, mitochondria and lysosomes engage in bidirectional crosstalk, enabling reciprocal regulation of their respective functions. These 'organelle conversations' can occur through direct interactions at membrane contact sites where both organelles physically interact via stabilization by molecular tethers, or at a distance through signaling pathways. Here we discuss recent progress in our understanding of the mechanisms underlying mitochondria-lysosome crosstalk and how this communication is altered in pathological conditions.

DOI: https://doi.org/10.1016/j.ceb.2026.102627
Autophagy. 2026 Mar 05.

α-hemolysin targets LGALS3 (galectin 3) to promote intracellular survival of Staphylococcus aureus via lysosomal disruption and autophagy inhibition.

Yanhao Zhang, Zhuo Zhao, Pu Han, Jianxun Qi, Mingzhou Zhang, Liting Wang, Yumin Meng, Jing Li, Yun Yang, Longlong Chen, Jinyong Zhang, Jiang Gu, Ping Luo, Weijun Zhang, Liangbo Sun, Quanming Zou, Hao Zeng.

  Intracellular persistence caused by Staphylococcus aureus (S. aureus) is among the primary reasons for recurrence and difficulty in eradicating S. aureus infections. In this study, we identify the secreted protein Hla (α-hemolysin) by S. aureus as a key factor enabling its intracellular retention. We demonstrate that intracellular Hla secreted by S. aureus inhibits lysosome degradation via disrupting lysosomal function, which sustains the survival and proliferation of S. aureus within autophagosomes. Furthermore, we identify the interaction between Hla and intracellular LGALS3 (galectin 3) as crucial for sustaining intracellular survival of S. aureus, resolve the structure of the Hla-LGALS3 complex, and identify the Loop 68-75 region of Hla as the key binding domain with LGALS3. Moreover, the interaction between Hla and LGALS3 influences the recruitment of PDCD6IP/ALIX (programmed cell death 6 interacting protein) to the damaged lysosomal surface, resulting in disruption of lysosomal degradative function. Our results highlight an unknown role of Hla in the intracellular survival of S. aureus and suggest that interrupting the interaction between Hla and LGALS3 May be a potential therapeutic strategy for treating S. aureus infections.

Keywords:  Autophagy; galectin 3; intracellular survival; lysosome; staphylococcus aureus; α-hemolysin

DOI:  https://doi.org/10.1080/15548627.2026.2642331
FEBS J. 2026 Mar 04.

GCN2 in proteostasis: structural logic, signalling networks and disease.

JiaYi Zhu, Stefan J Marciniak.

  Proteostasis is the finely tuned balance of protein synthesis, folding and degradation essential for cellular health. When this equilibrium is disrupted, misfolded proteins accumulate, triggering adaptive stress responses such as the unfolded protein response and the integrated stress response (ISR). Central to the ISR is the kinase GCN2, a sensor of amino acid deprivation and ribosomal stress. Upon activation, GCN2 phosphorylates eIF2α, dampening global translation while selectively enhancing the synthesis of the stress-responsive transcription factors ATF4 and CHOP. ATF4 orchestrates a broad transcriptional programme that supports amino acid metabolism, redox homeostasis, autophagy and proteasomal degradation, which are key processes for restoring proteostasis. Beyond its canonical role, GCN2 interfaces with other regulatory networks modulating mTORC1 to promote autophagic clearance of damaged proteins and organelles, facilitating stress granule formation, and integrating signals from oxidative and endoplasmic reticulum stress to rebalance the proteome. Dysregulated GCN2 activity has been implicated in diverse pathologies including neurodegeneration, cancer and pulmonary vascular disease, positioning it as a promising therapeutic target. In this review, we explore how GCN2 links nutrient sensing to translational control and metabolic adaptation, and how its central role in proteostasis may inform new strategies for treating diseases driven by protein misfolding and stress pathway imbalance.

Keywords:  GCN2; amino acid sensing; integrated stress response; proteostasis; translational control

DOI:  https://doi.org/10.1111/febs.70480
Autophagy. 2026 Mar 06.

Autocrine SFRP2 (secreted frizzled related protein 2) enhances lung myofibroblast fibrogenic activity by suppressing PINK1-mediated mitophagy initiation.

Yingying Lin, Tianxiang Lei, Yifan Jia, Meiling Yao, Xiaofeng Wang, Shaojie Huang, Zhongxing Wang, Xiaofan Lai.

  Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease driven by persistent activation of pulmonary myofibroblasts, but the regulatory mechanisms sustaining this pathological state remain incompletely understood. Using single-cell RNA sequencing (scRNA-seq), we identified SFRP2 (secreted frizzled related protein 2) as a critical mediator of profibrotic myofibroblasts in IPF lungs. Functional studies revealed that SFRP2 acted in an autocrine manner to promote myofibroblast activation and extracellular matrix (ECM) production. Mechanistically, SFRP2 activated FZD5-mediated non-canonical WNT-Ca2 + signaling, leading to PPP3/calcineurin-dependent translocation of PINK1 from the outer to the inner mitochondrial membrane (IMM), where it was degraded, thereby inhibiting PINK1-mediated mitophagy. Furthermore, therapeutic intervention with AAV6-shSfrp2, SFRP2-neutralizing antibody, or the autophagy inducer rapamycin significantly ameliorated lung fibrosis in bleomycin (BLM)-induced mouse models. Our results define a novel autocrine SFRP2-mitophagy regulatory axis that perpetuates myofibroblast activation and represents a promising therapeutic target for pulmonary fibrosis.

