bims-auttor 2026-03-01 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–03–01
39 papers selected by
Viktor Korolchuk, Newcastle University

Regulation of mitophagy by Fis1 and Fascin1-organized actin.
Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity.
Gl Rac Regulates a Noncanonical, ATG8-Independent Autophagy-Like Pathway in Giardia lamblia.
Autophagy as a therapeutic linchpin in metabolic Diseases and obesity-associated diabetes.
Control of phagophore membrane expansion: Atg8-Atg1 as the master switch.
A lineage-specific selective autophagy receptor module mediates P-body turnover.
The AAA-ATPase Yta4 inhibits the interaction between Ppa2 and Atg43 to promote Atg43 phosphorylation and mitophagy.
The Degradation Pathway of COP9 Signalosome-Cullin-RING Ubiquitin Ligase Complexes via Autophagy.
Hyperglycemia-induced SIRT3 inhibition contributes to diabetic cardiomyopathy by impairing Cav-3-mediated mitophagy.
Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells.
C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.
Autophagy in Sensorineural Hearing Loss: Jekyll or Hyde?
Microautophagy: current understanding of its molecular mechanisms and functions.
PP2A and CDK16 antagonistically regulate WIPI2B phosphorylation and neuronal autophagosome biogenesis.
Regulation of autophagy-mediated pathways by diet, physical activity, and sleep in Alzheimer's disease.
Nature-Inspired Surface Modification Strategy Reverses the Autophagic Flux Impairment of Mitochondrial Transplantation for Attenuating Ischemic Strokes.
Membrane atg8ylation and autophagy in protection against Mycobacterium tuberculosis.
Degradation of alpha-synuclein/SNCA mRNA by RNautophagy.
p62 Coordinates Autophagy, cAMP Signalling, and Cell-Fate Determination in Dictyostelium discoideum.
Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
Ubiquitin ligase Nedd4 regulates the abundance and toxicity of mutant huntingtin.
The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation.
Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.
Monitoring neuronal mitophagy and locomotion deficits in a C. elegans model of Alzheimer's disease.
TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates.
Next questions of autophagy in neurodegenerative diseases: From mechanisms to therapeutics.
Coacervate-Mediated Lysosome-Targeting Antibody Delivery for Protein Degradation.
Linking mitochondrial DNA release to neurodegeneration and cognitive decline.
Muscle-specific expression of Atg2 and high-fat diet influence age-related deterioration of skeletal muscle in aged drosophila via the ATGL/Sirt1/PGC-1α pathway.
Metformin for Longevity and Sarcopenia: A Therapeutic Paradox in Aging.
Tubulin acetylation governs organelle remodeling and lysosomal reformation during neuronal differentiation.
Precise Mapping of the Proteasome Interaction Region (PIR) of p62/SQSTM1: Decoupling Condensate Formation from Proteasome Recruitment.
Skin Organoids in Proteostasis Research: Early Insights into Aging.
The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease.
Bnip3lb-driven mitophagy maintains fate of the embryonic hematopoietic stem cell pool.
Novel mechanism of neuronal hypoxia response: HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against neuronal injury.
The Role of Autophagy-Lysosomal Pathways in Photoreceptor Death in the rd10 Mouse Model of Inherited Retinal Degeneration.
A cellular basis for the mammalian nocturnal-diurnal switch.

Curr Biol. 2026 Feb 24. pii: S0960-9822(26)00134-X. [Epub ahead of print]

Regulation of mitophagy by Fis1 and Fascin1-organized actin.

Shintaro Nakajima, Ting-Yu Wang, Tsui-Fen Chou, Yogaditya Chakrabarty, David C Chan.

