bims-auttor 2026-11-08 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–11–08
thirty papers selected by
Viktor Korolchuk, Newcastle University

Rhes as a Potential Modulator of PINK1/Parkin-Dependent Mitophagy in Huntington's Disease.
Gcn5 and mTORC1 mediated regulation of autophagy controls Drosophila blood cell homeostasis.
Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging.
PHB2 connects mitochondrial membrane remodeling to selective autophagy.
Mitoxyperilysis and mitochondrial quality control in Parkinson's disease: emerging links to autophagy and neuronal death.
Cell type-dependent activation of autophagic flux by D-amino acids.
Nutrients and Their Role in Autophagy Regulation.
PRKN-independent mitophagy regulators in dopaminergic neurons identified by genome-wide CRISPR screening.
RICTOR regulates an interspecies crosstalk that influences longevity through a methionine cycle-mitophagy axis.
Amyloid beta governs mitochondrial lipid metabolism defects and neurodegenerative lysosomal stress.
Decoding the role of ADAptor2 (ADA2) of HAT complex in autophagy and phospholipid metabolism to maintain ER homeostasis and triterpene regulation.
Ume6 Coordinates Lysosomal Remodeling and Autophagy Through Transcriptional Repression in S. cerevisiae.
Lysosomal alkalinization: a convergent mechanism in lysosomal storage disorders and classical neurodegenerative diseases.
MOSPD3 reads an FFNT motif to anchor ATG2A on the ER.
Stress-induced Golgiphagy sustains tumor-promoting glycosylation in breast cancer.
Branched-chain amino acids in skeletal and cardiac muscles: a review of metabolic variations and cancer's impact.
Constitutive Activation of Skeletal Muscle mTORC1 Drives Pro-Inflammatory Gene Expression in Skeletal Muscle of Aged Mice.
In vivo imaging of autophagy dynamics in the intact mammalian brain using a fluorescence lifetime-based sensor.
Safe lysosomal sequestration of ferrous iron is mediated via cholesterol shielding and drives senescence and ferroptosis resistance.
PIKfyve inhibition induces LRRK2 activation through phosphatidylinositol 3-phosphate and CASM.
Brain clearance of protein aggregates in degenerative diseases: the role of microglia and astrocytes.
The FOXA2-BNIP3 axis alleviates acute necrotizing pancreatitis by promoting mitophagy in pancreatic acinar cells to inhibit mtDNA-Mediated AIM2 inflammasome activation.
KIF1A-driven entry of degradative lysosomes into the axon is developmentally regulated by the microtubule environment at the axon initial segment.
TSC2-Mutant Yucatan Minipig Cardiac Rhabdomyoma Model Reveals mTORC1 Activation and MITF/TFE Expression Signature.
The multifaceted roles of lysosomes in cancer.
Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing.
A rare TMEM175 mutation drives Parkinson's disease pathology by disrupting proton gating and lysosomal acidification.
Polyglutamine aggregation in the C. elegans nervous system is driven by stochastic nucleation events.
ADA2 controls autophagy-dependent mitochondrial fitness to restrain type I interferon activation.
The transport of protein aggregates to the vacuole suggests a role for lipid droplets in waste disposal in Saccharomyces cerevisiae.

J Integr Neurosci. 2026 Oct 26. 25(10): 53852

Rhes as a Potential Modulator of PINK1/Parkin-Dependent Mitophagy in Huntington's Disease.

Muhammad Saim, Hayder Al-Kazzaz, Haris Ahmad.

  Huntington's disease (HD) is an inherited neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin (HTT) gene, resulting in progressive motor, cognitive, and psychiatric impairment. Despite the widespread expression of mutant huntingtin (mHTT), disease progression is characterized by the selective degeneration of striatal neurons. Mitochondrial dysfunction and impaired mitophagy have emerged as important contributors to HD pathogenesis; however, the mechanisms underlying defective mitochondrial quality control remain incompletely understood. Ras homolog enriched in the striatum (Rhes), a small striatal-enriched guanosine triphosphatase (GTPase), has been implicated in mitophagy-related signalling. In this study, we examined the potential relationship between Rhes and PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy in HD. We propose that Rhes contributes to selective striatal vulnerability by promoting mitochondrial depolarization through BCL2 interacting protein 3-like (NIX/BNIP3L), facilitating activation of the PINK1/Parkin mitophagy pathway, while enhancing autophagosome biogenesis through Beclin-1 signalling. If validated, our proposed pathway would open new avenues for therapeutic development in HD.

Keywords:  Huntington disease; autophagy; huntingtin protein; mitochondria; mitochondrial diseases; mitophagy; neurodegenerative diseases; neurons; proteins; ubiquitination

DOI:  https://doi.org/10.31083/JIN53852
Elife. 2026 Nov 05. pii: RP91615. [Epub ahead of print]13

Gcn5 and mTORC1 mediated regulation of autophagy controls Drosophila blood cell homeostasis.

Arjun Aji Reeja, Mincy Kunjumon, Suraj Math, Laxmi Kata, Rohan Jayant Khadilkar.

  Blood progenitors are regulated by a variety of systemic and nutritional cues from their environment. In the Drosophila lymph gland (LG), the Posterior Signaling Center acts as a stem cell niche striking a balance between progenitors and differentiated blood cells. Autophagy is a vital cellular process that maintains homeostasis by removing unnecessary or dysfunctional cell components through autophagic degradation and recycling. Here, using genetic perturbation analysis, we show that autophagy plays a critical role in regulating LG blood cell homeostasis. General control non-derepressible 5 (Gcn5), a histone acetyltransferase, is expressed in the primary LG lobe, and modulation of Gcn5 levels perturbs LG homeostasis. Our results show that hemocyte-specific Gcn5 modulation controls autophagic flux in the hemocytes. Furthermore, we show that modulation of mTORC1 activity can perturb hematopoiesis. Our results indicate that organismal Gcn5 levels respond to dietary shifts and are modulated by mTORC1 signaling. Chemical intervention shows that mTORC1 overrides the effect exerted by Gcn5 in regulating LG hematopoiesis. Taken together, our findings demonstrate that Gcn5 and mTORC1 regulate autophagy to maintain blood cell homeostasis in Drosophila.

Keywords:  D. melanogaster; Drosophila; Gcn5; autophagy; developmental biology; hematopoiesis

DOI:  https://doi.org/10.7554/eLife.91615
Front Aging Neurosci. 2026 ;18 1903701

Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging.

Emilie M Legault, Juan-Pablo Izabal Gamez, Janelle Drouin-Ouellet.