Keywords:  Extracellular matrix; PINK1-mediated mitophagy; WNT-Ca2 + signaling; idiopathic pulmonary fibrosis; mitochondrial reactive oxygen species; myofibroblast fibrogenic activity

DOI:  https://doi.org/10.1080/15548627.2026.2642341
Autophagy. 2026 Mar 05.

Duloxetine ameliorates cerebral ischemic injury by inhibiting autophagy.

Alice Viotti, Claudia Molinaro, Jessica Perego, Andrea Fossaghi, Chiara Parravicini, Eliana Laurenzano, Antonella Borreca, Marco Piccoli, Luigi Anastasia, Susanna Manenti, Annamaria Finardi, Alessandra Mandelli, Michela Matteoli, Ivano Eberini, Paola Panina, Gianvito Martino, Luca Muzio.

  Ischemic stroke is a severe medical condition characterized by diminished blood flow to the brain, resulting in a shortage of oxygen and nutrients. During ischemia, neurons surrounding the cerebral infarct initiate macroautophagy. However, the implications of this activation for neuronal cell survival are still debated. The identification of new autophagy modulators could aid in understanding autophagy's role in brain ischemia and lay the groundwork for innovative therapeutic strategies aimed at minimizing brain damage in this life-threatening neurological emergency. In this study, we developed a robust and sensitive screening platform to identify autophagy modulators from a library of bioactive compounds. Selected compounds underwent further in vitro validation, leading to the identification of duloxetine, a Food and Drug Administration (FDA)-approved drug, as an effective autophagy inhibitor at low-micromolar concentrations. Following its original characterization, the molecule, a serotonin-norepinephrine re-uptake inhibitor (SNRI) family member, was subsequently tested in young and aged mice subjected to photothrombotic stroke. Our results demonstrated that duloxetine significantly reduced infarct size and improved locomotor performance in mice that had undergone a stroke. Similar protective effects were observed in transgenic mice lacking the autophagy gene Atg5 (autophagy related 5) in SLC17A6/Vglut2+ (solute carrier family 17 member 6) excitatory cortical neurons. Finally, we elucidated the underlying mechanism of action that involves duloxetine-mediated inhibition of TRPM2 (transient receptor potential cation channel subfamily M member 2) ion channels. Altogether, our findings suggest that early autophagy inhibition is neuroprotective in stroke, and duloxetine serves as an effective means of achieving this inhibition.

Keywords:  Brain ischemia; SNRI; TRPM2; duloxetine; macroautophagy

DOI:  https://doi.org/10.1080/15548627.2026.2641616
Nat Aging. 2026 Mar 06.

Dietary restriction in aging and longevity.

Tomas Schmauck-Medina, Sofie Lautrup, Andrea Di Francesco, Sarah J Mitchell, Christoffer Clemmensen, Linda Partridge, George S Roth, Rozalyn M Anderson, Julie A Mattison, Rafael de Cabo, John R Speakman, Arlan Richardson, Donald K Ingram, Richard Weindruch, Mark P Mattson, Evandro F Fang.

Different types of dietary restriction (DR) have been practiced by humans for religious and medical purposes for millennia, but only during the past three decades has the scientific study of DR at cellular and molecular levels proliferated. Here we review the evidence testing a variety of DR paradigms in the context of aging, focusing on mammalian findings. We discuss potential DR mimetics that modulate autophagy, FGF21, AMPK, mTORC1, NAD+ metabolism, SIRTs, GLP-1R and other pathways as well as organismal and cellular adaptations to DR, including the roles of fasting, hunger, changes in body temperature and fat loss. We also consider the potential negative effects of DR such as increased vulnerability to infections and impaired wound healing. Further, we discuss preclinical evidence evaluating the potential of DR to improve healthspan and treat, prevent or delay age-related diseases including cancer, cardiovascular diseases and neurodegeneration. Finally, we consider the future opportunities for translation, and the challenges inherent to this complex research field.

DOI: https://doi.org/10.1038/s43587-026-01091-5
PeerJ. 2026 ;14 e20871

Integration of metabolomics and transcriptomics to reveal metabolic characteristics and the role of mTORC1 in β-cell proliferation induced by a short-term high-fat diet.

Jiajia Wang, Jing Li, Yunshan Li, Mengran Liu, Shan Huang, Wenyi Li.

   Background: Pancreatic β-cell proliferation is essential for maintaining the balance of β-cell mass, and an elevated metabolic load can stimulate their proliferation. Numerous studies have shown that a short-term high-fat diet increases metabolic load without affecting insulin sensitivity, thereby promoting the proliferation of pancreatic β-cells. However, the underlying mechanisms of this effect remain to be fully elucidated.
Results: A model has been constructed in our study to emulate pancreatic β-cell proliferation induced by a short-term high-fat diet, aiming to scrutinize the underlying mechanisms. Integrated transcriptomic and metabolomic analyses suggest that the mTORC1 signaling pathway may be crucial in this induced proliferation. Further analysis revealed that rapamycin, a specific inhibitor of the mTORC1 pathway, can inhibit proliferation induced by the short-term high-fat diet.
Conclusion: Our study confirms the significant role of the mTORC1 signaling pathway in pancreatic β-cell proliferation induced by a short-term high-fat diet.

