bims-auttor 2026-09-27 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–09–27
thirty-six papers selected by
Viktor Korolchuk, Newcastle University

Lysosomal function and homeostasis: From cellular adaptation to disease pathogenesis.
CDKL5 deficiency impairs TBK1-mediated autophagy and clearance of neuronal protein aggregates.
mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes.
It's apples and oranges (or chalk and cheese, depending on where you live): RPM versus RCF.
The Role of the Mammalian Target of Rapamycin in Microglial Phenotypic Polarization.
Mitophagy's impact on obesity-related tissues.
Chronic Contractile Activity Remediates Lysosomal Dysfunction in a Muscle Cell Lysosomal Disease Model.
Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila.
ATG8 protein clustering: a HOTS topic in autophagy.
PP2A and CDK16 antagonistically regulate WIPI2B phosphorylation and neuronal autophagosome biogenesis.
Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.
Dynamin-2 promotes Atg9A retrieval from phagophores during autophagy.
Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.
Autophagy and Mitophagy in Hypertensive Chronic Kidney Disease: Evidence Grading, Cell-Type Divergence, and a Working Lysosomal Hypothesis.
Breaking the proteasome balance: α-synuclein and the ubiquitin-proteasome system.
mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.
Sex matters in macroautophagy: Sex-driven differences in autophagic function in aging and aging related-diseases.
Autophagy in endothelial cells: A gatekeeper of immune cell trafficking and function.
Autophagy in hypothalamic POMC and AgRP neurons: mechanisms and therapeutic implications for obesity.
TRPML1 agonist ML-SA5 attenuates pulmonary fibroblast activation by suppressing mTOR and restoring autophagic flux.
Sigma-1 receptor protects against renal ischemia-reperfusion injury by enhancing mitophagy via Rac1 regulation.
In situ visualization of autophagy reveals the presence of vesicles at the expanding phagophore rim.
Silent controllers: non-coding RNAs drive autophagic response in myocardial ischemia reperfusion injury.
Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.
A quantitative redox proteome of the human muscle response to exercise.
Novel mTORC1 Booster LAPTM4A Potentiates Pathological Cardiac Hypertrophy.
Rapamycin across biology and medicine: From molecular mechanisms to clinical and translational frontiers.
Molecular insights into ATP synthase c-ring accumulation in BMP-deficient lysosomes in Batten disease.
Asb2-KIF11 Axis Protects Against Heart Failure by Restoring Lysosomal Distribution and Mitochondrial Homeostasis.
Beyond Translation Initiation: Translational Elongation, Decoding Fidelity, and Ribosome Surveillance During Branched-Chain Amino Acid Deprivation, with a Focus on Mammalian Systems.
PINK1 deficiency exacerbates age-related bone loss in association with enhanced inflammatory adipocyte differentiation.
mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis.
Strawberry leaf extract protects dopaminergic neurons by restoring redox and mitochondrial homeostasis.
Src inhibition attenuates neuroinflammation via promoting p62 UFMylation-dependent microglial mitophagy.
Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43G376D ALS Patient-Derived Fibroblasts.
LC3 forms functional nanoclusters on autophagosomes.

Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(26)00034-1. [Epub ahead of print]406 1-42

Lysosomal function and homeostasis: From cellular adaptation to disease pathogenesis.

Satoshi Minami, Maho Hamasaki.

  Lysosomes were once considered terminal degradative organelles responsible for disposing of cellular waste. However, recent studies have revealed that lysosomes serve as dynamic signalling and metabolic hubs at the center of diverse biological processes, including nutrient sensing, metabolic regulation, membrane trafficking, autophagy, inflammation, and cell death. To support this broad functional repertoire, lysosomes must possess robust mechanisms to maintain their integrity in the face of damage or stress. In response to lysosomal membrane damage, cells engage multilayered adaptive mechanisms that act in coordination-membrane repair (Repair), selective removal of damaged organelles (Removal), and de novo biogenesis of lysosomes (Regeneration). These processes are mediated by a range of molecular pathways, including the ESCRT complex, the PITT pathway, lysophagy, and TFEB-dependent lysosomal regeneration. Notably, recent findings highlight the noncanonical autophagy-like pathway known as ATG8ylation (conjugation of ATG8s on single membranes), which is activated via the STING-V-ATPase-ATG16L1 axis and functions as a critical hub connecting multiple arms of the lysosomal damage response. In this review, we systematically outline the molecular basis of lysosomal damage responses, including ATG8ylation, and explore how these networks are implicated in a broad spectrum of pathological conditions such as aging, neurodegeneration, cancer, obesity-related disorders, and immune dysfunction. Understanding these lysosomal quality control mechanisms not only sheds light on the fundamental principles of organelle homeostasis but also opens new avenues for therapeutic innovation.

Keywords:  Lysophagy; Lysosome; Organelle damage; Selective autophagy

DOI:  https://doi.org/10.1016/bs.ircmb.2026.04.002
bioRxiv. 2026 Sep 18. pii: 2026.09.13.751248. [Epub ahead of print]

CDKL5 deficiency impairs TBK1-mediated autophagy and clearance of neuronal protein aggregates.

Zhongju Zou, Bilal Kahn, Salwa Sebti, Jason Lucavs, Giomar Rivera-Cancel, Josephine Thinwa.

The clearance of unwanted protein aggregates is essential for maintaining proteostasis and cellular function, particularly in long-lived cells such as neurons, yet the signaling pathways that activate selective autophagy of protein aggregates remain incompletely understood. Here, we identify the neurodevelopmental kinase CDKL5 as an upstream regulator of a signaling pathway involving the TBK1 adaptor SINTBAD and the selective autophagy receptors p62 and TAX1BP1. CDKL5-deficient mice show age-dependent accumulation of detergent-insoluble protein aggregates in the brain, accompanied by impaired TAX1BP1 recruitment and reduced p62 Ser405 phosphorylation. In cultured cells and primary cortical neurons, loss of CDKL5 delays clearance of puromycin- and proteasome-inhibitor-induced aggregates in a manner dependent on CDKL5 kinase activity. Mechanistically, CDKL5 kinase activity is required for SINTBAD Ser504 phosphorylation, a SINTBAD modification that promotes TBK1 activation, resulting in p62 Ser403/405 phosphorylation and TAX1BP1-dependent aggregate clearance. Phosphomimetic SINTBAD rescues these responses in CDKL5-deficient cells. These findings define a CDKL5/SINTBAD/TBK1 signaling axis that couples proteotoxic stress to activation of selective autophagy receptors and identify impaired proteostasis as a previously unrecognized consequence of CDKL5 deficiency.

DOI: https://doi.org/10.64898/2026.09.13.751248
Aging (Albany NY). 2026 Sep 19. 18(1): 1280-1315

mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes.

Natalia Bobok.

  The mechanistic target of rapamycin (mTOR) pathway is an important integrator of processes involved in aging and longevity, coordinating nutrient sensing, metabolic adaptation, and cellular stress responses. This review presents a three-section framework in which mTOR functions as a dynamic signaling hub coordinating multiple biological processes underlying the aging process. Evidence from genetic, experimental, and translational studies supports a causal role for mTOR signaling in lifespan regulation in model organisms, whereas human data remain predominantly associative but biologically consistent. mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) regulate distinct yet complementary aspects of cellular metabolism, proteostasis, autophagy, stress adaptation, and tissue homeostasis. Major geroprotective interventions-including autophagy activation, dietary interventions, physical activity, and senotherapeutics-partly converge on mTOR signaling but also engage parallel pathways. This adaptive regulation restores anabolic-catabolic balance, enhances stress resilience, and improves metabolic flexibility. Collectively, the available evidence identifies mTOR as an important integrative node linking multiple hallmarks of aging and diverse geroprotective interventions. Rather than representing a single therapeutic target, mTOR should be viewed as a context-dependent signaling hub which precise, tissue-specific modulation may promote healthy aging and support future geroscience-based interventions.

Keywords:  geroprotective interventions; hallmarks of aging; mTOR signaling; mTORC1; mTORC2

DOI:  https://doi.org/10.18632/aging.206423
Autophagy. 2026 Oct;22(10): 2521

It's apples and oranges (or chalk and cheese, depending on where you live): RPM versus RCF.

Daniel J Klionsky.

  At Autophagy we request that authors express centrifugal values as relative centrifugal force (RCF) or g-force as opposed to revolutions per minute (RPM). This is not an arbitrary decision but to understand the reason we need to provide a brief explanation of the difference between these two terms and, yes, there is a difference. Hence, it is annoying when during the editing process we request that an author convert a stated value such as "12,000 RPM" to "×g" and they simply return the paper with "12,000 ×g." The problem is that "12,000 RPM" is not equivalent to "12,000 ×g."