   Introduction: In humans, aging is associated with an increased risk of developing neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). In neurons, the effect of aging on intrinsic molecular processes, and how they tie to age-related neurodegeneration remains unclear. Animal studies have shown that mitochondrial function decline, autophagy impairment and defective elimination of damaged mitochondria by mitophagy are all central features of neuronal aging. However, very few studies have investigated such events in human neurons, due to a lack of models showing aging features. Therefore, there is a crucial need for a better understanding of the effect of aging on neuronal health.
Methods: Here, we use direct neuronal reprogramming, which maintains signatures of cellular aging, to study the effect of aging on mitochondrial health and mitophagy in human neurons derived from healthy donors ranging from 11 to 91 years old. We use confocal imaging to assess colocalization of mitochondria with autophagic structures following mitophagy induction.
Results: We show age-related mitochondrial impairment in neurites of induced neurons (iNs) derived from older donors. Additionally, in these neurites, we show an accumulation of mitochondria targeted for degradation in autophagosomes and LAMP1-positive lysosomal vesicles following mitophagy induction. These impairments culminate into incomplete elimination of damaged mitochondria, despite preserved activity of the lysosomal enzymes assessed.
Conclusion: This study shows for the first time age-related mitophagy impairment in human neurons, and confirms findings of age-related mitochondrial impairments in human neurons. By doing so, this study paves the way for more in-depth mechanistic studies that would allow for the identification of therapeutic targets for anti-aging treatment and in the context of age-associated neurodegenerative diseases.

Keywords:  aging; direct neuronal reprogramming; human neurons; induced neurons; lysosomal function; mitochondria; mitochondrial health; mitophagy

DOI:  https://doi.org/10.3389/fnagi.2026.1903701
Autophagy. 2026 Nov 04.

PHB2 connects mitochondrial membrane remodeling to selective autophagy.

Yong Wu, Qi Wu, Zi-Jun Zhan, Yuxiong Guo, Chuang Wang, Guang Lu.

  PHB2 (prohibitin 2), a well-known inner mitochondrial membrane mitophagy receptor, has recently emerged as a potential sensor of intracellular bacteria. A recent study shows that increased exposure of the inner mitochondrial membrane protein PHB2 enables its interaction with bacterial surface proteins and the recruitment of the E3 ubiquitin ligases ARIH1 (ariadne RBR E3 ubiquitin protein ligase 1) or PRKN (parkin RBR E3 ubiquitin protein ligase), thereby promoting xenophagy. This finding expands the role of damaged mitochondria from autophagic cargo to an active platform for antibacterial defense. It also raises broader questions regarding how an inner mitochondrial membrane protein becomes accessible to invading bacteria, why PHB2 can recognize bacterial proteins, and what determines whether exposed PHB2 promotes mitophagy, xenophagy, or co-degradation of both cargos. Here, we discuss PHB2 as a potential damage-unmasked bacterial sensor, the contribution of mitochondrial membrane remodeling to its exposure, and the evolutionary relationship between mitochondrial and bacterial recognition. We further consider whether impaired mitophagy may compromise xenophagic competence in aging and disease.

Keywords:  Innate immunity; PHB2; mitochondrial membrane; mitophagy; xenophagy

DOI:  https://doi.org/10.1080/15548627.2026.2759481
Apoptosis. 2026 Nov 03. pii: 256. [Epub ahead of print]31(11):

Mitoxyperilysis and mitochondrial quality control in Parkinson's disease: emerging links to autophagy and neuronal death.

Xinghua Tian, Biao Zhang, Jianshe Wei.

  Parkinson's disease (PD) is the second‑most prevalent central‑nervous‑system neurodegenerative disorder, pathologically characterized by progressive midbrain dopaminergic neuron loss and α‑synuclein‑aggregated Lewy bodies. Impaired mitophagy‑autophagy‑lysosomal quality control is a well‑documented upstream feature of PD; however, its characterization as a core causal driver-and how, or whether, mitophagy insufficiency is converted into irreversible dopaminergic neuronal death-remains incompletely resolved and lacks direct human evidence. Mitoxyperilysis is a recently described non‑caspase‑dependent lytic regulated cell‑death pathway. It can be triggered by combined innate‑immune activation and cellular metabolic disturbance, featuring mitochondrial oxidative stress, stable mitochondria‑plasma‑membrane anchoring and focal lipid‑peroxidation‑driven membrane rupture under the primary regulatory influence of the mTORC2-RhoA-cytoskeleton axis, a regulatory role established primarily in non-PD innate-immune and metabolic stress models. Mitophagy deficiency cannot directly initiate mitoxyperilysis but increases neuronal susceptibility by enabling persistent accumulation of ROS‑generating damaged mitochondria. This review summarizes mitoxyperilysis's core features, regulatory cascades and detection approaches, focusing on its bidirectional crosstalk with the mitophagy‑autophagy‑lysosomal system. We discuss how PD‑associated genetic variants, α‑synuclein aggregation and neuroinflammation disrupt mitophagy‑lysosomal homeostasis and may predispose dopaminergic neurons to mitoxyperilysis‑related injury. We overview pre‑clinical therapeutic candidates and potential biomarkers, and consider plausible links to other neurodegenerative diseases, peripheral pathology and aging. Critical caveats are highlighted: most supporting data derive from cell and animal models, and unambiguous evidence for bona‑fide mitoxyperilysis in human PD tissues remains absent. We outline translational bottlenecks and future priorities centred on autophagy‑mitophagy‑mitoxyperilysis signalling crosstalk, offering proposed mechanistic perspectives that may connect mitophagy-lysosomal dysfunction to neuronal demise, a causal linkage that has not yet been directly demonstrated in human PD, together with conceptual considerations for PD drug discovery and early intervention.

Keywords:  Mitochondrial dysfunction; Mitoxyperilysis; Oxidative stress; Parkinson''s disease; mTORC2

DOI:  https://doi.org/10.1007/s10495-026-02465-1
Biochem Biophys Res Commun. 2026 Oct 19. pii: S0006-291X(26)01537-8. [Epub ahead of print]842 154771

Cell type-dependent activation of autophagic flux by D-amino acids.

Hiroto Seki, Yuki Marugame, Reina Mimata, Nanami Inoue, Takenori Tanaka, Fumihiko Okumura, Satoshi Yano, Taichi Hara.

  Although D-amino acids were long considered to have limited biological significance because they are less abundant in vivo than L-amino acids, they have now been detected in various mammalian tissues, and their physiological functions have been identified for some of them. Autophagy maintains cellular homeostasis and is implicated in aging and a wide range of diseases. Its regulation by L-amino acids is well established, but whether D-amino acids modulate autophagic flux across cell types remains unclear. Here, we screened 20 D-amino acids in HeLa, Caco-2, SH-SY5Y, and HaCaT cells expressing the GFP-LC3-RFP(-LC3ΔG) autophagic flux reporter. The responses differed substantially by cell type: D-Asp and D-Met increased autophagic flux in all four cell lines, whereas D-Ser and D-Pro increased autophagic flux only in SH-SY5Y and HaCaT cells, respectively. To investigate whether mTORC1 suppression accompanied these responses, we measured the phosphorylation of its downstream target p70 S6 kinase. Unlike the mTOR inhibitor Torin1, d-amino acids that altered autophagic flux did not reduce p70 S6 kinase phosphorylation. These findings reveal both shared and cell type-dependent responses to d-amino acids and suggest that d-amino acids promote autophagy, at least in part, independently of mTORC1 inhibition. This study provides a basis for investigating the biological roles of d-amino acids and their potential relevance to food science.

Keywords:  Autophagic flux; Caco-2 cells; HaCaT cells; SH-SY5Y cells; d-amino acid; mTORC1

DOI:  https://doi.org/10.1016/j.bbrc.2026.154771
Biochemistry. 2026 Nov 03. 65(21): 3349-3370

Nutrients and Their Role in Autophagy Regulation.