Keywords:  Short-time high-fat diet; Transcriptomics and metabolomics; mTORC1; β cell proliferation

DOI:  https://doi.org/10.7717/peerj.20871
Cell Commun Signal. 2026 Mar 02.

UBA1 promotes cardiac hypertrophy by suppressing autophagy via targeting ATG5 for ubiquitination.

Qiu-Yue Lin, Wei-Jia Yu, Jia-Xin Li, Wen-Xi Jiang, Shu-Jing Liu, Hai-Lian Bi, Hui-Hua Li.

   BACKGROUND: Pathological cardiac hypertrophy frequently leads to heart failure (HF). UBA1, the key E1 ubiquitin-activating enzyme, initiates ubiquitin-proteasome signaling and contributes to various diseases, yet its mechanism in cardiac hypertrophy remains unclear.
METHODS: Cardiac hypertrophy model was induced by either Ang II stimulation or TAC in vitro and in vivo. Mice received rAAV9-UBA1-siRNA or rAAV9-UBA1 for UBA1 knockdown or overexpression, respectively.
RESULTS: We found UBA1 upregulated in murine and human hypertrophic hearts. Cardiomyocyte-specific UBA1 knockdown protected against TAC-induced hypertrophy, fibrosis, oxidative stress, and dysfunction, with downregulation of ATG5 and autophagy induction, whereas myocardial UBA1 overexpression exacerbated these effects. Mechanistically, UBA1 directly interacted with ATG5 and promoted its ubiquitination for degradation, leading to autophagy inactivation and hypertrophy. Furthermore, ATG5 deletion abrogated the protection of UBA1 knockdown against cardiomyocyte hypertrophy.
CONCLUSIONS: UBA1 regulates cardiac hypertrophy through suppression of ATG5-mediated autophagy and propose UBA1 as a therapeutic target for hypertrophic cardiomyopathy.

Keywords:  ATG5; Autophagy; Cardiac hypertrophy; UBA1; Ubiquitination

DOI:  https://doi.org/10.1186/s12964-026-02761-y
Kidney Int. 2026 Feb 27. pii: S0085-2538(26)00140-7. [Epub ahead of print]

Increased Smoothened signaling promotes kidney fibrosis through inhibiting autophagy in fibroblasts.

Xiaonan Wang, Ye Liang, Jiemei Li, Xiaoxu Wang, Weijie Zhong, Yabing Xiong, Wenting Ye, Canzhen Liu, Xian Ling, Jinhua Miao, Weiwei Shen, Shan Zhou, Ping Meng, Youhua Liu, Fan Fan Hou, Xiaolong Li, Lili Zhou.

   INTRODUCTION: Kidney fibrosis progressively induces kidney function loss, leading to kidney failure. Myofibroblast transition from fibroblast is significantly involved in the development of kidney fibrosis. Previous studies revealed that sonic hedgehog (Shh), the upstream ligand of Smoothened (Smo) receptor signaling, contributes to kidney fibrosis. However, the role of Smo in fibroblast activation remains unclear.
METHODS: Here, fibroblast-specific Smo and β-catenin knockout mice were generated, primary kidney fibroblasts were isolated and cultured. Single-nucleus (snRNA-seq) plus bulk RNA sequencing were performed. Autophagy capacities, including autophagy flux, autophagy vacuoles, and autophagy-related gene expression, were assessed.
RESULTS: From snRNA-seq data of the human atlas combined with bulk RNA sequencing of primary mouse kidney fibroblasts, we discovered Smo was upregulated in kidney fibroblasts in chronic kidney disease (ureteral obstruction, ischemia/reperfusion, Adriamycin nephrosis and 5/6th nephrectomy models). This was accompanied by substantially diminished autophagic capacity. Shh stimulation or ectopic Smo deactivated autophagy, exaggerated myofibroblast proliferation and activation in the fibroblasts. These effects were further enhanced in autophagosome protein ATG5 knockout fibroblasts. Moreover, Smo, through the β-arrestin 1/Src/β-catenin pathway, induced the transcription of mammalian target of rapamycin. This mediated autophagy suppression in fibroblasts, leading to myofibroblast activation and kidney fibrosis. Fibroblast-specific knockout of Smo or β-catenin greatly preserves autophagy capacity and ameliorates kidney fibrosis. Notably, NVP-LDE225, a specific Smo antagonist, effectively restored fibroblast autophagy and retarded kidney fibrotic lesion formation.
CONCLUSIONS: Our study defines a prominent mechanism of myofibroblast activation and supplies a potential avenue for targeting fibroblast Smo to treat chronic kidney disease.

Keywords:  Renal fibrosis; Smo; autophagy; fibroblast; β-catenin

DOI:  https://doi.org/10.1016/j.kint.2026.01.028
Autophagy. 2026 Mar 02. 1-16

STING1 exacerbates iodinated contrast-induced acute kidney injury by promoting ferroptosis through chaperone-mediated autophagic degradation of FTH1.

Ting Wu, Xi Wu, Juan Cai, Cheng-Yuan Tang, Xiu-Fen Wang, Mei-Yu Zeng, Yu-Ting Liu, Ying Tang, Zhi-Wen Liu, Wen Meng, Shao-Bin Duan.