Keywords:  G-force; RCF; RPM; rotor; stop annoying the editor

DOI:  https://doi.org/10.1080/15548627.2026.2685350
Cells. 2026 Sep 14. pii: 1654. [Epub ahead of print]15(18):

The Role of the Mammalian Target of Rapamycin in Microglial Phenotypic Polarization.

Kaitlyn J Partridge, Allison D Ebert.

  Microglia are adaptive immune cells that maintain central nervous system homeostasis and respond dynamically to injury, infection, and other neurological insults. While traditionally classified into resting, pro-inflammatory "M1", and anti-inflammatory "M2" states, advances in multi-omic profiling technologies have established that microglial phenotypes exist along a multidimensional and context-dependent continuum. The mammalian target of rapamycin (mTOR), a central regulator of cellular metabolism, growth, survival, and protein synthesis, has emerged as a potential central mediator of these state transitions through distinct activities downstream of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). In this review, we examine current evidence linking mTOR signaling to microglial phenotypic polarization and functional plasticity. Generally, evidence suggests that mTORC1 acts as a context-dependent amplifier of inflammatory responses, whereas mTORC2 promotes anti-inflammatory and neuroprotective programs; however, the effects of either complex vary according to disease context. Understanding the balance and coordination of mTORC1 and mTORC2 signaling programs may clarify mechanisms that underly chronic neuroinflammation and guide the development of targeted therapies for neuroinflammatory disorders including Alzheimer's disease, stroke, and epilepsy.

Keywords:  mammalian target of rapamycin; microglia; neuroinflammation

DOI:  https://doi.org/10.3390/cells15181654
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00166-2. [Epub ahead of print]406 87-130

Mitophagy's impact on obesity-related tissues.

Rana El Nahas, Sandra Cutanda-Tesouro, Meritxell Espino-Guarch, Pablo M Garcia-Roves.

  Obesity, a global health crisis, results from an energy imbalance, leading to metabolic dysfunction and associated conditions such as type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease. A strong link exists between obesity and mitochondrial dysfunction, characterized by reduced mitochondrial mass, impaired oxidative capacity, and decreased ATP production. Mitophagy, a specific type of autophagy targeting mitochondria for degradation, plays a complex, tissue-specific role in regulating metabolism and mitigating the harmful effects of obesity. Both insufficient and excessive mitophagy can negatively influence disease progression. In white adipose tissue, mitophagy functions as a quality control mechanism that reduces oxidative stress and helps maintain insulin sensitivity. However, chronic obesity impairs mitophagy due to overactivation of mTORC1 and inhibition of AMPK, leading to inflammation and insulin resistance. In brown adipose tissue, mitophagy is essential for thermogenesis and energy expenditure, but excessive activation in obesity may impair thermogenesis. In the liver, mitophagy is crucial for preserving mitochondrial function and preventing metabolic dysfunction-associated steatotic liver disease. In the heart, mitophagy supports cardiac function, particularly in obesity-related cardiomyopathy. In skeletal muscle, obesity worsens impairments in mitochondrial quality control, disrupting the clearance of damaged mitochondria. Therefore, there is a pressing need for therapies that restore mitophagic balance in a context- and depot-specific manner, as the dysregulation of mitophagy contributes not only to local dysfunction but also to broader metabolic phenotypes.

Keywords:  autophagy; mitochondria and metabolic dysfunction; mitophagy; obesity

DOI:  https://doi.org/10.1016/bs.ircmb.2025.12.003
J Cell Physiol. 2026 Sep;241(9): e70231

Chronic Contractile Activity Remediates Lysosomal Dysfunction in a Muscle Cell Lysosomal Disease Model.

Debasmita Bhattacharya, Neushaw Moradi, David A Hood.

  Lysosomes are important organelles for the degradation of unwanted biomolecules via autophagy. Lysosomal dysfunction is apparent in ageing tissues, and can cause various neurodegenerative diseases. It is imperative to understand the mechanisms and implications of lysosomal malfunction and to find strategies to ameliorate diseases. To investigate this, we induced lysosomal dysfunction with Bafilomycin A1 (BAF), a drug that hinders lysosomal acidification by blocking vATPase-mediated proton pumping, in myoblasts and myotubes. Myotubes were subjected to chronic contractile activity (CCA) to mimic "exercise" to evaluate any therapeutic potential and reversal of pathophysiology. Induced lysosomal dysfunction was evident from impaired processing of the protease cathepsin B, enhanced lysosomal accumulation and increased autophagic markers Lamp1, p62, and the LC3II/I ratio. BAF attenuated lysosomal protease degradation measured using the substrate DQ-BSA in both myoblasts and myotubes. Many of the adverse effects generated by BAF in myotubes were reversed by CCA, manifested by a decrease in immature cathepsin B, a down-regulation of Lamp1, p62, LC3II/I and partial restoration of lysosomal protein degradation enzymatic capacity. To investigate further improvements in lysosomal function in a healthy cellular model, we treated myotubes with C1, a curcumin analogue. C1 decreased Lamp1, p62 and the LC3II/I ratio, all of which indicate improved lysosomal function and autophagosome clearance with a greater lysosomal ability to degrade substrates. Additionally, C1 was able to mimic the improved mitochondrial content induced by CCA. Thus, contractile activity and curcumin analogues may provide useful therapeutic potential to resuscitate lysosomal function, improve muscle health and ameliorate lysosome-mediated diseases. NEW AND NOTEWORTHY: This study explores the potential of chronic contractile activity (CCA) in reversing the compromised lysosomes caused by the disruption of lysosomal acidification in myotubes. Remarkably, CCA mitigated the effects of Bafilomycin A1-induced lysosomal dysfunction, enhancing protease activity and increased mitochondrial content. Treatment of myotubes with the curcumin analogue C1 reduced lysosomal accumulation and enhanced mitochondrial content suggesting that contractile activity-based interventions and small-molecule modulators of lysosomal pathways may represent promising complementary strategies for treating lysosome-related diseases and enhancing muscle health.

Keywords:  autophagy; bafilomycin A; exercise; lysosomes; mitochondria

DOI:  https://doi.org/10.1002/jcp.70231
Nature. 2026 Sep 23.

Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila.

Jun Wang, Zixin Cai, Jiaojiao Gu, Shiqi Xiong, Jianhan Yi, Meng Yang, Kexin Chang, Xinrui Ning, Yilin Wen, Yan Yan, Jiongming Lu, Yirong Wang, Zongzhao Zhai.

Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing1. mTORC1 preferentially regulates the translation of 5'-terminal oligopyrimidine (TOP) motif-containing mRNAs (which encode mainly ribosomal proteins) through the 4E-BP translational repressor2; however, this function of mTORC1 is resistant to rapamycin inhibition3. TOP mRNAs are exceptionally abundant, and thus impose a major translational burden on cells, but how their translation is physiologically tuned and linked with lifespan remains unclear. Here we show that Lsp2, which was previously known to be a storage protein4, is also an adipose effector and feedback activator of mTORC1 that modulates lifespan in Drosophila. Expression of Lsp2 is induced by essential amino acids through mTORC1 and is gated by additional signals of nutrient sufficiency. Genetic ablation of Lsp2 robustly extends lifespan without impairing key life history traits such as reproduction. Translatomic profiling shows that loss of Lsp2 selectively reduces global TOP mRNA translation in a 4E-BP-dependent manner, thereby extending lifespan through a mechanism distinct from the effects of rapamycin. Evolutionarily, TOP motifs co-emerged with 4E-BP and are present in nearly all Drosophila ribosomal protein mRNAs. Moreover, we show that the role of TOP motifs in translational control extends to Drosophila. Collectively, our findings reveal a nutrient-induced physiological factor that amplifies mTORC1 output in TOP mRNA translation and regulates organismal longevity.

DOI: https://doi.org/10.1038/s41586-026-11029-x
EMBO Rep. 2026 Sep 25.

ATG8 protein clustering: a HOTS topic in autophagy.

Yongjia Duan, James H Hurley.

DOI: https://doi.org/10.1038/s44319-026-00930-1
iScience. 2026 Oct 16. 29(10): 117518

PP2A and CDK16 antagonistically regulate WIPI2B phosphorylation and neuronal autophagosome biogenesis.

Heather Tsong, M Neal Waxham, Andrea K H Stavoe.