Niall Wilson, Gamze Kocak, Sovan Sarkar, Yoana Rabanal Ruiz, Viktor I Korolchuk.

  Autophagy is a fundamental catabolic pathway that maintains cellular homeostasis through the degradation and recycling of intracellular components in response to nutrient limitation and metabolic stress. Increasing evidence indicates that autophagy is tightly regulated by cellular metabolism, with nutrients and metabolites acting not only as energy substrates and biosynthetic intermediates, but also as signaling molecules that directly modulate the autophagic machinery. In this review, we discuss how different metabolites regulate autophagy through interconnected nutrient- and energy-sensing pathways. We further examine how these metabolic signals coordinate distinct stages of autophagosome biogenesis and autophagic flux under conditions of nutrient deprivation or energy stress. Collectively, metabolite-autophagy crosstalk emerges as a central mechanism that enables cells to balance metabolic demand with intracellular resource availability, while its dysregulation contributes to metabolic imbalance and age-associated pathology.

Keywords:  autophagy; cellular homeostasis; endoplasmic reticulum (ER); metabolism; phagophore assembly site (PAS)

DOI:  https://doi.org/10.1021/acs.biochem.6c00482
Neurosci Res. 2026 Nov 05. pii: S0168-0102(26)00141-0. [Epub ahead of print] 105154

PRKN-independent mitophagy regulators in dopaminergic neurons identified by genome-wide CRISPR screening.

Takanori Nishimura, Yuya Kunisada, Hongmei Lisa Li, Chad A Highfill, Koji Nagasawa, Yoshiyuki Tsujihata.

  Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Genetic and epidemiological studies have suggested that mitochondrial dysfunction is implicated in the development of PD. PRKN/Parkin is known to play an essential role in mitochondrial quality control and mitophagy. Indeed, mutations and inactivation of this gene are associated with hereditary and idiopathic forms of PD. Despite extensive studies on PRKN-dependent mitophagy, the molecular regulators of PRKN-independent mitophagy in dopaminergic neurons remain incompletely understood. We generated a PRKN knockout iPSC-derived dopaminergic neuronal line expressing the fluorescent mitophagy biosensor mito-SRAI, which reports the delivery of mitochondria to lysosomes as an increase in the TOLLES/YPet fluorescence ratio. We used this cell line to conduct a genome-wide CRISPR knockout screen to reveal genetic regulators involved in PRKN-independent mitophagy. Dozens of genes were identified whose knockout increased the TOLLES/YPet ratio in an uncoupler-dependent manner. Of these, several genes emerged as candidates with potential therapeutic implications, one of which was Cathepsin F (CTSF). CCCP treatment increased the TOLLES/YPet ratio in neurons with siRNA-mediated CTSF knockdown, and CTSF knockdown partially preserved the proportion of tyrosine hydroxylase-positive dopaminergic neurons after paraquat exposure. These results suggest that CTSF is a candidate regulator of PRKN-independent mitophagy and that this lysosomal enzyme may represent a potentially druggable candidate target for PD.

Keywords:  CRISPR screen; CTSF; PRKN; Parkinson’s disease; iPSC-derived dopaminergic neurons; mitophagy

DOI:  https://doi.org/10.1016/j.neures.2026.105154
Nat Commun. 2026 09 14. pii: 11299. [Epub ahead of print]17(1):

RICTOR regulates an interspecies crosstalk that influences longevity through a methionine cycle-mitophagy axis.

Simran Motwani, Somya Bhandari, Shivani Chitkara, Rajat Ujjainiya, Prerona Ghosh, Shantanu Sengupta, Arnab Mukhopadhyay.

Adaptive modulation of physiological traits in response to dietary fluctuations is essential for organismal fitness and is governed by complex gene-diet interactions that remain mechanistically unexplored. Here, we identify the conserved mTORC2 component RICTOR as a critical regulator of dietary plasticity in Caenorhabditis elegans. Loss of rict-1/RICTOR confers enhanced osmotic stress tolerance and longevity on vitamin B12-rich bacterial diets containing optimal methionine. These adaptations require two B12-dependent enzymes: methionine synthase (METR-1), functioning in the one-carbon cycle (Met-C), and methylmalonyl-CoA mutase (MMCM-1), a mitochondrial enzyme essential for propionate catabolism which generates succinyl-CoA, and via the TCA cycle, succinate. Elevated succinate induces mitochondrial fragmentation, activating mitophagy that is indispensable for the stress resilience and longevity of rict-1 mutant worms. This host Met-C-mitophagy axis is tuned by microbial inputs, constituting an interspecies interaction. Early-life fragmentation potentiates sustained mitophagy into late adulthood, preserving tubular mitochondria as the rict-1 mutant worms age, unlike wild-type worms. Thus, RICTOR restrains host sensitivity to microbe-derived metabolite fluctuations through organellar quality control, regulating lifespan.

DOI: https://doi.org/10.1038/s41467-026-77722-7
EMBO Rep. 2026 Nov 02.

Amyloid beta governs mitochondrial lipid metabolism defects and neurodegenerative lysosomal stress.

Chase Walton, Natalia Oleinik, Mohamed Faisal Kassir, Han Gyul Lee, Narayan R Bhat, Kumar Sambamurti, Onder Albayram, Peggi Angel, Gavin Y Wang, Rajendran J C Bose, Khanh Ha, Jason R McCarthy, Besim Ogretmen.

Mechanisms linking amyloid peptides to mitochondrial dysfunction and impaired mitophagy in Alzheimer's disease (AD) remain poorly defined. Here, we report that, in healthy aging neurons, mitochondrial ceramide synthase 1 (CerS1) localization accompanies increased mitochondrial C18-ceramide and mitophagy in damaged mitochondria. In neuronal, mouse, and human AD tissues, amyloid precursor protein (APP) or Aβ40, but not Aβ42, shows increased proximity or co-association with TOM20/TOM40 alongside reduced mitochondrial CerS1/C18-ceramide accumulation and mitophagy. Mitochondria-excluded mutant APP does not reproduce these responses in neuronal cells. WT-APP expression is associated with reduced p17/PERMIT-ICT1 proximity, which does not establish direct APP-ICT1 binding or disruption of complex formation. Reduced mitophagy also accompanies lysosomal Aβ42 accumulation and secretion from neurons. Aged CerS1top/top mice, expressing catalytically inactive CerS1, exhibit mitochondrial dysfunction, behavioral deficits, and amyloid-positive plaque accumulation. Treatment with the peptide-targeted nanoparticle Pen-Cera-LCL768, which accumulates in the brain after intranasal administration, increases mitophagy-related readouts, reduces plaque burden, and improves behavioral performance in aged 3xTg and CerS1top/top mice. Mdivi-1 attenuates treatment effects in 3xTg mice, but its lack of specificity limits conclusions about mitophagy dependence.

DOI: https://doi.org/10.1038/s44319-026-00984-1
Arch Biochem Biophys. 2026 Nov 04. pii: S0003-9861(26)00316-4. [Epub ahead of print] 111043

Decoding the role of ADAptor2 (ADA2) of HAT complex in autophagy and phospholipid metabolism to maintain ER homeostasis and triterpene regulation.