  Iodinated contrast-induced acute kidney injury (CI-AKI) is a common clinical complication with poor prognostic outcomes, yet its molecular mechanisms remain incompletely understood. Ferroptosis, a regulated form of cell death driven by iron overload and lipid peroxidation, has been implicated in CI-AKI. However, its involvement and precise regulation in CI-AKI remain unclear. Here, we identify STING1 (stimulator of interferon response cGAMP interactor 1) as a key mediator of ferroptosis in renal proximal tubular cells (RPTCs). We demonstrate that iodinated contrast media (ICM) activate STING1, triggering ferroptosis. Using proximal tubule-specific sting1 knockout mice and primary RPTCs, we show that Sting1 deficiency mitigates ferroptosis and alleviates CI-AKI. Mechanistically, STING1 interacts with HSPA8/HSC70 (heat shock protein family A (Hsp70) member 8) in patients with acute tubular necrosis and experimental CI-AKI models, facilitating the chaperone-mediated autophagic degradation of FTH1 (ferritin heavy chain 1) and GPX4 (glutathione peroxidase 4). Notably, inhibition of chaperone-mediated autophagy (CMA) via LAMP2A (lysosomal associated membrane protein 2A) knockdown inhibits FTH1 and GPX4 degradation, and attenuates ferroptosis. These findings uncover a novel STING1-driven mechanism linking CMA to ferroptosis in CI-AKI and highlight the STING1 pathway as a potential therapeutic target for contrast-induced renal injury.Abbreviations: 3-MA: 3-methyladenine; AIFM2/FSP1: AIF family member 2, ferroptosis suppressor; CLBD: cytoplasmic ligand-binding domain; CGAS: cyclic GMP-AMP synthase; CI-AKI: contrast-induced acute kidney injury; CMA: chaperone-mediated autophagy; CQ: chloroquine; CTT: C-terminal tail; DHE: dihydroethidium; FTH1: ferritin heavy chain 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GPX4: glutathione peroxidase 4; GSH/GSSG: glutathione/glutathione oxidized; KO: knockout; HK-2 cell: human renal proximal tubular epithelial cell; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; IRI: ischemia-reperfusion injury; KFERQ: CMA recognition pentapeptide; LAMP2A: lysosomal associated membrane protein 2A; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator 4; PT: proximal tubule; RPTCs: renal proximal tubule cells; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TMD: transmembrane domain; WT: wild-type.

Keywords:  Acute kidney injury; HSPA8; STING1; chaperone-mediated autophagy; ferroptosis; iodinated contrast media

DOI:  https://doi.org/10.1080/15548627.2026.2626388
Life Sci. 2026 Mar 03. pii: S0024-3205(26)00105-0. [Epub ahead of print]392 124296

USP24 inhibits autophagy in diabetic myocardial disorder by regulating TRAF6-mediated ubiquitination of Beclin-1.

Shenglin Wu, Yueran Zhou, Mengjuan Shu, Hongwei Zhang, Qiwei Situ, Zhijun Bao, Zuoqi Hu, Jinxiu Zhu.

   AIMS: Although autophagy inhibition is implicated in the onset and progression of diabetic myocardial disorder (DMD), its molecular mechanisms remain poorly understood. Herein, we assessed the regulatory role of the USP24-TRAF6-Beclin-1 pathway in autophagy and its potential therapeutic value in DMD.
MATERIALS AND METHODS: A diabetic mouse model was established using a high-fat diet combined with streptozotocin injection. Primary neonatal mouse cardiomyocytes and H9c2 cells were cultured in vitro under high-glucose and palmitate conditions to mimic DMD. Autophagic flux was assessed by transmission electron microscopy, the mRFP-GFP-LC3 reporter assay, and Western blot analysis of LC3, p62, and Beclin-1. Molecular mechanisms were explored using Co-immunoprecipitation, Western blotting, lentiviral-mediated knockdown or overexpression, and Cell Counting Kit-8 assays.
KEY FINDINGS: USP24 and TRAF6 were upregulated in DMD both in vivo and in vitro, accompanied by decreased Beclin-1, an elevated LC3-II/LC3-I ratio, increased p62, and impaired autophagolysosomal formation. USP24 directly interacted with and deubiquitinated TRAF6, thereby stabilizing its protein. TRAF6 bound to and ubiquitinated Beclin-1, promoting its degradation. Silencing USP24 reduced TRAF6, restored Beclin-1, enhanced autophagic flux, increased Bcl-2, and improved cardiomyocyte viability in DMD. Overexpression of TRAF6 reversed the effects induced by USP24 knockdown.
SIGNIFICANCE: USP24 inhibits autophagy in DMD, specifically by deubiquitinating TRAF6 and stabilizing its expression, while TRAF6 promotes Beclin-1 ubiquitination and degradation. Targeting the USP24 may offer a novel therapeutic strategy for DMD.

Keywords:  Autophagy; Beclin-1; Diabetic cardiomyopathy; Diabetic myocardial disorder; TRAF6; USP24; Ubiquitination

DOI:  https://doi.org/10.1016/j.lfs.2026.124296
Acta Neuropathol. 2026 Mar 04. pii: 23. [Epub ahead of print]151(1):

Association of mitochondrial genetic background with pS65-Ub in Lewy body disease.