  Mitophagy, the autophagic degradation of mitochondria, plays a central role in controlling the quality and quantity of mitochondria, thereby ensuring cellular health. The mitochondrial outer membrane protein Fis1 is important for several types of mitophagy, but its mechanism of action remains unclear. F-actin is recruited to autophagic cargo and is important for autophagic progression, but the mechanism for its recruitment is poorly understood. To address the molecular function of Fis1, we performed affinity purification of Fis1 and mass spectrometry and identified the actin-bundling protein Fascin1 as a physical interactor. We demonstrate that Fis1 is required for recruitment of Fascin1 as well as F-actin to mitochondria under stress conditions, including mitochondrial depolarization and iron chelation. Iron chelation also triggers mitophagy that is independent of the Parkinson's associated gene Parkin, and we show that Fis1 enables recruitment of Fascin1-organized F-actin to facilitate proper morphogenesis of autophagosomes and the ensuing mitochondrial degradation. In contrast, although Parkin-mediated mitophagy also relies on Fis1, it is unaffected by loss of Fascin1 or F-actin recruitment. These findings indicate that Fis1 has distinct modes of action in mitophagy, depending on the triggering cellular stress. They establish Fis1 as a key driver of Fascin1 and F-actin recruitment to mitochondria, events that are critical for autophagosome morphogenesis during iron-chelation-induced mitophagy.

Keywords:  Fascin1; Fis1; actin; autophagy; mitochondria; mitophagy

DOI:  https://doi.org/10.1016/j.cub.2026.01.062
Mol Biol Cell. 2026 Feb 25. mbcE24030109

Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity.

Corey J Theodore, Lianna H Wagner, Kenneth G Campellone.

Autophagy is an intracellular degradation process that maintains homeostasis, responds to stress, and plays key roles in preventing aging and disease. Autophagosome biogenesis, vesicle rocketing, and autolysosome tubulation are controlled by multiple actin cytoskeletal factors, but the impact of actin assembly on completion of the autophagic degradation pathway is not well understood. Here we studied autophagosomes and lysosomes in mouse fibroblasts harboring an inducible knockout (iKO) of the Arp2/3 complex, an essential actin nucleator. Arp2/3 complex ablation resulted in increased basal levels of autophagy receptors and lipidated membrane proteins from the LC3 and GABARAP families. Such phenotypes were accompanied by the steady-state presence of abnormally high numbers of autolysosomes and an inability of the Arp2/3 complex-deficient cells to complete autolysosome turnover due to lysosomal damage. When normal cells were treated with a lysosomal membrane-disrupting agent, the Arp2/3-activating protein WHAMM was recruited to lysosomes, and Arp2/3 complex activity was required for restoring intact lysosomal structure. Deletion of WHAMM in mouse or human fibroblasts decreased Arp2/3 localization to lysosomes and increased lysosomal damage. These results reveal the importance of the Arp2/3 complex and WHAMM for autophagic degradation and uncover a new role for the actin nucleation machinery in maintaining lysosomal integrity.

DOI: https://doi.org/10.1091/mbc.E24-03-0109
bioRxiv. 2026 Feb 19. pii: 2026.02.17.706457. [Epub ahead of print]

Gl Rac Regulates a Noncanonical, ATG8-Independent Autophagy-Like Pathway in Giardia lamblia.

Angélica Hollunder Klippel, Grant Reed, Corryn Newman-Boulle, Dule Dule, Saanya Kedia, Wai Pang Chan, Han-Wei Shih, Alexander R Paredez.

Autophagy is a conserved catabolic process essential for cellular homeostasis and stress adaptation. The protozoan parasite Giardia lamblia lacks most canonical autophagy-related (ATG) genes, including the hallmark ATG8, raising longstanding questions about whether it can perform autophagy. Here, we show that Giardia mounts a regulated autophagic-like response. Double-membrane compartments resembling autophagosomes are induced in up to 30% of encysting cells and 91% of starved trophozoites, supporting roles in differentiation and survival under nutrient stress. Their clearance is triggered by amino acid replenishment but not by glucose, indicating a nutrient-specific sensing mechanism. Gl Rac, the parasite's sole Rho family GTPase, labels these structures and regulates their formation, as evidenced by a threefold increase in compartment levels upon constitutive activation and a significant reduction after knockdown. This extends the conserved role of Rho GTPases in regulating autophagy to an evolutionarily early-branching eukaryote. Of nine putative ATG orthologs tested, none localized as clearly as Gl Rac to autophagic structures. These organelles acidify and recruit cathepsin proteases, consistent with degradative capacity. A newly developed live-cell actin marker reveals robust recruitment to these structures, implicating actin-driven remodeling. Finally, quinacrine, an FDA-approved antigiardial drug, promotes the accumulation of autophagic structures, consistent with its known effects on mammalian autophagy. Together, our findings establish Gl Rac as a regulator of an ATG8-independent autophagic response in Giardia , demonstrate that this parasite retains key features of autophagy despite its streamlined genome, and highlight this pathway as a potential therapeutic target.
Significance: Autophagy is a self-degradative process essential for stress adaptation and cellular recycling. Although considered ancient and broadly conserved, this pathway was long thought to be absent in the protozoan parasite Giardia lamblia , which lacks many canonical autophagy genes, including the classic marker ATG8. Here, we demonstrate that Giardia performs a regulated autophagic-like response. We identify Gl Rac, the parasite's sole Rho family GTPase, as a regulator that marks autophagosome-like organelles, underscoring the conserved role of Rho GTPases in autophagy across eukaryotes. We also show that quinacrine, a clinically used antigiardial drug, perturbs the autophagic response in this organism. These findings reveal an unrecognized aspect of Giardia biology and support autophagy as a promising therapeutic target for this widespread parasite.