  Autophagy is a homeostatic mechanism for recycling cellular constituents. In primary murine neurons, autophagosome biogenesis declines during aging. Importantly, this decline can be restored by the ectopic expression of key autophagy component WIPI2B. The phosphorylation state of WIPI2B serine 395 is critical for this restoration, suggesting that WIPI2B S395 phosphorylation regulates autophagosome biogenesis. Here, we identified protein phosphatase 2A (PP2A) and CDK16 as regulators of WIPI2B S395 phosphorylation and neuronal autophagy. Using Caenorhabditis elegans, we showed that PP2A and CDK16 regulate neuronal autophagy through the same genetic pathway as WIPI2B. Further, purified mammalian PP2A and CDK16 directly modified WIPI2B S395 phosphorylation in vitro. In primary murine neurons, PP2A and CDK16 colocalized with WIPI2B at autophagosomes, and manipulation of PP2A and CDK16 expression altered WIPI2B puncta formation and rates of autophagosome biogenesis. Altogether, our data support the conclusion that PP2A and CDK16 regulate WIPI2B S395 phosphorylation, modulating autophagosome biogenesis in neurons.

Keywords:  C. elegans; autophagy; neuron; phosphorylation

DOI:  https://doi.org/10.1016/j.isci.2026.117518
Aging Cell. 2026 Oct;25(10): e70720

Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.

Ning Jin, Li Zhou, Haixia Gui, Jingjing Tang, Xiaozhen Huang, Wenting Wang, Guorong Jin, Haiqin Cheng, Yuxiang Liang, Xinyi Geng, Zhiwei Peng, Hong Zhao, Zhizhen Liu, Jun Xie.

  Mitochondrial quality control is severely impaired in the aging heart, largely attributed to disrupted mitophagy homeostasis. However, the key molecular drivers remain poorly defined, and the translational value of mitochondria-targeted therapy for cardiac aging is still underexplored. Here, we report prominent mitophagy flux congestion in aged cardiac tissue and confirm that mitochondrial transplantation efficiently rescues impaired mitophagy, ultimately rejuvenating the aging heart. Mechanistically, we identify a novel HIF-3α-BNIP3 signaling axis in the aging heart: HIF-3α, conventionally recognized as a transcriptional repressor, is aberrantly upregulated in senescent cardiomyocytes and directly regulates excessive BNIP3 expression to trigger mitophagy congestion. Notably, we establish an innovative translational strategy that mitochondrial transplantation restrains pathological overactivation of the HIF-3α-BNIP3 axis via improving intracellular ATP homeostasis, thereby reconstructing normal mitophagy flux and reversing cardiac aging. Our findings uncover an unrecognized upstream regulator of age-related mitophagy defects and provide a mitochondrial-based intervention approach for the treatment of aging-associated cardiac dysfunction.

Keywords:  HIF‐3α‐BNIP3 axis; aging heart; mitochondrial transplantation; mitophagy flux

DOI:  https://doi.org/10.1111/acel.70720
Biol Open. 2026 Sep 21. pii: bio.062632. [Epub ahead of print]

Dynamin-2 promotes Atg9A retrieval from phagophores during autophagy.

Andrew Caliri, Alejandro Martorell Riera, Panagiota Kolitsida, Akash Saha, Cinta Iriondo Martinez, Samuel Itskanov, Janos Steffen, Carla M Koehler, Alexander M van der Bliek.

  Autophagy involves the rapid growth of phagophores through membrane addition. This growth is triggered by vesicles containing the Atg9A protein. However, Atg9A is not incorporated into mature autophagosomes. We now demonstrate that Dynamin-2 (Dnm2) colocalizes with the BAR domain protein Endophilin-B1 (EndoB1/Bif-1/SH3GLB1) and other autophagy proteins when autophagy is induced. Our data suggest that Atg9A is retrieved from phagophores via fission, with help from Dnm2. Blocking Atg9A recycling, either by mutating Dnm2, using RNA interference, or applying chemical inhibitors, results in Atg9A remaining in autophagosomes and being degraded during autophagy. Overall, these findings provide new insights into the roles of Dnm2 in autophagy.

Keywords:  Atg9A; Autophagy; Dynamin; Endophilin; LC3

DOI:  https://doi.org/10.1242/bio.062632
Int J Mol Sci. 2026 Sep 11. pii: 8086. [Epub ahead of print]27(18):

Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.

Yongxu Chen, Chunsheng Wang.

  Parkinson's disease (PD) is a clinically and biologically heterogeneous neurodegenerative disorder in which variable symptom profiles, progression rates, and treatment responses likely reflect distinct but partially convergent pathogenic mechanisms. Among these, mitochondrial dysfunction recurs across both familial and sporadic PD; however, this broad concept alone cannot explain disease heterogeneity. To preserve mitochondrial homeostasis, cells rely on a complex mitochondrial quality control (MQC) system that encompasses protein import and proteostasis, redox surveillance, organellar dynamics and positioning, biogenesis, and selective elimination of damaged mitochondria. MQC also depends on coordination with other organelles, particularly the endoplasmic reticulum and lysosomes. In this review, we discuss how different layers of MQC maintain mitochondrial integrity and how these pathways are functionally coupled. We further consider how an MQC-based framework may help explain the clinical heterogeneity of PD, including selective neuronal vulnerability, subtype formation, and divergent disease progression, and how it can frame recent therapeutic advances aimed at biologically stratified intervention.

Keywords:  Parkinson’s disease; heterogeneity; mitochondrial quality control; selective vulnerability; stratified transformation

DOI:  https://doi.org/10.3390/ijms27188086
Life (Basel). 2026 Sep 04. pii: 1481. [Epub ahead of print]16(9):

Autophagy and Mitophagy in Hypertensive Chronic Kidney Disease: Evidence Grading, Cell-Type Divergence, and a Working Lysosomal Hypothesis.

Suyeon Han, Yoon-Kyung Chang, Janghyun Jo, Dae Eun Choi.

  Hypertension is a major attributed cause of chronic kidney disease (CKD) and kidney failure, yet the cellular mechanisms linking chronic hemodynamic and neurohormonal stress to progressive nephron loss remain incompletely defined. Interpretation is further complicated by the clinical heterogeneity and limited pathological validation of hypertensive nephrosclerosis. Autophagy and mitophagy are important intracellular quality-control pathways and have been increasingly implicated in hypertensive kidney injury. In this review, we critically appraise the available evidence using a multidimensional ACGEM framework that evaluates autophagy/mitophagy measurement (A), cell-type resolution (C), genetic manipulation (G), experimental causality (E), and disease-model relevance (M) as independent dimensions. The available literature does not support a uniform increase or decrease in autophagy during hypertensive kidney disease. Rather, autophagic responses appear to depend on renal cell type, hypertensive stimulus, disease stage, and the component of the pathway being measured. In podocytes, chronic angiotensin II exposure provides evidence of impaired autophagic flux with a protective role for intact autophagy, whereas mineralocorticoid stress can induce a compensatory increase in autophagic flux. Tubular studies likewise suggest protective roles for effective autophagic and mitochondrial quality control, although direct cell-specific causal evidence in hypertensive models remains limited. Across the field, most studies rely on static autophagy-associated markers and bulk kidney measurements, while dynamic flux assessment, cell-specific genetic approaches, and direct evaluation of lysosomal competence remain uncommon. Observations from APOL1-associated kidney disease, chronic interstitial nephritis in agricultural communities, proteinuric overload, aging, and obesity provide mechanistic or pathological precedent for lysosomal vulnerability but do not constitute direct evidence for classical hypertensive nephrosclerosis. We therefore propose, as a falsifiable working hypothesis rather than an established mechanism, that lysosomal clearance may become rate limiting in a subset of hypertensive CKD. Testing this model will require longitudinal, cell-type-resolved flux measurements, direct assessment of lysosomal function, and pathological validation in biopsy-confirmed human hypertensive nephrosclerosis.

Keywords:  autophagy; chronic kidney disease; hypertension; lysosome; mitophagy; podocyte

DOI:  https://doi.org/10.3390/life16091481
Front Cell Dev Biol. 2026 ;14 1906331

Breaking the proteasome balance: α-synuclein and the ubiquitin-proteasome system.

Tariq T Ali, Blagovesta Popova, Gerhard H Braus.