Ngan Le Kim Tran, Xu Hou, Michael G Heckman, Fabienne C Fiesel, Shunsuke Koga, Molly M Watkins, Hanna J Sledge, J Raphael Gibbs, Bryan J Traynor, Clifton L Dalgard, Sonja W Scholz, Dennis W Dickson, Wolfdieter Springer, Owen A Ross.

  Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, where respiratory defects and downstream bioenergetic failures arise from impaired mitophagy or the accumulation of damaged mitochondria. Mitophagy is a mitochondrial quality-control pathway in which mitochondria tagged with ubiquitin phosphorylated at Serine 65 (pS65-Ub) are targeted for degradation via the autophagy-lysosome system. We previously identified a significant genome-wide association between apolipoprotein E ε4 [APOE ε4] with pS65-Ub levels in the hippocampus of Lewy body disease (LBD). However, the relationship between genetic background in the mitochondrial genome and the PINK1-PRKN pathway biomarker pS65-Ub remains to be elucidated. In this study, we examined whether mitochondrial DNA (mtDNA) variation contributes to changes in pS65-Ub level in 514 neuropathologically confirmed LBD brains, with replication in an independent cohort of 384 LBD brains. No individual mtDNA haplogroup was significantly associated with pS65-Ub levels after correction for multiple testing (P < 0.005 considered significant); mtDNA haplogroup V exhibited a nominally significant (P < 0.05) association, but this association was not observed in an independent replication series. Our data reveal an overall lack of direct evidence linking mtDNA variations to mitophagy marker pS65-Ub levels in LBD, suggesting that mitochondrial damage is unlikely to be explained by major mtDNA determinants alone and may instead reflect cumulative and multilayered perturbations of mitochondrial function. Single cell analyses combined with larger replication cohorts integrating multi-omics datasets will be essential to validate these findings and to advance the discovery of biomarkers for mitochondrial dysfunction in neurodegeneration.

Keywords:  Lewy body disease; Mitochondrial haplogroup; Neuropathology; mtDNA

DOI:  https://doi.org/10.1007/s00401-026-02993-9
Geroscience. 2026 Mar 06.

A compound enhancing lysosomal function reduces tau pathology, microglial reactivity and rescues working memory in 3xTg AD mice.

Zachary Mayeri, Georgia Woods, Anand Rane, Alex Kifle, Manish Chamoli, Shikha Shukla, Chaska C Walton, Julie K Andersen.

  Recent advancements in Alzheimer's disease (AD) therapeutics have validated the use of amyloid beta (Aβ)-clearing antibodies, which reduce Aβ pathology but leave other disease hallmarks largely unaddressed. Since AD involves multiple pathological processes, additional strategies are needed to target complementary mechanisms. One such target is autophagy, a lysosomal mediated degradation pathway essential for cellular homeostasis that removes toxic protein aggregates and damaged organelles. This process is implicated in AD, as impaired lysosomal function promotes Aβ and tau accumulation. Our laboratory recently identified a novel natural mitophagy inducing compound (MIC) that may serve as a therapeutic intervention for AD. We evaluated the effects of MIC in aged 3xTgAD mice, a transgenic model displaying both Aβ and tau pathology. Mice received either standard diet or diet containing MIC beginning at age 4 months until 20 months on alternating weeks. Age-matched non-transgenic (NonTg) controls were included under standard and MIC-supplemented diets to assess compound effects during normal aging. Neuropathological changes were assessed using immunohistochemistry (IHC) for Aβ, phosphorylated tau (pTau), and microglial reactivity. Cognitive performance was evaluated using the Morris Water Maze (MWM) to assess spatial learning and memory and the Y-maze to measure working memory. At 20 months of age, our neuropathological assessment showed that 3xTgAD mice fed an MIC-supplemented diet had a significant reduction in pTau accumulation and microglial reactivity, although Aβ burden remained unchanged. At 15 months, MIC diet also improved spatial learning and memory in aged NonTg controls but not in 3xTgAD mice. However, in younger 8 month-old 3xTgAD mice, MIC restored working memory performance to NonTg levels, indicating an age-dependent therapeutic response. MIC emerges as a potential modulator of tau pathology and neuroinflammation. As a naturally derived compound, MIC offers potential for combination therapy with FDA-approved Aβ-clearing antibodies, enabling a multimodal approach to AD treatment that addresses amyloid, tau, and microglia-related pathology.

Keywords:  3xTg AD mice; Alzheimer's disease; Autophagy-lysosome pathway activation; Cognitive rescue; Drug treatment; Tau pathology

DOI:  https://doi.org/10.1007/s11357-026-02139-5
NPJ Aging. 2026 Mar 05.

Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.

Claudia Jara, Leslye Venegas-Zamora, Han S Park-Kang, Matías Lira, Micaela Ricca, Sebastian Valenzuela, Cheril Tapia-Rojas.

The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.

DOI: https://doi.org/10.1038/s41514-026-00351-3
Ageing Res Rev. 2026 Feb 27. pii: S1568-1637(26)00065-6. [Epub ahead of print]118 103073

Proteostasis, disease and the ageing neuron: Compartmental complexity in non-renewing cells.

Rosemary A Coleman, Michaela E Johnson, Anna Konopka, Yee Lian Chew.