Alka Rathore, Budarapu Gouri Priya, Niveditha N Nawada, Degala Venkata Shashank, Monala Jayaprakash Rao, Manjushri Anbarasu, Ravi Manjithaya, Ashutosh K Tiwari, C H Ratnasekhar, D K Venkata Rao.

  In yeast, transcriptional adaptor 2 (ADA2; SAGA complex subunit ADA2), a member of histone acetyltransferase (HAT) complex, regulates transcription through cell signalling, but its precise role in cellular metabolism remains unclear. In this study, genetic loss of ADA2 (ada2Δ) induces squalene (SQ) accumulation, indicating aberrant triterpene metabolism, coupled with endoplasmic reticulum (ER)/nuclear ER (nER) expansion. Lipid analyses of ada2Δ revealed elevated phosphatidic acid (PA) and phosphatidylcholine (PC) levels, indicating disrupted phospholipid metabolism. The expanded ER causes basal autophagy elevation, cellular recycling, and nER phagy, suggesting a regulatory role for ADA2 in autophagy. Downregulation of phosphatidate cytidylyltransferase (CDS1) and inositol-3-phosphate synthase (INO1), coupled with elevated PA and PC in ada2Δ, points to a significant disruption in cytidine-diphosphate-diacylglycerol and phosphatidylinositol pathway. Overexpression of CDS1 or INO1, or the inositol supplementation, in ada2Δ restores SQ, basal autophagy and ER phagy. The observed target of rapamycin Ser/Thr kinase complex (TORC1) activity in ada2Δ is due to the high PA content. Rapamycin-mediated inhibition of TORC1 reduced SQ, PA and ER expansion while increasing lipid droplets. In contrast, a rapamycin-treated ada2Δpah1Δ strain retained high PA, SQ and ER expansion, underscoring the functional role of TORC1-nuclear envelope morphology protein 1 (Nem1)/sporulation-specific protein SPO7 (Spo7)-Pah1 axis. Notably, SQ levels remained unchanged in a rapamycin-treated ada2Δatg39Δ strain, suggesting that loss of nER-phagy receptor, Atg39, impairs the effectiveness of TORC1 inhibition. In conclusion, our data unveiled a critical role for Ada2 in maintaining the intricate relationship between lipid and triterpene/sterol metabolism and connecting autophagy and ER homeostasis.

Keywords:  ADA2; CDS1; INO1; autophagy; phospholipids; squalene; sterol

DOI:  https://doi.org/10.1016/j.abb.2026.111043
bioRxiv. 2026 Oct 30. pii: 2026.10.29.762757. [Epub ahead of print]

Ume6 Coordinates Lysosomal Remodeling and Autophagy Through Transcriptional Repression in S. cerevisiae.

Olivia Evans, Alexis Hoy, Isabel Woo, Xi Yang.

Lysosome function and autophagy are highly regulated processes that must be coordinated to enable cellular adaptation to stress. However, the transcriptional mechanisms linking these pathways remain incompletely understood. Here, we identify Ume6 as a transcriptional repressor that regulates vacuolar protein composition and autophagy in Saccharomyces cerevisiae (budding yeast). Dysregulation of Ume6 alters vacuolar protein composition through two distinct mechanisms: increased abundance of multiple vacuolar components and enhanced degradation of selected vacuolar membrane proteins by elevated expression of the vacuolar E3 ubiquitin ligases. UME6 deletion also increases autophagic activity, whereas UME6 overexpression delays autophagy induction. Furthermore, we find that Ume6 coordinates with another transcriptional repressor, Rph1, and its regulatory activity is regulated by multiple protein kinases, including Rim15, Rim11, and Mck1. Together, our study reveal a broad transcriptional regulatory mechanism through which Ume6 coordinates vacuolar protein composition and autophagy, providing new insights into the regulation of lysosome-related functions in response to cellular stress.

DOI: https://doi.org/10.64898/2026.10.29.762757
Cell Commun Signal. 2026 Aug 08. pii: 596. [Epub ahead of print]24(1):

Lysosomal alkalinization: a convergent mechanism in lysosomal storage disorders and classical neurodegenerative diseases.

Ankur Rakesh Dubey, Saurabh Kumar, Ruchira Singh.

  Lysosomes are important cellular organelles involved in the recycling of biomolecules in the cell. The acidic intraluminal pH of the lysosome is necessary for the functioning of various hydrolytic enzymes involved in the recycling of biomolecules. Elevated lysosomal pH has been consistently documented in pathological conditions associated with progressive neurodegeneration, including several classical neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease) and lysosomal storage disorders or LSDs (e.g., Gaucher disease, CLN3 disease). This review focuses on the molecular mechanisms of lysosomal pH regulation, describing the critical roles of vacuolar ATPases and ion channels in maintaining lysosomal pH homeostasis. Further, we highlight how defective acidification of the lysosome can promote common cellular defects linked with both classical neurodegeneration and LSDs. The review also draws a parallel between the pathological consequences of experimentally-induced lysosomal alkalinization and two complex classes of disorders: classical neurodegeneration and LSDs. This comparison raises the possibility that lysosomal pH is one of the multiple shared contributing mechanisms for both conditions and, therefore, a conceivable therapeutic target of classical neurodegeneration and LSDs.

Keywords:  Lysosomal acidification; Lysosomal alkalinization; Lysosome; Lysosome Storage Disorder; Neurodegeneration

DOI:  https://doi.org/10.1186/s12964-026-03118-1
Autophagy. 2026 Nov 03. 1-3

MOSPD3 reads an FFNT motif to anchor ATG2A on the ER.

Nanxin Ye, Wei-Ke Ji.

  ATG2A and ATG2B are bridge-like lipid transfer proteins that carry glycerophospholipids from the endoplasmic reticulum (ER) to the expanding phagophore. The phagophore end of the bridge is well described, but how the ER end is held in place has remained unclear. Our recent study identified MOSPD3, an atypical member of the VAMP-associated protein (VAP) family, as an ER receptor for ATG2A: its major sperm protein (MSP) domain captures an FFNT (two phenylalanines in a neutral tract) motif near the N terminus of ATG2A, whereas ATG2B is recruited redundantly by MOSPD1 and MOSPD3. These findings identify a receptor-based anchor at the ER end of the bridge and raise new questions about how it is organized and regulated.Abbreviations: ATG: autophagy related; ER: endoplasmic reticulum; ERES: ER exit sites; FFAT: two phenylalanines in an acidic tract; FFNT: two phenylalanines in a neutral tract; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MOSPD1: motile sperm domain containing 1; MOSPD3: motile sperm domain containing 3; MSP: major sperm protein; SEC31A: SEC31 homolog A, COPII coat complex component; TMEM41B: transmembrane protein 41B; VAP: VAMP-associated protein; VMP1: vacuole membrane protein 1; WDR45/WIPI4: WD repeat domain 45; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.

Keywords:  ATG2A; FFNT motif; MOSPD1; MOSPD3; autophagosome; endoplasmic reticulum

DOI:  https://doi.org/10.1080/15548627.2026.2758481
Autophagy. 2026 Nov 06. 1-3

Stress-induced Golgiphagy sustains tumor-promoting glycosylation in breast cancer.

Jiaxin Xu, Yixian Cui.