  Aging is the major risk factor for synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. However, the molecular mechanisms linking aging to. α-Synuclein cytotoxicity remain incompletely understood. The progressive decline of proteostasis is central among these mechanisms, as the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway fail to maintain the turnover of aggregation-prone proteins. In this review, we focus on the bidirectional crosstalk between α-Synuclein and the proteasome as a key driver of proteostasis collapse in synucleinopathies. Proteasome activity declines during aging, and proteasomal dysfunction is closely associated with disease progression. We first discuss how. α-Synuclein structure and posttranslational modifications determine whether the protein is targeted for degradation by the UPS or autophagy or instead acts as a proteolytic inhibitor. Next, the mechanisms by which pathogenic α-synuclein species interact with and impair 20S/26S proteasomes, affecting proteolytic activity, subunit composition, and complex assembly, are discussed. These interactions establish a self-amplifying cycle of proteasome inhibition and α-Synuclein accumulation. As a consequence, the cellular capacity to clear misfolded proteins progressively declines, promoting toxic α-Synuclein aggregation and neurodegeneration. We further discuss the importance of autophagy on α-Synuclein turnover and how this is impaired in synucleinopathies. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function and proteostasis. A deeper understanding of how α-Synuclein-proteasome interactions change during ageing may reveal new molecular targets and support the development of disease-modifying therapies for synucleinopathies.

Keywords:  20S proteasome; 26S proteasome; Parkinson disease; UPS; alpha-Synuclein; autophagy; posttranslational modifications; protein homeostasis

DOI:  https://doi.org/10.3389/fcell.2026.1906331
Sci Adv. 2026 Sep 25. 12(39): eaee1905

mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.

Alex Zaufel, Wenfei Sun, Nunzia Pastore, Ulrike Taschler, Carina Wagner, Hubert Hackl, Judith Sommer, Dagmar Silbert-Wagner, Jan G Hengstler, Brigitte Begher-Tibbe, Rudolf Stauber, Dagmar Kolb, Martin Troetzmueller, Benjamin Gottschalk, Chelsea Thorsheim, Eva-Lena Stange, Mathias W Hornef, Olga Pivovarova-Ramich, Andreas F H Pfeiffer, Kylie P Matchett, Anne Loft, Stephan Herzig, Neil C Henderson, Andrea Ballabio, Zoltan Arany, Christian Wolfrum, Peter Fickert, Tarek Moustafa.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal cues to regulate hepatic lipid metabolism with major implications for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we show that altered hepatic mTORC1-TFEB/TFE3 signaling is associated with coordinated remodeling of bile acid (BA) metabolism during metabolic adaptation. Our data support a model in which cross-talk between mTORC1 and TFEB/TFE3 is associated with divergent regulation of bile acid synthesis and transformation. Depending on the mTORC1 signaling state, changes in hepatic Cyp2c70 and Cyp8b1 expression, together with altered cholesterol trafficking, were associated with shifts toward non-12-OH or 12-OH bile acid species. These effects were attenuated or reversed by Tfe3 deletion or rapamycin treatment. Furthermore, protein restriction (which inhibits mTORC1) similarly reshaped the BA profile in mice and correlated with improved metabolic outcomes in MASLD patients. Together, these findings uncover BA homeostasis as an integral component of the metabolic adaptations orchestrated by mTORC1, underscoring a link between nutrient signaling and metabolic liver disease.

DOI: https://doi.org/10.1126/sciadv.aee1905
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(26)00106-1. [Epub ahead of print]406 213-273

Sex matters in macroautophagy: Sex-driven differences in autophagic function in aging and aging related-diseases.

José Ignacio García-Muñoz, Alicia Domenech-Bendaña, Lucia Gimeno-Mallench, Alejandro Ponce-Mora, Álvaro F Fernández, Daniel López-López, Jose Luis Nieto-Torres, Eloy Bejarano.

  Autophagy is a fundamental cellular process essential for maintaining homeostasis, particularly in the context of aging and age-related diseases. Increasing evidence highlights biological sex as a critical modulator of autophagy, influencing its basal activity, regulatory pathways, and responsiveness to stress. Distinct autophagic profiles in males and females (across tissues, species and developmental stages) may underlie sex-specific vulnerabilities and divergent disease trajectories. These differences are evident in conditions such as neurodegeneration, cardiovascular disease, cancer, sarcopenia or chronic inflammation, all of which are commonly associated with aging. Indeed, aging is a major risk factor for the onset and progression of these pathologies. Importantly, sex-dependent variations in autophagy might also impact the efficacy and safety of therapeutic interventions, challenging the validity of uniform treatment strategies. Despite growing recognition of these disparities, significant knowledge gaps remain. This review summarizes current understanding of sex-related differences in autophagy, focusing on genetic and hormonal influences across the lifespan. The evidence supports the need for future research to systematically incorporate sex as a biological variable in experimental design and data analysis, utilize dynamic assessments of autophagy flux and investigate the interplay among genetic, hormonal, epigenetic, and post-translational regulatory mechanisms. Developing preclinical models that reflect human diversity-including genetic heterogeneity and relevant hormonal states-is imperative. Embracing the complexity of sex-dependent autophagy regulation is essential for translating mechanistic insights into effective, personalized interventions that improve health outcomes for both women and men.

Keywords:  Aging; Autophagy; Biological sex

DOI:  https://doi.org/10.1016/bs.ircmb.2026.07.006
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(26)00003-1. [Epub ahead of print]406 131-163

Autophagy in endothelial cells: A gatekeeper of immune cell trafficking and function.

Guillermo Marcos-Zapatero, Dafne García-Mateos, Irene Carriles-Moar, Natalia Reglero-Real.

  Endothelial cells (ECs) are increasingly recognised as dynamic regulators of immunity rather than passive vascular barriers. By integrating inflammatory, metabolic, and mechanical cues, ECs actively shape leukocyte trafficking and determine inflammatory outcomes. Autophagy, a conserved lysosomal degradation pathway essential for cellular homeostasis, has emerged as a key determinant of endothelial function in health and disease. Recent work identifies EC autophagy as a context-dependent determinant of leukocyte trafficking, vascular inflammation, antigen presentation, and endothelial phagocytic capacity. Beyond controlling immune cell recruitment, EC autophagy intersects with xenophagy, efferocytosis, and vascular ageing, highlighting its broad immunomodulatory potential. In this review, we synthesise current evidence defining how autophagy within ECs regulates immune responses in a tissue-specific manner during acute and chronic inflammation. Collectively, these insights position EC autophagy as a central integrator of vascular and immune homeostasis and underscore its potential as a therapeutic target in chronic inflammatory and ageing-associated diseases.

Keywords:  Endothelial cells; autophagy; immunity; inflammation; leukocyte trafficking; neutrophils; vascular aging

DOI:  https://doi.org/10.1016/bs.ircmb.2026.02.001
Int J Obes (Lond). 2026 Sep 21.

Autophagy in hypothalamic POMC and AgRP neurons: mechanisms and therapeutic implications for obesity.

Dike Jing, Rao Dai, Shuwei Peng, Lishen Zeng, Jinyan Cai.

Obesity is increasingly recognized as a disorder involving impaired central endocrine regulation in which hypothalamic nutrient sensing, leptin responsiveness, and intracellular quality control are closely intertwined. Within the arcuate nucleus, autophagy exerts divergent metabolic effects in the two principal appetite-regulating neuronal populations. In pro-opiomelanocortin (POMC) neurons, autophagy supports metabolic homeostasis by promoting alpha-melanocyte-stimulating hormone (α-MSH) production, preserving leptin and insulin sensitivity, and activating peripheral lipophagy; its disruption predisposes to hyperphagia, leptin resistance, and obesity-related metabolic dysfunction. In contrast, autophagy in agouti-related peptide (AgRP) neurons promotes feeding and energy conservation by maintaining AgRP expression, integrating ghrelin signals, and sensing peripheral fatty acids; its inhibition alleviates diet-induced obesity in mice. This review critically evaluates discrepancies among models based on the deletion of autophagy-related gene 5,7, and 12 (Atg5, Atg7, and Atg12), as well as differences arising from developmental versus adult manipulations, dietary paradigms, and the reliance of static autophagy markers. We further discuss how POMC and AgRP neuron autophagy may interact with broader hypothalamic and extra-hypothalamic networks, including basonuclin 2 (BNC2), steroidogenic factor 1 (SF1) neurons in the ventromedial hypothalamus (VMH), and paraventricular hypothalamic nucleus (PVH) pathways, as well as extra-hypothalamic components involving the brainstem, glial and tanycytic cells, and neurovascular interaction. Chaperone-mediated autophagy (CMA) has emerged as a potential pathway potentially linking saturated fatty acid exposure, LAMP2A-dependent proteostasis, and insulin responsiveness in hypothalamic neurons, although direct evidence remains limited. Because direct demonstration of altered autophagic flux in human POMC or AgRP neurons remains lacking, hypothalamic autophagy should currently be viewed as a mechanistic and translational research framework rather than a validated clinical target. Future therapies will likely require pathway-biased, neuron-type-specific, and circuit-aware modulation rather than global activation or inhibition of autophagy.