  Proteostasis, the maintenance of protein homeostasis, is a critical cellular process for neuronal health that declines with age, contributing to neurodegenerative disease. This review examines the molecular architecture of the proteostasis network, how this is disrupted in ageing neurons, and its impact on neuronal function. We discuss unique challenges posed by the complexity arising from distinct neuronal compartments with distinct functions, as well as neurons' high energy demands, and post-mitotic status. We next detail how proteostasis mechanisms differ across neuronal compartments and neural subtypes, and how these differences influence susceptibility to stress and disease. Finally, we explore how these differences shape selective vulnerability in neurodegenerative diseases. By integrating recent transcriptomic and proteomic insights, this review highlights the need for compartment- and cell-type-specific approaches to mitigate proteostasis collapse in the ageing brain.

Keywords:  Ageing; Axon; Dendrite; Neurodegeneration; Proteostasis

DOI:  https://doi.org/10.1016/j.arr.2026.103073
FASEB J. 2026 Mar 15. 40(5): e71608

Overproduction of 42 Amino Acids Long Amyloid Beta Leads to Activation of Secretory Autophagy and Development of Drusen-Like Structures Originating From Retinal Pigment Epithelium.

Johanna Ruuth, Toni Tamminen, Elisa Toropainen, Heikki Tanila, Juha M T Hyttinen, Tarja Malm, Kai Kaarniranta, Ali Koskela.

  Age-related macular degeneration (AMD) is a global vision threatening disease affecting the macular region of the retina. AMD is classified into two forms: dry and wet AMD. There are no effective treatment options available for dry AMD (80% of cases). The cellular pathology includes oxidative stress and dysfunctional autophagy challenging the homeostasis of the retinal pigment epithelial (RPE) cells. Clinical findings include the formation of drusen deposits beneath the RPE cells consisting of 42 amino acids long amyloid beta (Aβ) among other components. However, the origin of drusen remains elusive. The 5xFAD (familiar Alzheimer's disease) mouse model of Alzheimer's disease produces abundant levels of Aβ making it an interesting model to study the possible relationship of Aβ to the formation of extracellular deposits and AMD-like pathology. An immunohistology analysis of the 5xFAD mouse model showed accumulation of autophagic markers SQSTM1 (sequestosome 1) and ubiquitin in the RPE. Concurrently, the markers of secretory autophagy enabling the delivery of the intracellular material to the extracellular lumen were upregulated. Aβ, SQSTM1, ubiquitin, catalase, and TRIM16 (tripartite motif containing 16) shifted age-dependently from intracellular origin to drusen-like deposits beneath the RPE cells. Additionally, classical proteins secreted via secretory autophagy, IL-1β (interleukin 1β), HMGB1 (high mobility group box-1), and ferritin showed similar accumulation which became visible in fundus age-dependently. These findings suggest a role for Aβ in the cellular pathogenesis of AMD. Furthermore, this model showed activated secretory autophagy pathway suggesting a role for Aβ in drusen-like deposition formation.

Keywords:  5xFAD; age‐related macular degeneration; retinal deposits; retinal pigment epithelium; secretory autophagy

DOI:  https://doi.org/10.1096/fj.202502464RRR
Vet Microbiol. 2026 Feb 03. pii: S0378-1135(26)00058-1. [Epub ahead of print]315 110927

ANKFY1 suppresses PDCoV replication by degrading viral nsp8 protein via p62-dependent selective autophagy.

Yufan Xu, Yangyang Zhang, Huixin Zhu, Xiaomeng Yu, Jinxiu Lou, Mingyu Liu, Gongguan Liu, Juan Bai, Ping Jiang, Zhen Yang, Xianwei Wang.

  Porcine deltacoronavirus (PDCoV) is an emerging enteric pathogen that causes severe gastrointestinal disease in neonatal piglets and poses a potential risk of cross-species transmission. Although viral strategies that counteract host immune responses have been widely studied, host factors that restrict PDCoV replication remain poorly characterized. In this study, we identify ANKFY1 as a previously unrecognized host factor that restricts PDCoV replication. PDCoV infection markedly upregulated ANKFY1 expression in LLC-PK1 cells. Using gain- and loss-of-function approaches, we demonstrated that ANKFY1 significantly suppresses PDCoV replication, whereas depletion of ANKFY1 restored both viral RNA synthesis and progeny virus production. Mechanistically, ANKFY1 specifically interacts with the viral nonstructural protein nsp8 and promoted its degradation. We further show that ANKFY1 recruits the E3 ubiquitin ligase Cullin 3 to catalyze K63/K33-linked ubiquitination of nsp8, primarily at lysine 58. The ubiquitinated nsp8 is subsequently recognized by the selective autophagy receptor p62 and delivered to autolysosomes for degradation. Disruption of p62 or autophagy flux abolished ANKFY1-mediated nsp8 degradation and antiviral activity, underscoring the essential role of the ANKFY1-Cullin3-p62 axis. Collectively, our results reveal a novel host defense mechanism in which ANKFY1 mediates selective autophagic degradation of PDCoV nsp8 to restrict viral replication. This study not only advances our understanding of PDCoV-host interactions but also identifies the ANKFY1-Cullin3-p62 pathway as a potential target for developing of broad-spectrum antiviral strategies.