DOI: https://doi.org/10.64898/2026.02.17.706457
Autophagy. 2026 Feb 23.

Autophagy as a therapeutic linchpin in metabolic Diseases and obesity-associated diabetes.

Omid Vakili, Daniel J Klionsky, Russel J Reiter, Jun Ren, Aabha Deshpande, Kwang Seok Ahn, William C Cho, Kiavash Hushmandi, Alan Prem Kumar.

  Autophagy, a conserved lysosomal degradation pathway, is increasingly recognized as a central regulator of metabolic health. Its impairment contributes directly to obesity and type 2 diabetes by disrupting nutrient sensing, stress adaptation, and organelle quality control. Hyperactivation of MTORC1 with insufficient AMPK and SIRT1 signaling suppresses autophagic flux, driving lipid accumulation, insulin resistance, and mitochondrial dysfunction. Clinically relevant consequences include adipose inflammation and hypertrophy, hepatic steatosis with impaired β-oxidation, pancreatic β-cell failure from unresolved ER stress, and skeletal muscle atrophy due to loss of proteostasis. Moreover, defective autophagy across the gut - liver - brain axis exacerbates intestinal barrier dysfunction, endotoxemia, and neuroendocrine imbalance, amplifying systemic metabolic deterioration. Emerging interventions that restore autophagic capacity, including exercise-induced AMPK activation, dietary modulation of unsaturated fatty acids, pharmacological inducers, and nanotechnology-based lysosomal re-acidification show promise in preclinical models. However, the tissue-specific duality of autophagy, where suppression may be beneficial in some contexts but harmful in others, highlights the complexity of therapeutic targeting. This review highlights current mechanistic and translational insights to position autophagy as a therapeutic linchpin in obesity-associated metabolic disease. By aligning molecular pathways with clinical outcomes, we herein highlight opportunities to develop precision strategies that harness autophagy to combat the global burden of obesity and metabolic disorders.

Keywords:  Autophagy; diabetes mellitus; metabolic adaptation; metabolic syndrome; metabolism; nutrient sensing; obesity

DOI:  https://doi.org/10.1080/15548627.2026.2636096
Autophagy. 2026 Feb 25. 1-3

Control of phagophore membrane expansion: Atg8-Atg1 as the master switch.

Yi-He Feng, Jing Zhu, Yu Ding, Fan Yan, Zhiping Xie.

  Autophagosome formation is catalyzed by multiple branches of Atg protein machineries, calling for the existence of a master regulator to coordinate their distinct activities. A prime candidate of such a regulator is Atg8. This protein has a well-established role in controlling phagophore expansion. But the signaling mechanism has been unclear. Our recent work demonstrates that Atg8 recruits activated Atg1 to the phagophore, together forming such a master switch. Our data indicate that different branches of Atg proteins localize to spatially separated zones. The physical distances among the zones, at times exceeding 250 nm, would limit signal transduction efficiency if a signaling molecule were exclusively localized to a single zone. By covering the phagophore surface, Atg8 maintains physical proximity to different Atg machineries, and transmits a permissive signal by recruiting activated Atg1. Compromising Atg8-mediated Atg1 recruitment leads to confinement of Atg1 to the initiation protein condensate and failure of phagophore expansion. Conversely, the Atg8-Atg1 switch can be manually augmented to substantially increase autophagosome size and autophagic flux. Our work thus reveals a critical regulatory circuit of macroautophagy/autophagy that is built on the spatial organization of Atg protein machineries.