DOI: https://doi.org/10.1038/s41366-026-02223-y
FEBS Open Bio. 2026 Sep 24.

TRPML1 agonist ML-SA5 attenuates pulmonary fibroblast activation by suppressing mTOR and restoring autophagic flux.

Jiatong Yao, Xiaoting Kang, Lulu Meng, Shaoxuan Zhang, Qiujie Li, Jinyu Zhou, Mengyue Xue, Chu Li, Hua Zhu, Pengzhou Hang, Jing Zhao.

  Modulating autophagic processes has shown promise as a treatment for pulmonary fibrosis (PF) with recent studies identifying transient receptor potential mucolipin-1 (TRPML1), a lysosomal ion channel, as a novel regulator involved in PF. However, the mechanism by which TRPML1 modulates autophagy in the context of PF remains incompletely understood. Here we establish in vitro PF models by exposing human embryonic lung fibroblasts (MRC-5) or primary lung fibroblasts to transforming growth factor (TGF-β1). We then assessed the effects of the TRPML1 agonist ML-SA5 on migratory capacity, the levels of fibrosis-related proteins and autophagy markers, and autophagic flux. Our findings show that TGF-β1 stimulation reduced TRPML1 protein levels, while ML-SA5 treatment suppressed TGF-β1-induced cell migration, reduced the expression of fibrotic markers, increased LC3II levels, and restored autophagic flux in lung fibroblasts. Finally, investigating the role of mammalian target of rapamycin (mTOR) signaling in these effects using rapamycin (an mTOR inhibitor) and MHY1485 (an mTOR activator), we found ML-SA5 inhibited mTOR signaling. Specifically, the anti-fibrotic effects of ML-SA5 were enhanced by co-treatment with rapamycin and reversed by MHY1485. Thus, we conclude that ML-SA5 attenuates TGF-β1-induced migration and collagen synthesis in pulmonary fibroblasts, at least in part through suppression of mTOR signaling and restoration of autophagic flux.

Keywords:  TRPML1; autophagy; lung fibroblast; mTOR; pulmonary fibrosis

DOI:  https://doi.org/10.1002/2211-5463.70346
Ren Fail. 2026 Dec;48(1): 2728429

Sigma-1 receptor protects against renal ischemia-reperfusion injury by enhancing mitophagy via Rac1 regulation.

Siyuan Gong, Yonghong Xiong, Wenyuan Li, Yan Leng, Xinqi Deng, Bihan Wang, Baichuan Yang, Yuhang Yang, Wei Li.

  Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury and is associated with mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and tubular cell apoptosis. Sigma-1 receptor (Sigma1R), an intracellular chaperone, helps maintain mitochondrial homeostasis and cell survival. Here, Sigma1R expression was significantly downregulated in renal IRI. Fluvoxamine treatment ameliorated renal dysfunction and reduced apoptosis in vivo, whereas Sigma1R overexpression preserved mitochondrial membrane potential and attenuated ROS accumulation in HK-2 cells subjected to hypoxia/reoxygenation. The findings support the functional involvement of Rac1 in Sigma1R-mediated enhancement of PINK1/Parkin-mediated mitophagy, which may facilitate the clearance of damaged mitochondria and restore mitochondrial quality control. Overall, Rac1 is involved in Sigma1R-mediated mitophagy and mitochondrial protection, highlighting Sigma1R as a potential therapeutic target for renal IRI.

Keywords:  Ischemia-reperfusion injury; Rac1; mitophagy; sigma-1 receptor

DOI:  https://doi.org/10.1080/0886022X.2026.2728429
J Cell Sci. 2026 Sep 24. pii: jcs.265302. [Epub ahead of print]

In situ visualization of autophagy reveals the presence of vesicles at the expanding phagophore rim.

Claire Ortmann de Percin Northumberland, Mariya Licheva, Rahel Dabrowski, Rubén Gómez-Sánchez, Sabrina Berkamp, Philipp Schönnenbeck, Martin Graef, Claudine Kraft, Carsten Sachse.

  The autophagy core machinery mediates the enclosure of cytosolic cargo destined for degradation in the lysosome. The Atg9-Atg2-Atg18 complex coordinates phagophore expansion via directed lipid transfer until closure of the phagophore rim. Using an Atg2 variant (Atg2-PM4) as a model of decelerated autophagosome biogenesis, we visualized the morphological states prior to autophagosome closure by cryogenic correlative light and electron microscopy in S. cerevisiae. Using in situ cryo-electron tomography, we find an enlarged rim morphology of an expanding phagophore in Atg2-PM4 cells in comparison with Atg2 wildtype condition. Analysis of segmented rim membrane features reveal surrounding and membrane-attached vesicles. The dimensions of the enlarged rims are consistent with fusion of cytosolic vesicles with the growing phagophore. High-resolution imaging in this study suggests that, apart from the initial nucleation phase, vesicle fusion can also contribute to phagophore expansion during later stages of autophagosome biogenesis.

Keywords:  Atg2; Autophagosome biogenesis; Autophagy; Correlative light and electron microscopy; Cryo-electron microscopy; Lipid transfer; Membrane analysis; Phagophore expansion

DOI:  https://doi.org/10.1242/jcs.265302
Front Cardiovasc Med. 2026 ;13 1889759

Silent controllers: non-coding RNAs drive autophagic response in myocardial ischemia reperfusion injury.

Afifa Azhar, Suhail Al-Salam.

  Acute myocardial infarction (AMI) continues to be a major contributor to global illness and death. Restoring coronary blood flow is a key strategy for limiting myocardial damage after infarction. Nevertheless, the re-establishment of circulation can paradoxically trigger ischemia-reperfusion (IR) injury through multiple intricate mechanisms. Consequently, IR injury remains an important obstacle in the effective management of myocardial infarction. Aberrant autophagy represents a major factor causing IR-related cardiomyocyte death. Autophagy, a catabolic process essential for cellular homeostasis, plays a bimodal role in myocardial IR -protective during ischemia yet potentially deleterious during reperfusion. Recent research highlights the pivotal regulatory function of non-coding RNAs (ncRNAs) which include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in modulating autophagy during myocardial IR injury, particularly in murine models. ncRNAs influence key autophagy regulators such as Beclin-1, ULK1, ATG5, ATG7, ATG12, LC3 and mTOR, forming complex regulatory networks that determine cardiomyocyte fate. This review synthesizes current evidence on how ncRNAs orchestrate autophagy in the setting of myocardial IR injury, elucidating underlying mechanisms and translational potentials. Understanding ncRNA-mediated modulation of autophagy opens avenues for targeted interventions to ameliorate IR injury related cardiac damage.

Keywords:  autophagy; heart; ischemia-reperfusion injury; myocardial injury; non-coding RNAs

DOI:  https://doi.org/10.3389/fcvm.2026.1889759
J Biol Chem. 2026 Sep 22. pii: S0021-9258(26)02464-6. [Epub ahead of print] 113592

Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.

Michael D Guile, Kyle A Anderson, Akash Jain, Alexandre Toulmay, William A Prinz, Catherine F Clarke.

  Coenzyme Q (CoQ) is an important lipid found in nearly all cellular membranes in eukaryotes. Biosynthesis of CoQ occurs within mitochondria, where it functions as an electron carrier in oxidative phosphorylation and participates in key metabolic pathways. In both mitochondrial and non-mitochondrial membranes, the hydroquinone form of CoQ (CoQH2) also functions as a radical-scavenging antioxidant and participates in other processes required for cell maintenance and survival. Individuals with CoQ deficiency may benefit from high-dose CoQ supplementation; however, its bioavailability is limited, and treatment responses can vary. Here, we sought to gain mechanistic insight into how exogenous CoQ is trafficked to mitochondria. We used the yeast model system Saccharomyces cerevisiae, that produce CoQ6 with a polyisoprenyl tail containing six isoprene units. A CoQ6-deficient (coq2Δ) yeast mutant is used to investigate genes and corresponding pathways required for the cellular uptake and trafficking of exogenous CoQ6 to mitochondrial respiratory complexes. Specifically, we identify essential residues in the dynamin-like protein Vps1 that are required for CoQ6 trafficking and show that yeast vps1 mutants with known defects in autophagy are incapable of trafficking exogenously supplemented CoQ6 to mitochondria. Importantly, we identify a non-canonical role for several autophagic proteins in CoQ6 trafficking. Taken together, our data suggest that uptake of exogenous CoQ6 and its delivery to the mitochondria relies on a novel, specialized lipid trafficking pathway comprised of select autophagic and endosomal membrane trafficking proteins, and the lytic compartment which serves as a transport hub.