  Golgiphagy contributes to Golgi quality control, yet its regulatory mechanisms and physiological functions remain poorly understood. We identify the deubiquitinase USP28 as an upstream regulator of TM9SF3-dependent Golgiphagy. Nutrient deprivation and Golgi stress induce CRM1-dependent nuclear export of USP28, enabling its translocation to the Golgi, where it removes K48-linked ubiquitin chains from TM9SF3 to prevent its proteasomal degradation and promote Golgiphagy. TM9SF3-dependent Golgiphagy regulates glycosyltransferase abundance through selective degradation of cargo such as MGAT5, thereby maintaining glycosylation homeostasis. Genetic or pharmacological inhibition of the USP28-TM9SF3-Golgiphagy pathway disrupts glycosylation homeostasis and suppresses breast tumor growth. Together, these findings establish the USP28-TM9SF3 axis as a regulatory mechanism linking Golgiphagy to glycosylation homeostasis and breast cancer progression.Abbreviations: CRM1: chromosome region maintenance 1; ER: endoplasmic reticulum; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MGAT5: alpha-1,6-mannosylglycoprotein 6-beta-Nacetylglucosaminyltransferase; TM9SF3: transmembrane 9 superfamily member 3; USP28: ubiquitin specific peptidase 28.

Keywords:  Glycosyltransferase turnover; Golgi quality control; MGAT5; TM9SF3; USP28; proteasomal degradation; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2759222
Front Physiol. 2026 ;17 1943433

Branched-chain amino acids in skeletal and cardiac muscles: a review of metabolic variations and cancer's impact.

Julian Chrzanowski, Wojciech Graboń, Karolina Buchajska, Agnieszka Cudnoch-Jędrzejewska.

  Branched-chain amino acids (BCAA) - leucine, isoleucine, and valine - serve as essential regulators of energy homeostasis, protein turnover, and nutrient signaling in striated muscle. However, their metabolic processing varies substantially across tissues. This review contrasts BCAA metabolism in skeletal versus cardiac muscle and evaluates how cancer alters it. Skeletal muscle functions as the main site for whole-body BCAA transamination and oxidation, distributing these amino acids between protein synthesis and oxidative catabolism in line with physiological needs. In comparison, the myocardium maintains low baseline BCAA oxidation, depends primarily on fatty acids and glucose, and tightly limits BCAA catabolic flux to prevent the buildup of intermediates that would undermine mitochondrial function. In malignancies, BCAA metabolism is reconfigured in a way that depends on tumor type: many tumors increase BCAA uptake and suppress catabolism in order to preserve intracellular stores, as a result maintaining mechanistic target of rapamycin complex 1 (mTORC1) signaling and supporting proliferation. Using lung, pancreatic and colorectal cancers as main examples, we outline how this tumor-driven metabolic rewiring is linked to cancer cachexia - a multi-organ syndrome in which inflammation, mitochondrial dysfunction, and impaired anabolic signaling promote muscle and cardiac wasting rather than simple substrate limitation. We describe first the mechanisms shared by skeletal and cardiac muscle, then the features specific to each tumor type, and we distinguish throughout between cardiac evidence obtained in tumor-bearing hosts and inferences extrapolated from heart failure. We conclude that interventions directed at BCAA are most reasonable early in the disease course, and only when paired with approaches that suppress inflammation and restore mitochondrial quality control. We also identify priorities for tissue-specific biomarkers and for future research.

Keywords:  BCAA catabolism; branched-chain amino acids; cancer cachexia; cardiac muscle; muscle wasting; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2026.1943433
Aging Cell. 2026 Nov;pii: e70805. [Epub ahead of print]25(11):

Constitutive Activation of Skeletal Muscle mTORC1 Drives Pro-Inflammatory Gene Expression in Skeletal Muscle of Aged Mice.

Erik D Marchant, Hanna Kalenta, Jacquelyn May, Zhao Lai, Adam B Salmon, Blake B Rasmussen.

  mTORC1 activity is increased in muscle with aging and is implicated as a potential driver of age-related declines in muscle health. While pharmacological inhibition of mTORC1 improves lifespan and healthspan, it remains unclear whether chronic activation of mTORC1 is sufficient to accelerate aging in skeletal muscle. We aimed to address this question using an inducible model of muscle-specific knockout of Depdc5, which encodes the protein DEP domain containing 5 (DEPDC5), a negative regulator of mTORC1. In 27-month-old mice, Depdc5 knockout induced a robust upregulation of inflammatory and immune-related genes, accompanied by alterations in metabolic and angiogenic pathways. Additionally, Depdc5 knockout mice exhibited an increase in TNF-α protein expression. However, these transcriptional and protein changes were not associated with an altered macrophage phenotype or with changes in muscle capillary density. Dietary rapamycin partially reversed mTORC1 signaling and some of the transcriptional changes, including those related to angiogenesis, but did not suppress inflammation-related transcripts or protein expression. These findings demonstrate that constitutive activation of mTORC1 is sufficient to drive pro-inflammatory changes in aged skeletal muscle, adding to the inflammation that already occurs with aging.

Keywords:  aging; geroscience; inflammaging; inflammation; mTOR; nutrient sensing

DOI:  https://doi.org/10.1111/acel.70805
bioRxiv. 2026 Oct 30. pii: 2025.12.25.693346. [Epub ahead of print]

In vivo imaging of autophagy dynamics in the intact mammalian brain using a fluorescence lifetime-based sensor.

Maya Maman, Kota Ando, Natalie Fisher, Connon Thomas, Yoel Levy, Gregory Bond, Tomer Kagan, Nikol Malchenko, Muriel Desbois, Shelly Ben Zaken, Shay Orovan, Gal Uzan, Sharbel Eid, Guy Naftchi, Shireen Sarji, Michal Lapidot, Rebecca Rapaport, Emanuela Perah Break, Maayan Gal, Anza Darehshouri, Brock Grill, Yusuke Hirabayashi, Benjamin Scholl, Tal Laviv.

Autophagy regulates neuronal development, plasticity, and metabolism, yet our ability to monitor its spatial and temporal organization within intact mammalian neural circuits remains limited. We developed an imaging approach combining a pH-sensitive fluorescence lifetime readout with independent morphological labeling to quantify autophagic vesicle state, abundance, and trafficking in vivo. Following pharmacological, genetic, and ultrastructural validations, we resolved compartment-specific autophagy levels across somata, dendrites, and axons of layer 2/3 cortical excitatory neurons in the intact mouse brain. We uncovered distinct patterns of dendritic autophagy in vivo, revealing faster autophagic vesicle trafficking in distal than proximal dendrites, that were preferentially sensitive to sensory experience. Using a newly generated transgenic mouse line, we found distinct cell-type-specific basal autophagy in excitatory neurons, interneurons, astrocytes, and oligodendrocytes. These findings reveal the spatial, cell-type-specific, and activity-dependent organization of autophagy in the brain and establish a framework for investigating its regulation during development, plasticity, and disease.

DOI: https://doi.org/10.64898/2025.12.25.693346
EMBO J. 2026 Nov 02.

Safe lysosomal sequestration of ferrous iron is mediated via cholesterol shielding and drives senescence and ferroptosis resistance.