Keywords:  Autophagy; kinase; membrane biogenesis; membrane expansion; protein trafficking; ubiquitin-like protein

DOI:  https://doi.org/10.1080/15548627.2026.2636092
Dev Cell. 2026 Feb 23. pii: S1534-5807(26)00040-7. [Epub ahead of print]

A lineage-specific selective autophagy receptor module mediates P-body turnover.

Alibek Abdrakhmanov, Elizabeth Ethier, Aleksandra S Anisimova, Nenad Grujic, Ranjith K Papareddy, Marion Clavel, G Elif Karagöz, Erinc Hallacli, Yasin Dagdas.

  Processing bodies (P-bodies) are conserved ribonucleoprotein granules central to RNA metabolism across eukaryotes. Although the mechanisms underlying their assembly are well understood, the pathways governing their selective turnover remain unclear. Here, we identify the conserved decapping proteins Enhancer of mRNA decapping 4 (EDC4) and decapping protein 1 (DCP1) as a selective autophagy receptor pair responsible for P-body turnover in the model plant Marchantia polymorpha. MpEDC4 engages ATG8 via a canonical ATG8-interacting motif, while MpDCP1 contains a previously unrecognized reverse ATG8-interacting motif within its intrinsically disordered region. Mutations disrupting these motifs impair the autophagic degradation of P-bodies, demonstrating a cooperative receptor mechanism. Notably, this autophagic function is lineage-specific, as orthologs in Arabidopsis and humans lack ATG8-binding capacity. Strikingly, the heterologous expression of MpEDC4 in human cells promotes the degradation of α-synuclein, a protein linked to Parkinson's disease etiology. Our findings uncover an evolutionary innovation that links RNA metabolism to selective autophagy and open avenues for the cross-kingdom engineering of targeted protein degradation pathways.

Keywords:  ATG8; Marchantia; P-body; RNP-granules; autophagic flux; receptor engineering; selective autophagy; selective autophagy receptor; targeted protein degradation; α-synuclein degradation

DOI:  https://doi.org/10.1016/j.devcel.2026.01.017
J Biol Chem. 2026 Feb 25. pii: S0021-9258(26)00196-1. [Epub ahead of print] 111326

The AAA-ATPase Yta4 inhibits the interaction between Ppa2 and Atg43 to promote Atg43 phosphorylation and mitophagy.

Ke Liu, Jiajia He, Yifan Wu, Chenhui Zhao, Shuaijie Yan, Fangyuan Xiong, Xing Liu, Xuebiao Yao, Chuanhai Fu.

  AAA-ATPase Yta4/Msp1/ATAD1 is a well-known quality control factor that clears mistargeted tail-anchored proteins and precursor proteins on mitochondria. However, whether Yta4 preserves mitochondrial homeostasis through alternate pathways remains unclear. Traditionally, mitophagy has been recognized as a crucial pathway for eliminating dysfunctional mitochondria, thereby ensuring the maintenance of mitochondrial homeostasis. In this study, we unveil a novel role for Yta4 in sustaining mitochondrial homeostasis by facilitating mitophagy in fission yeast. The absence of Yta4 delays the phosphorylation of the mitophagy receptor Atg43 and specifically inhibits mitophagy. Additionally, Atg43 phosphorylation sites Ser32, Ser35, and Ser36, which are crucial for mitophagy, were identified. We further found that the phosphatase Ppa2 plays a major role in Atg43 dephosphorylation and inhibits excessive mitophagy. Yta4 physically interacts with both Atg43 and Ppa2, and coordinates with Ppa2 to modulate Atg43 phosphorylation and mitophagy. Moreover, Yta4 and Ppa2 bind to the same cytosolic region of Atg43, and Yta4 inhibits the interaction between Atg43 and Ppa2. Collectively, our findings suggest that Yta4 promotes mitophagy by ensuring the effectiveness of Atg43 phosphorylation. Thus, our findings reveal the novel function of Yta4 in regulating mitophagy and expand the understanding of the molecular mechanisms underlying mitophagy in fission yeast.