Keywords:  Saccharomyces cerevisiae; Vps1; autophagy; dynamin; lipid raft; lipid trafficking; mitochondria; ubiquinone; vacuole; yeast

DOI:  https://doi.org/10.1016/j.jbc.2026.113592
bioRxiv. 2026 Sep 17. pii: 2026.09.15.751463. [Epub ahead of print]

A quantitative redox proteome of the human muscle response to exercise.

Yu Lei, Jonathan J Petrocelli, Anita Reddy, Carlos Henríquez-Olguin, Nils Burger, Sanghee Shin, Bingsen Zhang, Taylor Covington, Markus Waldeck-Weiermair, Jiuchun Zhang, Shelley M Wei, Thomas E Jensen, Christian T Voldstedlund, Christian S Carl, Bente Kiens, Erik A Richter, Edward T Chouchani.

Reactive oxygen species (ROS) regulate protein function through reversible cysteine oxidation. In human skeletal muscle, exercise-induced ROS initiates adaptations such as mitochondrial biogenesis, increased insulin sensitivity, and hypertrophy. However, specific protein targets of ROS regulation during exercise remain unclear owing to longstanding challenges in analyzing redox proteomes in vivo . We applied cysteine derivatization and multiplexed proteomics to map muscle protein cysteine oxidation in humans during exercise. The OxiMuscle dataset quantifies reversible modifications across 9,177 unique cysteine sites on 2,782 proteins, comprising 17,492 individual cysteine site measurements in young men undergoing three types of exercise, providing the first comprehensive, site-resolved and quantitative analysis of the exercise-regulated redox cysteine proteome in humans. We systematically define cysteine oxidation targets regulated by at least one form of exercise, many of which reside in proteins with established roles in muscle physiology. Among these sites is a redox-regulated cysteine on the autophagy receptor protein p62. We demonstrate that reversible oxidation of this cysteine regulates p62-mediated autophagy upon myotube contraction and mouse muscle adaptation to exercise in vivo . Together, these results define a redox-driven mechanism linking exercise-induced autophagy to muscle adaptation. More broadly, our findings offer a comprehensive resource on redox-signaling networks in human muscle, accessible at http://oximuscle-alb-1899330623.us-east-1.elb.amazonaws.com/ .

DOI: https://doi.org/10.64898/2026.09.15.751463
Circulation. 2026 Sep 22.

Novel mTORC1 Booster LAPTM4A Potentiates Pathological Cardiac Hypertrophy.

Yufeng Hu, Wei Li, Manli Hu, Song Tian, Siyi Zhou, Jiayi Liu, Xu Cheng, Changjiang Zhang, Yingjie Zuo, Jiaxing Zhang, Dianyu Liu, Yang Hu, Yuanbao Chen, Xin Li, Lei Luo, Hailong Yang, Lan Bai, Hui Liu, Péter Ferdinandy, Mario Chiong, Mayarling Francisca Troncoso, Jinying Wen, Jingjing Cai, Xiao-Jing Zhang, Zhi-Gang She, Xin Zhang, Hongliang Li.

   BACKGROUND: Excessive unnecessary protein accumulation in cardiomyocyte is a leading contributor for pathological cardiac hypertrophy and has been found closely regulated by the mTORC1 (mechanistic target of rapamycin complex 1) signaling and lysosome transmembrane proteins. However, the precise regulatory mechanism stratifying mTORC1 signaling and the specific functions of lysosomal proteins in protein homeostasis of cardiomyocytes remain largely unidentified.
METHODS: We screened lysosomal genes conserved in mice, rats, and humans. Adenoviral infection of rat cardiomyocytes was used to assess the functional role of LAPTM4A (lysosome-associated protein transmembrane 4A). To evaluate its effects in vivo, adeno-associated virus 9 driven by the cardiac troponin T promoter was used for cardiomyocyte-specific expression. RNA sequencing and mass spectrometry-based proteomics were performed to elucidate the underlying molecular mechanisms. Last, a dual-luciferase reporter assay was used to screen a Food and Drug Administration-approved drug library for compounds that suppress LAPTM4A expression.
RESULTS: Lysosomal transmembrane proteins expressed in cardiomyocytes were screened for their roles in regulating hypertrophy, and LAPTM4A emerged as a potent promoter of cardiomyocyte hypertrophy and prohypertrophic gene expression. Overexpression of LAPTM4A aggravated cardiac remodeling and dysfunction by enhancing mTORC1-p70S6K (70-kDa ribosomal protein S6 kinase)/4EBP1 (eukaryotic translation initiation factor 4E-binding protein 1)-mediated protein synthesis, without affecting lysosomal autophagy, in a NEDD4L (neural precursor cell expressed developmentally downregulated 4-like)-dependent manner. Mechanistically, LAPTM4A directly interacted with NEDD4L, facilitating K63-linked ubiquitination of AKT (protein kinase B [v-akt murine thymoma viral oncogene homolog]) and subsequent activation of mTORC1 signaling. Cardiomyocyte-specific deletion of LAPTM4A significantly attenuated myocardial hypertrophy and fibrosis induced by transverse aortic constriction in mice. Furthermore, a dual-luciferase reporter screen identified magnolol, a Food and Drug Administration-approved compound, as a suppressor of LAPTM4A expression with marked cardioprotective effects in vivo.
CONCLUSIONS: Our study identified a novel mTORC1 booster LAPTM4A and verified interrupting the LAPTM4A-mTORC1 axis can significantly inhibit excessive protein synthesis and pathological cardiac hypertrophy, which might represent an attractive therapeutic approach for this disease.

Keywords:  LAPTM4A; abnormal protein accumulation; cardiac hypertrophy; mTORC1

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.080371
Biochim Biophys Acta Gen Subj. 2026 Sep 24. pii: S0304-4165(26)00109-1. [Epub ahead of print] 131009

Rapamycin across biology and medicine: From molecular mechanisms to clinical and translational frontiers.

Lyvia Neves Rebello Alves Nolasco, Eldamária de Vargas Wolfgramm Dos Santos, Raquel Silva Dos Reis Trabach, Débora Dummer Meira, Iúri Drumond Louro.

  Rapamycin is a macrolide compound originally identified for its antifungal activity and subsequently recognized as a potent inhibitor of the mechanistic target of rapamycin (mTOR), a conserved signaling kinase that integrates nutrient availability, growth factor signals, and cellular stress responses to regulate cell growth and metabolism. This review examines rapamycin across biological and medical fields, covering its discovery, chemical and pharmacological properties, and the central role of mTOR as its primary molecular target. We summarize established and emerging clinical applications of rapamycin and its analogs, while critically addressing the limitations and adverse effects associated with mTOR inhibition. Furthermore, advances in translational research and future perspectives are also discussed. Collectively, current evidence supports mTOR inhibition as a unifying biological strategy for the prevention, treatment, and delayed onset of multiple chronic diseases, as well as for promoting healthspan. As the first clinically approved mTOR inhibitor, rapamycin has therefore become a foundational pharmacological tool for exploring the therapeutic potential of modulating the evolutionarily conserved mTOR signaling network across a broad spectrum of human diseases and age-related conditions.

Keywords:  Healthspan; Molecular target; Rapalogs; Rapamycin; mTOR

DOI:  https://doi.org/10.1016/j.bbagen.2026.131009
Biophys J. 2026 Sep 21. pii: S0006-3495(26)00655-7. [Epub ahead of print]

Molecular insights into ATP synthase c-ring accumulation in BMP-deficient lysosomes in Batten disease.

Leonhard J Starke, Erik K Hansen, Kasparas Petkevicius, Anna L Duncan.

Bis(monoacylglycero)phosphate (BMP) is a signature lysosomal phospholipid that supports the catabolic functions of the lysosome. We recently demonstrated that BMP deficiency is associated with a variant of Batten disease, a neurodegenerative lysosomal storage disorder. This observation led us to investigate how BMP deficiency contributes to the previously reported accumulation of the ATP synthase c-ring in the lysosomes of Batten disease patients and preclinical models. The c-ring is an inner mitochondrial membrane (IMM) protein complex that interacts with cardiolipin, a mitochondrial phospholipid that shares structural features with BMP. Based on this, we hypothesised that BMP may perform an analogous function to cardiolipin in lysosomes. Specifically, we proposed that BMP preferentially interacts with the c-ring, dispersing it within lysosomal membranes and facilitating its degradation. To test this hypothesis, we conducted all-atom molecular dynamics simulations to examine the interactions of various BMP variants with the c-ring of human ATP synthase under different membrane conditions. We observed leaflet-specific preferential interactions of BMP with the protein interface. Replacement of BMP with anionic 16:0-18:1 phosphatidylglycerol (POPG) lipids resulted in a distinct binding mode and shorter residence time at the c-ring, indicating the importance of BMP's unique structure with respect to protein binding. Furthermore, BMP enrichment was enhanced when using the physiologically relevant di-22:6 BMP variant in membranes containing polyunsaturated lipids and cholesterol. Overall, our study suggests that BMP promotes lysosomal c-ring degradation via c-ring co-localisation, whereas BMP deficiency in Batten disease drives c-ring accumulation.