Keywords:  ANKFY1; Cullin3; Nsp8 protein; P62; PDCoV; Selective autophagy

DOI:  https://doi.org/10.1016/j.vetmic.2026.110927
Stem Cell Res. 2026 Feb 24. pii: S1873-5061(26)00042-5. [Epub ahead of print]92 103946

Mitochondrial deficits and activation of autophagy in human iPSC-derived midbrain dopaminergic progenitors from patients with Wilson's disease.

Shu-Hong Wang, Xiao-Zhong Jing, Xiao-Ping Wang.

  Wilson's disease (WD) is a disorder of copper metabolism that can cause severe neurological manifestations, including parkinsonism. This suggests that nigrostriatal dopaminergic system dysfunction may contribute to neurological WD. However, pathological changes in the central nervous system associated with WD remain poorly understood due to limited patient samples and the absence of animal models with robust neurological phenotypes. In our previous research, we established an induced pluripotent stem cell (iPSC) line from a WD patient carrying the R778L mutation. Here, we successfully differentiated iPSCs from both WD patients and healthy controls into midbrain dopaminergic progenitor cells (WD-mDAPCs and HC-mDAPCs, respectively). WD-mDAPCs exhibited cell-type-specific mitochondrial vulnerability, indicating that mitochondrial dysfunction may play an important role in WD neuropathogenesis. Furthermore, an increased number of autophagosomes was detected in WD-mDAPCs. Thus, we have established a novel cellular model for investigating neural abnormalities in WD. Therapeutic strategies targeting mitochondrial protection and autophagy activation may alleviate copper-induced neurological impairment in WD.

Keywords:  Autophagyactivation; Midbraindopaminergicprogenitorcells; Mitochondrialdysfunction; Wilson’sdisease

DOI:  https://doi.org/10.1016/j.scr.2026.103946
Geroscience. 2026 Mar 05.

Escitalopram accelerated aging via impaired IIS/autophagy signaling pathway.

Zi-Yi Chen, Cao-Yan Qi, Ji Feng, Kun Xue, Hong-Bo Quan, Jing Zhou, Wu-Zhong Liu, Guo-Dong Lu.

  Escitalopram is one of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs) for treating depression and anxiety disorders in adolescents and pregnant women. While some SSRIs have been reported to extend lifespan, the impact of escitalopram on the aging process remains unclear. Here, we demonstrated that escitalopram administration at juvenile, young, or old adult stages significantly shortens lifespan and impairs healthspan in Caenorhabditis elegans. This pro-aging phenotype was accompanied by increased lipofuscin accumulation and reduced stress resistance. Mechanistically, escitalopram induced mitochondrial dysfunction, characterized by elevated ROS production and diminished membrane potential. Genetic analyses established that these detrimental effects are mediated by the insulin/IGF-1 signaling (IIS) pathway, leading to the subsequent suppression of autophagy. Mutant worms in IIS (daf-2, daf-16, and sod-3) or autophagy-related genes (unc-51, atg-3, and atg-13) abolished the lifespan reduction. Consistently, in human BJ fibroblasts, escitalopram triggered premature cellular senescence, marked by increased SA-β-gal activity and upregulated P53/P21 expression, and impaired cell proliferation, which was mediated by impairment in fusion between autophagosome and lysosome. Collectively, our cross-species study reveals that escitalopram, contrary to some other SSRIs, accelerates aging through impairment of the evolutionarily conserved IIS/autophagy axis, suggesting its potential pro-aging toxicity with long-term use.

Keywords:   Caenorhabditis elegans ; Aging; Autophagy; Escitalopram; Insulin-like growth factor I

DOI:  https://doi.org/10.1007/s11357-026-02190-2
Eur Heart J. 2026 Mar 06. pii: ehag095. [Epub ahead of print]

Senescence-related myocardial dysfunction: keeping a young heart.

Ramzi A Ajjan, Robert T R Huckstepp, Naveed Akbar, Johann Bauersachs, Jesher Ching Wai Lok, Juel Choppy-Madeleine, Gary Christopher, Mayank Dalakoti, Emily Dawson-Plincke, John Dodds, Georgina M Ellison-Hughes, Costanza Emanueli, Christopher H George, Anushka Goyal, Victoria Higginbotham, Lorenz Holzner, Venkateswarlu Kanamarlapudi, Paolo Madeddu, Claudio Mauro, Fiona Lewis-McDougall, Andrew J Murray, Renita Peter Damien Genetus, Emma Short, Mark A Sussman, Adriana A S Tavares, Samuel Thompson, Morya Wadodkar, Stuart R G Calimport, Barry L Bentley.