Keywords:  ATAD1; PP2A; fission yeast; mitochondria; phosphatase; phosphorylation

DOI:  https://doi.org/10.1016/j.jbc.2026.111326
Biomolecules. 2026 Feb 02. pii: 218. [Epub ahead of print]16(2):

The Degradation Pathway of COP9 Signalosome-Cullin-RING Ubiquitin Ligase Complexes via Autophagy.

Dawadschargal Dubiel, Roland Hartig, Wolfgang Dubiel.

  In Mammalia, the COP9 signalosome (CSN) is associated with cullin-RING ubiquitin ligases (CRLs). This study focuses on the variants CSNCSN7A and CSNCSN7B, which form complexes with CRL3 and CRL4A, respectively. Although some research has been conducted on the assembly of the complexes, little is known about their breakdown. Here, we show that entire CSNCSN7A-CRL3 and CSNCSN7B-CRL4A complexes are degraded via autophagy. CSN-CRL complexes are degraded in the absence of serum via bulk autophagy and in the presence of the specific inhibitor of CSN, CSN5i-3, via selective macroautophagy. Surprisingly, the self-ubiquitylation of cullins in the CRLs was identified as a specific signal for selective macroautophagy. The self-ubiquitylation of cullins takes place in the presence of CSN5i-3, and CSN-CRL complexes are expelled from the nucleus to be degraded in the cytosol. Selective macroautophagy can be blocked by chloroquine, a specific inhibitor of autophagy. Interestingly, the process can also be inhibited by MLN4924, a neddylation inhibitor. Confocal fluorescence microscopy illustrates the interaction of CSN subunits with ATG8, as well as with RAB7, both in HeLa and in LiSa-2 cells. Confocal fluorescence microscopy produces images that suggest the localization of CSN-CRL particles in autophagosomes. Our data place CSN-CRL in the category of large complexes that are degraded through autophagy.

Keywords:  COP9 signalosome (CSN); CSN5i-3 inhibitor; bulk autophagy; cullin-RING ubiquitin ligase (CRL); selective macroautophagy

DOI:  https://doi.org/10.3390/biom16020218
Biochem Pharmacol. 2026 Feb 20. pii: S0006-2952(26)00166-8. [Epub ahead of print]248 117835

Hyperglycemia-induced SIRT3 inhibition contributes to diabetic cardiomyopathy by impairing Cav-3-mediated mitophagy.

Zhenshuai Jin, Yanwei Ji, Wating Su, Lu Zhou, Lei Gao, Xinyu Wen, Hepeng Tang, Zhong-Yuan Xia, Shaoqing Lei.

  Diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients, with impaired mitophagy contributing its pathogenesis. Sirtuin 3 (SIRT3) and caveolin-3 (Cav-3) are protective proteins involved in mitophagy, although their precise mechanisms remain unclear. This study investigated the interplay between SIRT3, Cav-3, and mitophagy in DCM. We found that the diabetic C57BL/6 mice exhibited impaired cardiac structure and function, accompanied by reduced mitophagy and decreased expression of SIRT3 and Cav-3. Cav-3 KO mice with diabetes showed further worsened cardiac dysfunction and mitophagy impairment without further affecting SIRT3 expression. In cultured H9C2 cardiomyocytes, both SIRT3 siRNA and Cav-3 siRNA exacerbated high glucose (HG)-induced cardiomyocyte damage and reduced mitophagy occurrence. Interestingly, SIRT3 siRNA significantly decreased Cav-3 expression, but vice not. Additionally, Cav-3 overexpression rescued HG-induced cardiomyocyte injury and mitophagy impairment without affecting SIRT3 expression. Collectively, our findings suggest that hyperglycemia-induced SIRT3 suppression contributes to DCM by impairing Cav-3-mediated mitophagy.

Keywords:  Cav-3; Diabetes; Diabetic cardiomyopathy; Mitophagy; SIRT3

DOI:  https://doi.org/10.1016/j.bcp.2026.117835
bioRxiv. 2026 Feb 18. pii: 2026.02.17.706183. [Epub ahead of print]

Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells.