DOI: https://doi.org/10.1016/j.bpj.2026.09.025
Circulation. 2026 Sep 22.

Asb2-KIF11 Axis Protects Against Heart Failure by Restoring Lysosomal Distribution and Mitochondrial Homeostasis.

Yicheng Lv, Zhao Sha, Shi Peng, Zhenzhen Duan, Qingye Zeng, Shengli Li, Hao Wu, Xiaoyu Zhang, Xiaoxun Huang, Jincheng Zhang, Shengkai Zuo, Deping Kong.

   BACKGROUND: Heart failure remains a leading cause of mortality globally, driven by persistent mitochondrial dysfunction and maladaptive cardiac hypertrophy. Although impaired autophagic flux contributes to cardiac deterioration, the precise molecular mechanisms are still unclear. The ubiquitin-proteasome system serves as a critical regulator linking protein ubiquitination to autophagic flux and mitochondrial homeostasis. Asb2 (ankyrin repeat-containing protein with suppressor of cytokine signaling box 2), a muscle-specific E3 ubiquitin ligase essential for embryonic cardiogenesis, is uncharacterized in adult cardiac homeostasis and disease pathogenesis.
METHODS: Male mice with inducible cardiomyocyte-specific Asb2 knockout were generated to investigate Asb2's role in cardiac remodeling. Adeno-associated virus 9-mediated cardiomyocyte-specific Asb2 overexpression and KIF11 (kinesin family member 11) downregulation were used in transverse aortic constriction-induced hypertrophy and aging models. RNA sequencing, metabolite profiling, and mass spectrometry were used to assess the molecular mechanism by which Asb2 regulates cardiac metabolism and hypertrophy.
RESULTS: Asb2β expression was significantly reduced in multiple forms of human cardiomyopathy and in hypertrophic murine hearts. Inducible Asb2 deletion in adult male mice led to the spontaneous development of cardiac hypertrophy and heart failure, accompanied by progressive accumulation of dysfunctional mitochondria and metabolic dysregulation. Mechanistically, Asb2 deficiency impaired ubiquitin-mediated degradation of KIF11, causing aberrant peripheral lysosomal redistribution and disrupting autophagosome-lysosome fusion, which resulted in impaired late-stage autophagic flux and metabolic disturbances. Notably, therapeutic restoration of Asb2 expression via adeno-associated virus 9-mediated delivery attenuated pressure overload-induced and age-related cardiac hypertrophy and heart failure. Moreover, both genetic and pharmacological inhibition of KIF11 effectively restored autophagic flux and mitochondrial homeostasis, thereby reversing pathological cardiac remodeling in Asb2-deficient hearts and transverse aortic constriction-induced cardiac dysfunction.
CONCLUSIONS: Asb2 is a novel regulator of mitochondrial quality control in cardiomyocytes via KIF11-mediated lysosomal redistribution. Targeting the Asb2-KIF11 axis may be a promising strategy for improving mitochondrial homeostasis and cardiomyocyte function in chronic heart failure.

Keywords:  Asb2; KIF11; autophagic flux; heart failure; lysosomal positioning; mitochondrial quality control

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.080625
Biology (Basel). 2026 Sep 16. pii: 1629. [Epub ahead of print]15(18):

Beyond Translation Initiation: Translational Elongation, Decoding Fidelity, and Ribosome Surveillance During Branched-Chain Amino Acid Deprivation, with a Focus on Mammalian Systems.

Mutsuki Ojima, Manami Matsuura, Miwako Deguchi, Dong-Ho Kim.

  In mammalian systems, translational responses to amino acid limitation are commonly framed as mechanistic target of rapamycin complex 1 (mTORC1) inhibition and activation of the general control nonderepressible 2 (GCN2)-eukaryotic initiation factor 2α (eIF2α) arm of the integrated stress response. Suppressing initiation, however, does not immediately relieve aminoacylated transfer RNA shortages for ribosomes already engaged on messenger RNA. Transfer RNA charging and ribosome profiling reveal codon- and isoacceptor-specific elongation constraints. Across mouse NIH3T3 and several human cell systems, leucine deprivation often appears initiation-dominant but can produce UUA-biased pausing and frameshifting in selected cancer cells. Valine deprivation can prolong decoding at all four valine codons, whereas separate isoleucine-deprivation studies report AUU/AUC-selective slowing, a cytoplasmic isoleucyl-tRNA synthetase 1 (IARS1)-linked isoleucine-to-valine signal in exogenous reporter peptides, and an isoleucine-to-methionine substitution signal of unresolved mechanism. Ribosome slowing can engage global, transcript-local, and quality-control feedback, but the inputs are stress- and system-dependent. We propose a two-layer kinetic framework separating (i) A-site competition among correct decoding, substitution, and abortive exit from (ii) collision formation set by ribosome influx and dwell time. It keeps protein quantity, sequence fidelity, retained function, and proteostasis cost separate, and defines a matched measurement roadmap from metabolite flux to protein function.

Keywords:  GCN2; aminoacyl-tRNA; branched-chain amino acids; integrated stress response; mistranslation; ribosome collision; ribosome stalling; ribosome-associated quality control

DOI:  https://doi.org/10.3390/biology15181629
Genes Dis. 2027 Jan;14(1): 102163

PINK1 deficiency exacerbates age-related bone loss in association with enhanced inflammatory adipocyte differentiation.

Min-Ji Sung, Hyun-Ju An, Hyunjeong Yeo, Sujin Choi, Min Heui Ha, Hye Yun Jeong, Jihyun Baek, Jung Sooyoung, So-Young Lee, Soonchul Lee.

  Age-related bone loss contributes to frailty, fractures, and increased mortality in the elderly, yet current osteoporosis treatments have limited long-term efficacy. Mitochondrial dysfunction is a hallmark of skeletal aging, but its role in mesenchymal lineage commitment remains unclear. Here, we investigated PTEN-induced kinase 1 (PINK1), a serine/threonine kinase essential for mitophagy, in regulating bone mass and adipogenic differentiation during aging. Using Pink1 knockout (Pink1 -/-) mice, we found that Pink1 deficiency exacerbated trabecular bone loss and promoted adipocyte hypertrophy in white adipose tissue. Calvarial pre-osteoblasts from Pink1 -/- mice displayed impaired osteogenic differentiation and increased adipogenesis, evidenced by reduced alkaline phosphatase (ALP) activity, mineralization, and osteogenic gene expression, alongside elevated lipid accumulation. In vitro, siRNA-mediated Pink1 knockdown in 3T3-L1 cells triggered adipogenic, inflammatory, and oxidative stress responses, while suppressing mitochondrial function and respiration. Collectively, these findings reveal that PINK1 preserves skeletal integrity by maintaining mitochondrial homeostasis and restraining stress-induced adipogenic reprogramming. Our study identifies the PINK1-mitophagy axis as a potential therapeutic target for preventing age-related bone loss and preserving bone health.

Keywords:  Adipogenesis; Age-related bone loss; Inflammation; Osteogenesis; PINK1

DOI:  https://doi.org/10.1016/j.gendis.2026.102163
Nature. 2026 Sep 23.

mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis.

Thomas L Li, John D Blair, Taesun Yoo, Gerald A Grant, Dirk Hockemeyer, Brenda E Porter, Helen S Bateup.

Tuberous sclerosis complex (TSC) is a genetic neurodevelopmental disorder characterized by focal brain malformations called cortical tubers, which are associated with severe, intractable epilepsy1. Tubers are thought to result from somatic second-hit mutations that disrupt the TSC1 or TSC2 genes in neural progenitor cells, driving hyperactive mTORC1 signalling2. Glial abnormalities are commonly observed in tubers3; however, whether glia actively cause disease or merely result from chronic seizure activity has remained unclear. To address this question, we used human brain organoid models to track the developmental fate of mutated progenitor cells in the absence of seizures. Here we show, using single-cell transcriptomics and cyclic immunostaining across human brain organoids and resected tuber tissue from patients, that loss of TSC2 biases neural progenitors to differentiate into enlarged, pro-inflammatory reactive astrocytes in a cell autonomous manner. These mutant astrocytes show downregulated glutamate transporter expression, increased inflammatory cytokine secretion and elevated expression of neurodegenerative disease risk genes such as APOE and CLU. Our findings demonstrate that reactive astrocytes emerge as a primary consequence of TSC2 loss. These results implicate glial dysfunction as a driver of TSC pathogenesis and highlight reactive astrocytes as potential therapeutic targets for TSC-related neuropathology.