Izumi Yanatori, Tasuku Hirayama, Raku Son, Yasuhiro Murakawa, Yuta Matsuoka, Yuki Sugiura, Masato Niwa, Tatsuya Katsuno, Masahiko Tsujimoto, Hiroyuki Yasui, Atsuyasu Sato, Makoto Nakanishi, Kazuhiro Iwai.

Iron accumulation is a conserved hallmark of cellular as well as organismal aging, yet its mechanistic role in senescence remains largely elusive. Here we show that the accumulation of ferrous iron (Fe2+) in lysosomes, a unique feature of senescent cells, is crucial for the induction of multiple senescence-associated phenotypes. Intriguingly, we found that this lysosomal Fe2+ sequestration is rendered "safe" by a dual metabolic adaptation that confers robust resistance to ferroptosis. First, Fe2+ accumulation triggers lysosomal alkalinization and subsequent cholesterol accumulation, which reinforces the lysosomal membrane against permeabilization. Second, senescent cells partition polyunsaturated fatty acids into lipid droplets, thereby depleting these ferroptosis-prone substrates from cellular membranes. Our findings establish that such cholesterol-enabled safe sequestration of Fe2+ serves as a central modulator linking senescence-associated remodeling to ferroptosis resistance. Modulating this lysosomal iron-centered pathway may provide new opportunities to target and control the behavior of senescent cells.

DOI: https://doi.org/10.1038/s44318-026-00939-1
Life Sci Alliance. 2027 Jan;pii: e202603939. [Epub ahead of print]10(1):

PIKfyve inhibition induces LRRK2 activation through phosphatidylinositol 3-phosphate and CASM.

Tomoki Kuwahara, Gen Yoshii, Maria Sakurai, Shoichi Suenaga, Hiroki Nakanishi, Matthew Jefferson, Thomas Wileman, Kentaro Tomii, Takeshi Iwatsubo.

LRRK2 is a Parkinson's disease-associated kinase that phosphorylates Rab GTPases. Hyperactivation of LRRK2, which is thought to cause Parkinson's disease, occurs on stressed endolysosomal membranes via conjugation of ATG8 to single membranes (CASM) and Rab, whereas the involvement of specific membrane lipids remained unclear. Here, we found that the inhibition of PIKfyve that metabolizes phosphatidylinositol 3-phosphate (PI3P) induces hyperactivation of LRRK2 and that additional inhibition of the class III phosphoinositide 3-kinase that generates PI3P suppressed LRRK2 hyperactivation. Cellular PI3P levels were indeed elevated when LRRK2 was activated. CASM-induced activation of LRRK2, but not CASM itself, was suppressed by phosphoinositide 3-kinase inhibitors, whereas inhibition of CASM or Rab12/Rab29 suppressed LRRK2 activation induced by PIKfyve inhibitors. LRRK2 and phospho-Rab10 were colocalized with PI3P on LAMP1-positive enlarged vacuoles, and LRRK2 directly bound PI3P in vitro via its N-terminal positively charged amino acids. Together, we propose an updated mechanism of LRRK2 hyperactivation that simultaneously requires CASM, Rab, and PI3P-rich membranes.

DOI: https://doi.org/10.26508/lsa.202603939
Transl Neurodegener. 2026 Nov 04. pii: 59. [Epub ahead of print]15(1):

Brain clearance of protein aggregates in degenerative diseases: the role of microglia and astrocytes.

Min Xiong, Yeyu Huang, Haiqiang Jiang, Zhentao Zhang.

  Protein aggregation and impaired clearance constitute central pathological hallmarks of numerous neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Misfolded proteins, both extracellular and intracellular, disrupt proteostasis and contribute to synaptic dysfunction, neuroinflammation, and neuronal loss. Within the central nervous system, glial cells serve as the primary mediators of pathological protein clearance. Microglia detect, phagocytose, and degrade aggregated proteins. However, under chronic pathological stress, microglial function turns from clearing pathological proteins to paradoxically facilitating their spread. Astrocytes, which provide metabolic and homeostatic support for neurons, also participate in the clearance of aggregates through phagocytosis and glymphatic drainage. Critically, crosstalk between astrocytes and microglia enhances the clearance: microglia can recruit and process aggregates internalized by astrocytes, while astrocyte-derived signals modulate the microglial phagocytic activity. Aging, genetic risk factors, or sustained neuroinflammation may reduce the efficiency of glial removal of aggregates and accelerate disease progression. Understanding the cellular and molecular underpinnings of microglial and astrocytic clearance pathways is essential for developing therapies aimed at restoring proteostasis and mitigating neurodegeneration.

Keywords:  Alzheimer’s disease; Autophagy; Neurodegeneration; Parkinson’s disease; Protein aggregation; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1186/s40035-026-00592-y
Autophagy. 2026 Nov 04.

The FOXA2-BNIP3 axis alleviates acute necrotizing pancreatitis by promoting mitophagy in pancreatic acinar cells to inhibit mtDNA-Mediated AIM2 inflammasome activation.

Zijian Huang, Liang Zhang, Hongyan Ma, Zixin Wang, Hongtao Li, Xuchen Hu, Man Zhou, Meng He, Junpeng Wu, Long Cheng, Tie Su, Yusen Feng, Yuan Ma, Wenjing Zhang, Liang Ji, Gang Wang.

  Acute necrotizing pancreatitis (ANP) is a severe inflammatory pancreatic disease characterized by pancreatic necrosis and systemic inflammation, with complex pathogenesis, rapid progression, and poor prognosis. Mitochondrial dysfunction in pancreatic acinar cells represents a pivotal early event in ANP; however, mitophagy, a central component of mitochondrial quality control, remains poorly characterized in terms of its role, regulatory networks, and therapeutic potential in ANP. In this study, we demonstrated that BNIP3 (BCL2 interacting protein 3) expression was significantly downregulated in patients with ANP and negatively correlated with inflammatory severity. Consistently, BNIP3-mediated mitophagy was impaired in the pancreatic tissue of ANP mouse models. Notably, restoration of BNIP3 expression using a novel adeno-associated virus targeting pancreatic tissue (AAV-PAN)-Bnip3 gene therapy vector alleviated pancreatic necrosis and systemic inflammatory injury, promoted mitophagy, and inhibited mitochondrial dysfunction and oxidative stress. Mechanistically, BNIP3-dependent mitophagy facilitated the clearance of damaged mitochondria and prevented mitochondrial DNA (mtDNA) release into the cytosol, thereby suppressing AIM2 (absent in melanoma 2) inflammasome activation and subsequent acinar cell pyroptosis. Furthermore, we identified the transcription factor FOXA2 (forkhead box A2) as a direct upstream regulator that bound to the Bnip3 promoter and positively regulated its expression. FOXA2 was downregulated in ANP, whereas pancreas-specific FOXA2 overexpression activated BNIP3-mediated mitophagy and conferred protection against inflammatory injury. Together, these findings uncovered a previously unrecognized mechanism whereby the FOXA2-BNIP3-AIM2 axis mitigated pancreatic and systemic inflammatory injury in ANP by enhancing mitophagy to restrain mtDNA-dependent AIM2 inflammasome activation, highlighting the FOXA2-BNIP3-AIM2 axis as a promising target for gene therapy.