Jie Zhu, Felix Darko, Fei Han, Summer Simeroth, Lingjun Li, Haiwei Gu, Pengchun Yu.

The lymphatic vascular system plays essential roles in tissue fluid drainage, dietary fat absorption and transport, and immune cell trafficking. To support these physiological functions, the lymphatic vasculature forms an extensive and highly organized network throughout the body. We have recently discovered that the mechanistic target of rapamycin complex 1 (mTORC1), with RAPTOR as an indispensable component, directs glycolysis and glutaminolysis in lymphatic endothelial cells (LECs) to promote lymphatic vessel formation. However, the role of mTORC1 in regulating LEC metabolism remains incompletely understood. Here, by conducting untargeted metabolomic profiling of control and RAPTOR-deficient LECs, we uncover a global impact of mTORC1 inhibition on amino acid utilization. Specifically, RAPTOR deficiency impairs the conversion of glutamine to glutamic acid, resulting in decreased levels of glutamic acid and aspartic acid, as well as reduced abundance of N-acetyl-glutamic acid and N-acetyl-aspartic acid-two metabolites unexpectedly detected in LECs. Integrated metabolomic and transcriptomic analyses further reveal that impaired glutaminolysis in RAPTOR-depleted LECs is accompanied by an increase in intracellular asparagine, arginine, and metabolites associated with arginine catabolism, potentially driven by upregulation of their respective transporters. In addition, RAPTOR depletion results in abnormal accumulation of branched-chain amino acids (BCAAs) and other essential amino acids primarily involved in protein synthesis. Mechanistically, our data suggest that defective BCAA catabolism and impaired translational control contribute to these metabolic alterations. Collectively, these findings reveal an important role of mTORC1 signaling in coordinating amino acid utilization and suggest that this regulation is critical for lymphatic vessel formation.

DOI: https://doi.org/10.64898/2026.02.17.706183
Front Cell Neurosci. 2026 ;20 1731669

C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.

James A K Lee, Chloe Moutin, Sarah Granger, Katie Roome, Allan Shaw, Scott P Allen, Laura Ferraiuolo, Pamela J Shaw, Heather Mortiboys.

   Introduction: ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however, reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited.
Results: iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced basal mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed.
Conclusion: Our data show that certain aspects of mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterization of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits.

Keywords:  ALS (Amyotrophic lateral sclerosis); ULK1; autophagy; mitochondria; mitophagy

DOI:  https://doi.org/10.3389/fncel.2026.1731669
Int J Mol Sci. 2026 Feb 22. pii: 2053. [Epub ahead of print]27(4):

Autophagy in Sensorineural Hearing Loss: Jekyll or Hyde?

María Beatriz Durán Alonso.

  Autophagy plays a key role in the development and homeostasis of the cochlear organ. Alterations in the autophagic pathways have been associated with damage to auditory cell types and hearing impairment caused by an array of factors like age, ototoxicity, exposure to high levels of noise, or genetic mutations. Cochlear damage frequently entails mitochondrial dysfunction, impaired mitophagy and the accumulation of high concentrations of free radicals. This review summarizes the observations made to date on the autophagic function in response to cochlear damage and the results of either activating or inhibiting these processes. The data demonstrate that autophagic activity is cell context-dependent and varies according to the cochlear cell type, the toxic agent, its levels and the length and timing of its administration; other factors that influence the autophagic response may be external to the auditory system or related to epigenetic changes or the expression of genetic variants. Modulation of the autophagic status has an effect on auditory cell loss and the progression to hearing impairment and this approach has thus become a promising avenue towards the protection of the hearing function. Nonetheless, this is no easy task and it will require the identification of reliable biomarkers to evaluate the dynamics of autophagic activity as well as the development of specific autophagy modulators that do not exert toxicity.

Keywords:  aging; autophagy; hearing loss; mitophagy; ototoxicity

DOI:  https://doi.org/10.3390/ijms27042053
Autophagy Rep. 2026 ;5(1): 2626661

Microautophagy: current understanding of its molecular mechanisms and functions.