The heart, a vital organ, works without interruption and constantly adjusts to the ever-changing demands on our body. It adapts to physiological and pathological changes, including exercise and emotional state, as well as metabolic, respiratory, and vascular abnormalities. The pumping action of the heart is determined by the health of the myocardium, which undergoes changes with ageing that are both under-investigated and incompletely understood, potentially impacting our approach to pathological conditions. Here, the alterations in cellular, tissue, and gross physiological function of the heart with age are discussed. At the molecular level, non-coding RNAs influence cellular senescence, and extracellular vesicles induce fibrosis through matrix remodelling. Mitochondrial dysfunction and altered fatty acid oxidation reduce cellular energetics, whilst accumulation of reactive oxygen species and steatosis, as well as telomere shortening coupled with reduced autophagy, limit the myocardium's regenerative capability. Loss of cardiomyocytes, combined with senescence, requires compensatory hypertrophy, inducing myocardial stiffness and altered muscle function. In addition to these direct alterations in myocardial characteristics with ageing, other factors that can affect the myocardium indirectly are addressed, including valve calcification, resulting in regurgitation and/or stenosis; vascular abnormalities, reducing compliance and exacerbating hypertension; fibrosis leading to cardiac arrhythmias; and autonomic dysregulation, reducing cardiac adaptability. Finally, potential modulation of cardiac ageing is discussed whilst also addressing which senescent modifications should be considered as ageing-related physiological changes of the myocardium. A better understanding of myocardial ageing will differentiate physiological changes from early, preventable, and reversible pathological changes, consequently helping to optimize management of individuals with or at risk of myocardial disease by taking into account diverse trajectories of myocardial ageing.

DOI: https://doi.org/10.1093/eurheartj/ehag095
Biochem Biophys Res Commun. 2026 Feb 27. pii: S0006-291X(26)00221-4. [Epub ahead of print]810 153457

Genistein alleviates Osteoporosis by inhibiting the differentiation and autophagy of osteoclasts via regulating the CYLD/p62/RANKL axis.

Jungao Zhu, Xiaoqin Huang, Chuanchuan Li, Weixian Liu, Xiaoqing Zhong.

  Osteoporosis is a highly prevalent metabolic bone disorder characterized by an imbalance in bone remodeling, primarily due to excessive osteoclast-mediated bone resorption. The present study systematically investigates the protective effects of genistein, a naturally occurring soy isoflavone, against osteoporosis by targeting osteoclast differentiation and autophagy, as well we the underlying mechanism. Using RANKL-stimulated RAW264.7 cells as an in vitro model, we found that genistein treatment significantly and dose-dependently inhibited osteoclast formation and autophagic activity, which was evidenced by reduced tartrate-resistant acid phosphatase (TRAP) activity, fewer autophagic vacuoles observed under transmission electron microscopy, decreased protein levels of LC3-II/I and Beclin1, and increased expression of p62. Mechanistic studies revealed that genistein upregulates the deubiquitinase CYLD, which stabilizes p62 through deubiquitylation, leading to inhibition of the RANKL signaling pathway. Importantly, the anti-osteoclastogenic effects of genistein were markedly attenuated upon CYLD or p62 knockdown or upon induction of autophagy with rapamycin. In an ovariectomized (OVX) rat model of postmenopausal osteoporosis, genistein administration (5 or 10 mg/kg/day) effectively ameliorated bone loss, as confirmed by micro-CT analyses showing improvements in bone mineral density (BMD), bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular separation (Tb.Sp). Consistent with in vitro findings, genistein reduced osteoclast numbers and modulated autophagy markers in femoral tissues. Collectively, these results demonstrate that genistein mitigates osteoporosis by suppressing osteoclast differentiation and autophagy through regulating the CYLD/p62/RANKL axis, highlighting its promising potential as a natural therapeutic agent for osteoporosis treatment.

Keywords:  Autophagy; Deubiquitylation; Genistein; Osteoclasts; Osteoporosis

DOI:  https://doi.org/10.1016/j.bbrc.2026.153457
Biochem Pharmacol. 2026 Feb 27. pii: S0006-2952(26)00181-4. [Epub ahead of print]248 117850

USP30 alleviates intestinal ischemia-reperfusion injury by deubiquitinating MFN2 mediating the mitochondrial endoplasmic reticulum pathway.

Ziyi Weng, Tulanisa Kadier, Ruili Ding, Yu Shi, Jingyuan Xie, Rong Chen, Qingtao Meng.

  Intestinal ischemia-reperfusion (IIR) injury can cause intestinal barrier damage, systemic inflammatory response, and high mortality. The key mechanism is the disorder of the mitochondrial-endoplasmic reticulum network. Ubiquitin-specific peptidase 30 (USP30), located on the outer mitochondrial membrane, can reverse the partial ubiquitination of Parkin substrates or completely remove the ubiquitin chain to maintain mitochondrial function. Mitofusin 2 (MFN2) is a mitochondrial outer membrane fusion protein that mediates mitophagy and endoplasmic reticulum stress and participates in the formation of mitochondria-associated endoplasmic reticulum (MAMs). Our research showed that IIR reduces the protein expression of USP30 and MFN2, and overexpression of USP30 can increase the stability of MFN2 through deubiquitination and alleviate the damage caused by IIR. After overexpression of MFN2, mitochondrial dysfunction and endoplasmic reticulum stress caused by IIR are restored, while knockdown of MFN2 weakens the protective effect of USP30 on the MAMs. USP30 alleviates endoplasmic reticulum stress and mitochondrial dysfunction caused by intestinal ischemia-reperfusion injury by reducing the ubiquitination level of MFN2. The regulation of USP30 may be a promising strategy for alleviating intestinal ischemia-reperfusion injury.

Keywords:  Endoplasmic reticulum stress; Intestinal ischemia-reperfusion; MAMs; MFN2; Mitochondrial dysfunction; USP30

DOI:  https://doi.org/10.1016/j.bcp.2026.117850