Keywords:  Acute necrotizing pancreatitis; mitochondrial DNA; mitochondrial dysfunction; mitophagy; pancreatic acinar cell death

DOI:  https://doi.org/10.1080/15548627.2026.2759842
bioRxiv. 2026 Oct 30. pii: 2026.10.29.762862. [Epub ahead of print]

KIF1A-driven entry of degradative lysosomes into the axon is developmentally regulated by the microtubule environment at the axon initial segment.

Nireekshit Addanki Tirumala, Surbhi Verma, Juan S Bonifacino.

Neuronal function requires precise transport of lysosomal vesicles along highly polarized processes, yet how this trafficking is spatially and developmentally regulated remains poorly understood. Here, we show that the neuronally enriched kinesin-3 motor KIF1A is required for dendritic and axonal localization of lysosomal vesicles in both immature and mature rat hippocampal neurons. Remarkably, the specialized microtubule environment of the axon initial segment (AIS) restricts KIF1A-driven transport of degradative, cathepsin D-positive lysosomal vesicles while permitting less degradative lysosomal vesicles to enter axons in mature neurons. Disrupting the AIS microtubule environment or expressing a hereditary spastic paraplegia type 30-associated KIF1A variant with increased affinity for GTP-tubulin bypasses this restriction, enabling degradative lysosomal vesicles to enter mature axons. In human iPSC-derived neurons, KIF1A depletion similarly disrupts axonal lysosomal vesicle transport, causes autophagic vesicle accumulation, and triggers axonal degeneration. Together, our findings reveal a developmentally regulated AIS gate that selectively controls KIF1A-driven lysosomal vesicle transport into axons and link its subversion to KIF1A-associated neurological disease.

DOI: https://doi.org/10.64898/2026.10.29.762862
JCI Insight. 2026 Nov 05. pii: e211025. [Epub ahead of print]

TSC2-Mutant Yucatan Minipig Cardiac Rhabdomyoma Model Reveals mTORC1 Activation and MITF/TFE Expression Signature.

Elias Bou Farhat, Heng Du, Chrystalle Katte Carreon, Jad Halawi, Sophie Kudler, Magdalena Losko, Zachary T Herbert, Adrienne L Watson, Daniel Carlson, Dennis A Webster, Derek M Korpela, David M Meredith, Elizabeth P Henske, David J Kwiatkowski.

  Tuberous sclerosis complex (TSC) is an inherited tumor predisposition syndrome caused by pathogenic variants in TSC1 or TSC2, yet no animal model faithfully recapitulates the cardiac rhabdomyomas (CR) that are among its earliest manifestations. We generated a heterozygous TSC2-mutant Yucatan minipig carrying the recurrent pathogenic TSC2 p.Arg505* variant and characterized its cardiac phenotype using histopathology, immunohistochemistry, and RNA sequencing. TSC2-mutant minipigs consistently developed multiple CR that closely resembled human lesions, including enlarged glycogen-rich spider cells and activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Comparative transcriptomic analyses demonstrated enrichment of a conserved TSC-associated gene expression program and activation of microphthalmia/transcription factor E (MITF/TFE)-regulated lysosomal pathways in both human and minipig tumors. Although other manifestations of TSC were not observed during the first year of life, this large-animal model faithfully reproduced the principal histopathologic and molecular features of human CR. These findings have established the TSC2-mutant Yucatan minipig as what we believe to be the first large-animal model of TSC-associated CR and provide a physiologically relevant platform for investigating tumor pathogenesis, mechanisms of spontaneous regression, and therapeutic strategies targeting mTORC1- and MITF/TFE-dependent signaling.

Keywords:  Genetics; Oncology; Tumor suppressors

DOI:  https://doi.org/10.1172/jci.insight.211025
Mol Oncol. 2026 Nov 04.

The multifaceted roles of lysosomes in cancer.

Jia Li, Kevin M Ryan.

  Cancer cells proliferate rapidly and require sustained supplies of nutrients and biosynthetic precursors. Lysosomes are more than terminal degradation sites: they recycle amino acids, sugars, lipids, nucleosides and ions, while also coordinating nutrient sensing, organelle communication and immune regulation. Consequently, lysosomal capacity can become selectively advantageous in tumours by linking nutrient salvage with growth control, organelle communication and inflammatory signalling. Enhanced lysosomal function can support tumour growth, invasion and therapy resistance. Here, we review four cancer-relevant dimensions of lysosomal capacity: catabolism and transport; mTORC1- and AMPK-linked nutrient sensing; membrane contact sites with the ER, mitochondria, and Golgi; and immune regulation spanning innate and adaptive responses and inflammatory control. These functions are context dependent: lysosomal quality control can restrain tumour initiation, whereas established cancers often exploit increased lysosomal capacity to support proliferation, invasion, metastasis and therapy resistance. Finally, we discuss lysosome-state biomarkers and lysosome-targeted strategies for patient stratification and rational combination therapy.

Keywords:  cancer; lysosome; membrane contact sites; metabolism; nutrient sensing; tumour immunity

DOI:  https://doi.org/10.1002/1878-0261.70349
bioRxiv. 2026 Oct 28. pii: 2026.10.27.762351. [Epub ahead of print]

Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing.

John T Murphy, Ryan Chang, Ziang Bi, Siana Kapoor, Haoying Zhang, David Seamons, Agastya Diwan, Micklaus Garcia, Moydul Islam, Kenji Rowel Q Lim, Daniel L Schneider, Brian M Egan, David Rawnsley, Xiucui Ma, Kerry Kornfeld, Abhinav Diwan.

How organisms recover from starvation to nutrient-replete physiology remains poorly understood. In C. elegans , we previously observed that transcription factor hlh-30 or a combination of glucose and linoleic acid in its absence are essential for survival with refeeding following starvation, i.e. recovery competence. A forward genetic screen to evaluate mechanisms identified depd-5 , which encodes a GATOR1 subunit, loss of which is expected to impair amino acid sensing with unrestrained raga-1 and mTOR activation. Surprisingly, glucose refeeding reduced recovery competence in depd-5(lf , loss-of-function) animals, which was rescued by amino acids, specifically tryptophan. Increasing tryptophan levels in depd-5(lf) worms through supplementation, reduced tryptophan catabolism with tdo-2 ablation and prolonged starvation restored recovery competence. raga-1(gf , gain-of-function) recapitulated whereas raga-1(lf) rescued the impaired recovery competence in starved depd-5(lf) worms. An analogous DEPDC5 mutation in mammalian cells impaired starvation-induced mTOR inactivation. We conclude that tryptophan counters unrestrained mTOR activity to restore recovery competence following starvation.

DOI: https://doi.org/10.64898/2026.10.27.762351
J Clin Invest. 2026 Nov 02. pii: e206733. [Epub ahead of print]136(21):

A rare TMEM175 mutation drives Parkinson's disease pathology by disrupting proton gating and lysosomal acidification.

Xiaotong Yang, Ping Li, Man Lv, Lingyong Wang, Ruyi Shan, Zikai Jiang, Danzhen Chen, Fangqian Huang, Weijie Cai, Liding Zhao, Zuoyou Guo, Xinhui Chen, Zhidong Cen, Yichang Wang, Wei Yang, Xinran Li, Wei Luo, Lin Yang, Meiqin Hu, Haoxing Xu.