Yasuyoshi Sakai, Christian Behrends, Jayanta Debnath, Masanori Izumi, Andreas Jenny, Maurizio Molinari, Shuhei Nakamura, Masahide Oku, Marisa S Otegui, Laura Santambrogio, Han-Ming Shen, Tomohiko Taguchi, Michael Thumm, Takashi Ushimaru, Zhiping Xie, Ana Maria Cuervo, Fulvio Reggiori.

  Microautophagy (MI-autophagy) is an umbrella term for intracellular degradative pathways that entail the invagination or protrusion of the limiting membranes of endolysosomal compartments, that is, late endosomes and mammalian lysosomes or yeast and plant vacuoles, followed by pinching-off of the membrane into the lumen of the organelle. During these processes, the material specifically and nonspecifically targeted for degradation is sequestered within the invaginating or protuberating membrane. In contrast to macroautophagy, the molecular mechanisms underlying MI-autophagy are largely unknown due to their diversity and complexity in location, regulation and molecular machinery requirements. Here, we review recent progress in the field of MI-autophagy, describing the molecular basis and functions of the MI-autophagic pathways reported to date in eukaryotic cells, from yeast to mammalian and plant cells.

Keywords:  Endosomes; lysosomes; multivesicular bodies; organelle turnover; proteolysis; vacuole

DOI:  https://doi.org/10.1080/27694127.2026.2626661
bioRxiv. 2026 Feb 13. pii: 2026.02.12.705597. [Epub ahead of print]

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

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

Autophagy is a recycling pathway that clears cellular constituents, supporting homeostasis. 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 in vivo . 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.

DOI: https://doi.org/10.64898/2026.02.12.705597
Alzheimers Dement. 2026 Feb;22(2): e71191

Regulation of autophagy-mediated pathways by diet, physical activity, and sleep in Alzheimer's disease.

Ajish Ariyath, Zoe Mputhia, Christopher Dougherty, Bushra Kaleelur Rahuman, W M A D Binosha Fernando, Belinda Brown, Samantha L Gardener, Stephanie R Rainey-Smith, Ralph Martins, Prashant Bharadwaj.

  Alzheimer's disease (AD) is a progressive, age-related, neurodegenerative disorder marked by cognitive decline, memory loss, and accumulation of amyloid beta (Aβ) plaques and tau tangles. A key feature of AD is impaired protein homeostasis, often driven by autophagy dysfunction. Autophagy, a cellular degradation and recycling process, plays a vital role in maintaining neuronal health and is increasingly recognized as a therapeutic target in AD. Lifestyle factors such as diet, physical activity, and sleep can positively influence autophagy and support cognitive function. Intermittent fasting (IF) and calorie restriction (CR) activate autophagy and promote longevity; physical activity enhances cerebral blood flow and neurotrophic signaling; and adequate sleep supports autophagic processes, while sleep deprivation disrupts them. However, excessive autophagy may be detrimental. Understanding how lifestyle modulates autophagy is essential for developing non-pharmacological strategies to delay or prevent AD. This review explores the mechanistic links between autophagy and lifestyle interventions to support brain health in aging.

Keywords:  Alzheimer's disease; amyloid beta protein; amyloid precursor protein; autophagy; calorie restriction; diet; exercise; fasting; lifestyle interventions; physical activity; sleep; sleep deprivation; sleep fragmentation

DOI:  https://doi.org/10.1002/alz.71191
Adv Sci (Weinh). 2026 Feb 25. e18969

Nature-Inspired Surface Modification Strategy Reverses the Autophagic Flux Impairment of Mitochondrial Transplantation for Attenuating Ischemic Strokes.

Nisha Wang, Qiyang Ding, Lei Shi, Ji Xia, Shuyue Zhang, Chenxin Jian, Yixiao Yan, Xiuhua Luo, Jiarui Wang, Ming Cheng, Yiqiong Jia, Hao Tian, Wei Gao.