DOI: https://doi.org/10.1038/s41586-026-11054-w
Front Nutr. 2026 ;13 1893670

Strawberry leaf extract protects dopaminergic neurons by restoring redox and mitochondrial homeostasis.

Chiharu Ueda, Tamaki Tokumatsu, Fuka Sogame, Nobuaki Chiba, Toshio Norikura, Yutaro Sasaki, Isao Matsui-Yuasa, Akiko Kojima-Yuasa.

   Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons, for which effective disease-modifying strategies remain limited. Mitochondrial dysfunction and oxidative stress are central drivers of PD pathogenesis, highlighting the importance of cellular defense mechanisms targeting these processes.
Methods: In the present study, we investigated the neuroprotective effects of strawberry leaf extract (SLE), an agricultural by-product rich in polyphenols, using both in vitro and in vivo models of PD.
Results: In SH-SY5Y cells, SLE significantly attenuated rotenone-induced loss of cell viability and suppressed intracellular reactive oxygen species (ROS) production. Mechanistically, SLE promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased the expression of antioxidant genes, including heme oxygenase-1 (HO-1) and p62. Pharmacological inhibition experiments further indicated that activation of AMP-activated protein kinase (AMPK) contributes to SLE-induced Nrf2 activation. In addition to redox regulation, SLE modulated mitochondrial quality control pathways. Time-dependent alterations in mitophagy-related markers, including PINK1, Parkin, LC3, and p62, were observed, accompanied by recovery of mitochondrial membrane potential. These findings suggest that SLE influences mitochondrial homeostasis under oxidative stress conditions. In a rotenone-induced PD mouse model, SLE administration ameliorated motor dysfunction and attenuated the loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra.
Discussion: Collectively, these results demonstrate that SLE exerts neuroprotective effects through coordinated regulation of the AMPK -Nrf2 signaling axis and mitochondrial quality control pathways. This study provides mechanistic insight into the potential of food-derived bioactive compounds as modulators of neurodegenerative processes and highlights SLE as a promising candidate for PD prevention or intervention.

Keywords:  AMPK; Nrf2; Parkinson’s disease; mitochondrial dysfunction; mitophagy; oxidative stress; strawberry leaf extract

DOI:  https://doi.org/10.3389/fnut.2026.1893670
Biochem Pharmacol. 2026 Sep 25. pii: S0006-2952(26)00845-2. [Epub ahead of print] 118503

Src inhibition attenuates neuroinflammation via promoting p62 UFMylation-dependent microglial mitophagy.

Yi-Rong Dong, Jin-Rong Wang, Yang Yang, Shou-Peng Cao, Mei-Chuan Zhou, Sen-Xiang Zeng, Hui-Qing Mi, Jia-Hui Wang, Cai-Xia Zang, Fang-Fang Li, Xiu-Qi Bao, Dan Zhang.

  Src tyrosine kinase, a prototypical oncogene, has recently emerged as a critical modulator of neuroinflammation. However, the precise molecular mechanisms underlying its regulatory role remain poorly characterized. Herein, pharmacological inhibition of Src attenuated lipopolysaccharide-induced neuroinflammatory responses in both in vivo and in vitro experiments. Proteomic analysis identified that microglial mitophagy and p62 UFMylation were involved in Src-mediated neuroinflammation. Further studies demonstrated that Src inhibition reduced the phosphorylation of UFL1, the E3 ligase of UFM1 conjugation, which correlated with decreased UFMylation of p62. Notably, the function of p62 was regulated by a dynamic interplay between UFMylation and ubiquitination. Consequently, diminished p62 UFMylation competitively facilitated ubiquitination of p62 at the same residue. This led to p62 degradation and induced microglial mitophagy, ultimately alleviating neuroinflammation. Moreover, Src inhibition significantly ameliorated neuroinflammatory pathology and cognitive deficits in LPS-challenged mice, an effect attributed to p62 UFMylation-mediated microglial mitophagy. Collectively, our findings revealed that the Src-UFL1-p62 signaling axis governing microglial mitophagy and neuroimmune homeostasis, positioning Src kinase as a promising therapeutic target for Alzheimer's disease and related neuroinflammatory disorders.

Keywords:  Alzheimer’s disease; Microglial mitophagy; Neuroinflammation; Src tyrosine kinase; UFMylation

DOI:  https://doi.org/10.1016/j.bcp.2026.118503
Antioxidants (Basel). 2026 Aug 22. pii: 1051. [Epub ahead of print]15(9):

Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43G376D ALS Patient-Derived Fibroblasts.

Giuseppe Petito, Maria Ventriglia, Victoria Stefania Del Fiore, Arianna Cuomo, Federica Cioffi, Francesco Manfrevola, Flora Guerra, Lucia Bertuccini, Giulia Ricci, Gilda Cobellis, Antonia Lanni, Cecilia Bucci, Roberta Romano, Rosalba Senese.

  Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder strongly associated with mitochondrial dysfunction and impaired proteostasis. Mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), contribute to disease pathogenesis through cytoplasmic mislocalization and aggregation. Among these, the ALS-linked TDP-43G376D mutation has been previously associated with oxidative stress, mitochondrial fragmentation, and impaired oxidative phosphorylation. Here, we investigated the impact of TDP-43G376D on Mitochondrial Quality Control (MQC) pathways using patient-derived dermal fibroblasts carrying the mutation at early and advanced disease stages, complemented by HEK293T and Neuro2a cellular models expressing mutant TDP-43. We show that TDP-43G376D impairs mitophagic flux, as evidenced by reduced delivery of damaged mitochondria to lysosomes. This was accompanied by pronounced disruption of mitochondrial cristae architecture and accumulation of mitochondrial DNA damage, indicating compromised mitochondrial genome integrity. Furthermore, TDP-43G376D induces sustained activation of the mitochondrial Unfolded Protein Response (UPRmt), consistent with persistent mitochondrial stress, while selectively impairing the sirtuin-dependent antioxidant branch. In parallel, activation of the Endoplasmic Reticulum UPR (UPRER) was observed, indicating a coordinated engagement of cellular stress pathways. Collectively, our findings identify coordinated alterations in multiple MQC pathways associated with TDP-43G376D rather than isolated mitochondrial defects, supporting further investigation of these pathways in larger and disease-relevant ALS models.

Keywords:  Amyotrophic Lateral Sclerosis (ALS); Endoplasmic Reticulum stress; Mitochondrial Quality Control (MQC); TDP-43; mitochondrial Unfolded Protein Response (UPRmt); mitochondrial dysfunction; mitophagy; oxidative stress

DOI:  https://doi.org/10.3390/antiox15091051
EMBO Rep. 2026 Sep 25.

LC3 forms functional nanoclusters on autophagosomes.

Saman Fatihi, Deepak M Khushalani, Joydipta Kar, Sourav Ghosh, Aayushi Singh, Suvapriya Roy, Anirban Banerjee, Nitin Mohan, Lipi Thukral.

Autophagosome biogenesis depends on the coordinated action of proteins and lipids. However, how LC3B organizes at high density and contributes to autophagy-associated functions remains unclear. Using molecular dynamics simulations and super-resolution microscopy, we show that LC3B self-assembles into higher-order nanoclusters approximately 150 nm in size. These clusters form spatially distinct LC3B "islands" on the autophagosome membrane and show a preferential association with phosphatidylinositol-3-phosphate (PI3P) lipids. Molecular analysis of 296 structural clusters reveals a putative LC3B homo-clustering interface characterized by a distinct alternating hydrophobic-polar motif. To experimentally validate this interface, we generated four LC3B mutants targeting the clustering motif. STORM imaging of the LC3 mutants demonstrates a complete alteration in clustering dynamics, with diffuse, smaller LC3 clusters on the autophagosome. Further, motility analysis and interaction with the autophagic adaptor protein FYCO1 show abrogated autophagosome motility. Finally, loss of LC3B nanoclustering also significantly compromises autophagic entrapment of Streptococcus pneumoniae and results in elevated intracellular bacterial survival. Taken together, our results reveal LC3 clustering as a potential organizing principle that coordinates the spatial and temporal dynamics of autophagy.

DOI: https://doi.org/10.1038/s44319-026-00931-0