  Transmembrane protein 175 (TMEM175), implicated in Parkinson's disease (PD) risk, has been variably proposed to function as a background K+ "leak" channel or a proton-activated proton channel in lysosomes. Here, we identified the rare TMEM175 variant p.L275R in a patient with early onset PD. Electrophysiological analyses revealed that TMEM175-L275R mutant proteins retain normal lysosomal expression and K+ "leak" activity, but specifically lose proton- and agonist-dependent activation gating. In skin fibroblasts isolated from the patient with PD harboring the monoallelic p.L275R mutation (TMEM175+/L275R), and in derived induced pluripotent stem cells and induced dopaminergic neurons, lysosomal H+ flux, acidification, and degradation were impaired. These lysosomal defects were corrected upon genome editing to produce the isogenic WT allele (+/+Cor), but appeared when the mutant allele was introduced onto a WT background (+/L275RMut). Pathological α-synuclein aggregation was facilitated in patient-derived (+/L275R) and mutation-introduced (+/L275RMut) neurons. Consistent with these genetic findings, pharmacological activation of TMEM175 with small-molecule agonists restored lysosomal functions and reduced α-synuclein aggregation in TMEM175+/L275R neurons. In in-vivo studies, equivalent-site-mutation knock-in mice demonstrated synucleinopathy and PD-like motor phenotypes. Collectively, our work provides genetic and pharmacological evidence that severe loss-of-function mutations may contribute causally to the onset age and pathogenesis of PD and identifies lysosomal proton channels and transporters as potential therapeutic targets for PD intervention.

Keywords:  Aging; Cell biology; Development; Ion channels; Lysosomes; Parkinson disease

DOI:  https://doi.org/10.1172/JCI206733
bioRxiv. 2026 Oct 26. pii: 2026.09.29.755284. [Epub ahead of print]

Polyglutamine aggregation in the C. elegans nervous system is driven by stochastic nucleation events.

Vera van Schijndel, Jorieke Tiggelaar, Myrthe S E Franken, Delano Remkes, Maithili Joshi, Deep Sandhu, Klaske Baars, Jesse D F de Graaf, Tessa Sinnige.

Fibrillar protein aggregation is the hallmark of a wide variety of neurodegenerative diseases. It is still poorly understood how soluble proteins transition to fibrillar aggregates, in particular within the complex environment of cells and tissues. Here, we employ the nematode Caenorhabditis elegans to elucidate the molecular mechanisms of polyglutamine aggregation in the nervous system of a multicellular animal. By using fluorescence microscopy in combination with mathematical modelling, we find that polyglutamine aggregation occurs by stochastic nucleation in individual neurons, at a rate that is of the same order of magnitude as previously determined for muscle cells. The J-protein DNAJB6 strongly suppresses polyglutamine aggregation in both tissues, consistent with a mechanism in which aggregation is limited by primary nucleation. We confirm that the same mechanism holds true for a construct including the disease-relevant flanking regions of huntingtin exon 1. Altogether, our data reveal that polyglutamine aggregation occurs spontaneously and largely independently of the cellular context, rather than as a consequence of ageing and the associated decline in protein homeostasis.

DOI: https://doi.org/10.64898/2026.09.29.755284
Cell Death Differ. 2026 Oct 31.

ADA2 controls autophagy-dependent mitochondrial fitness to restrain type I interferon activation.

Dimitri Bulté, Alessandro Romano, Andrea Ottorini, Chiara Rigamonti, Guido Pacini, Alessia Brix, Alessandra Rocco, Federica Barzaghi, Emanuela Pettinato, Sabrina Carbone, Laura Rudilosso, Camilla Visconti, Serena Scala, Antonella Insalaco, Fabrizio de Benedetti, Roberta Caorsi, Marco Gattorno, Daniela Cesana, Anna Pistocchi, Francesca Maltecca, Alessandro Aiuti, Alessandra Mortellaro.

Adenosine deaminase 2 (ADA2) is a secreted enzyme recently shown to localize to lysosomes and bind DNA, yet its cellular function remains elusive. ADA2 is highly expressed by innate immune cells, particularly macrophages, which are implicated in the inflammatory pathogenesis of ADA2 deficiency (DADA2). Accordingly, we investigated its function in macrophages and identified ADA2 as a key regulator of mitochondrial quality control. Transcriptomic profiling of patient monocytes revealed upregulation of nuclear-encoded mitochondrial genes, alongside stress-response and apoptotic programs. Consistently, ADA2-deficient macrophages exhibited increased mitochondrial mass, hyperpolarization, elevated mitochondrial ROS and ATP production, structural abnormalities in cristae, and defective mitophagy. These defects promoted mitochondrial DNA leakage via VDAC, triggering cytosolic DNA sensing, cGAS-STING activation, and hyperactive JAK-STAT-mediated IFN-I responses. Restoration of ADA2 partially rescued mitochondrial integrity and dampened IFN hyperactivation in macrophages and zebrafish. Together, our findings identify ADA2 as a key regulator of mitochondrial quality control that prevents organelle dysfunction and limits inflammation driven by aberrant IFN signaling.

DOI: https://doi.org/10.1038/s41418-026-01893-5
FEBS J. 2026 Nov 02.

The transport of protein aggregates to the vacuole suggests a role for lipid droplets in waste disposal in Saccharomyces cerevisiae.

Christoph Reiter, Patrick Ebner, Elli Leona Kronsteiner, Sophia Moustakakis, Markus Wiederstein, Astrid Obermayer, Ronald Thomas Huber, Christian Schloegelhofer, Florian Wieser, Jon Cedrick Richter, Isabelle Guirsch, Patrick Rockenfeller, Jana Vojtová, Tomáš Groušl, Thomas Klaus Felder, Mark Rinnerthaler.

  Lipid droplets (LDs) are organelles found in all eukaryotic cells, yet their contribution toward proteostasis is still poorly understood. In this study, we demonstrate that LDs in the model organism Saccharomyces cerevisiae function as transporters to which cytosolic protein aggregates attach for transport to the vacuole for degradation. With the help of chaperones and the yeast prion Rnq1, serving as an aggregation model, and using techniques such as live-cell imaging, super-resolution microscopy, electron microscopy, and biochemical analyses, we demonstrate that protein aggregates bind to LDs, are transported through the cytoplasm, and are ultimately transferred to the insoluble protein deposit (IPOD) on the vacuole surface. The efficiency of this process is highly dependent on the lipid composition of the LDs, with triacylglycerols identified as key determinants for aggregate docking. In LD-deficient cells, we observed severe fragmentation of the aggregates and a complete loss of IPOD, whereas stimulation of LD formation significantly increased the size of IPOD and vacuolar import activity. Overall, our results expand the understanding of cellular protein quality control and link lipid metabolism research to the regulation of protein aggregation. The evidence that LDs act as 'garbage trucks' transporting protein aggregates to the vacuole reveals a new interface between proteostasis and lipid metabolism that could also be significant in higher eukaryotes.

Keywords:  lipid droplets; prion; protein detoxification; proteostasis; yeast

DOI:  https://doi.org/10.1111/febs.70784