  Mitochondrial transplantation has emerged as a promising therapeutic intervention for ischemic strokes (IS). Although previous studies have demonstrated the therapeutic breakthroughs of mitochondrial transplantation facilitated by advances in biotechnology, in-depth investigations into the exact mechanisms underlying its beneficial effects remain insufficient. Here, we investigate how exogenous mitochondria interact with recipient cells to optimize therapeutic protocols and improve outcomes. Emerging evidence indicates that exogenous mitochondria act as triggers of mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin pathway. However, excessive reactive oxygen species (ROS) generated during ischemia-reperfusion injury activate the receptor-interacting protein (RIP)1/RIP3 pathway, leading to the blockage of autophagic flux. Hence, we devised a novel mitochondrial transplantation platform (MLSR) that utilizes functionalized starch as a stable coating for exogenous mitochondria and enables the co-delivery of the antioxidant resveratrol through the helical structure of the starch. Following internalization by recipient neurons, the exogenous mitochondria rapidly initiate mitophagy, while resveratrol escapes from the lysosome to inhibit the ROS-RIP1/RIP3-exosome axis. Experimental results demonstrate that MLSR effectively triggers and maintains positive autophagic flux, thereby suppressing the release of undegraded autophagosomes in the form of exosomes and preventing proinflammatory crosstalk between neurons and microglia. Therefore, our findings provide important implications for renewing the therapeutic potential of mitochondrial transplantation.

Keywords:  ROS‐RIP1/RIP3‐exosome axis; autophagic flux; mitochondrial transplantation; mitophagy

DOI:  https://doi.org/10.1002/advs.202518969
J Immunol. 2026 Feb 09. pii: vkaf359. [Epub ahead of print]215(2):

Membrane atg8ylation and autophagy in protection against Mycobacterium tuberculosis.

Vojo Deretic.

  Membrane atg8ylation is a broad homeostatic process of immunological import. It encompasses membrane repair and remodeling pathways, including canonical autophagy, in cells subjected to stress, damage, infection, and immune or metabolic signaling under microbe-induced or sterile inflammatory conditions. The initial reports on autophagy, which is one of membrane atg8ylation outputs, as a defense against Mycobacterium tuberculosis and other intracellular pathogens have ushered a new direction for immunological research but proved to be controversial once the studies have moved from in cellulo to in vivo studies in murine models. Recent research is beginning to resolve these controversies by revealing that membrane atg8ylation in general is key to host protection against M. tuberculosis. These developments inform us of how membrane atg8ylation and autophagy shape the innate and adaptive immunity against pathogens and invite further studies to identify downstream immunological effector mechanisms.

Keywords:  autophagy; macrophages; membrane atg8ylation; neutrophils; tuberculosis

DOI:  https://doi.org/10.1093/jimmun/vkaf359
Neurochem Int. 2026 Feb 24. pii: S0197-0186(26)00028-8. [Epub ahead of print] 106137

Degradation of alpha-synuclein/SNCA mRNA by RNautophagy.

Chihana Kabuta, Fumihiko Hakuno, Naoyuki Kataoka, Shin-Ichiro Takahashi, Tomohiro Kabuta.

  α-Synuclein is a neuronal protein and main component of Lewy bodies, the pathological hallmark of Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies. While the accumulation of α-synuclein in neurons is implicated in the pathogenesis of these disorders, the mechanisms underlying α-synuclein mRNA degradation remain poorly understood. RNautophagy is a lysosomal RNA degradation pathway in which RNA is directly taken up into lysosomes and subsequently degraded. SIDT2, a lysosomal membrane protein, mediates the uptake of RNA. In this study, we investigated whether SIDT2-mediated RNautophagy degrades α-synuclein mRNA. Knockdown of SIDT2 led to reduced degradation of α-synuclein mRNA, whereas overexpression of wild-type SIDT2 enhanced its degradation, suggesting its role in α-synuclein mRNA turnover. In contrast, overexpression of the RNA uptake-deficient S564A mutant did not enhance degradation, indicating that RNA uptake activity is required for SIDT2-mediated degradation of α-synuclein mRNA. Using a series of deletion mutants, we identified a guanine (G)-rich sequence within the 5' untranslated region (5'-UTR) of α-synuclein mRNA as a key determinant of SIDT2-dependent degradation. Furthermore, insertion of the G-rich sequence into the 5'-UTR of GFP mRNA promoted SIDT2-dependent degradation of GFP mRNA and reduced GFP protein expression. Taken together, these results indicate that SIDT2-mediated RNautophagy contributes to the degradation of α-synuclein mRNA via the G-rich region within the 5'-UTR. Our findings may also provide insights into the pathogenesis of Lewy body diseases.

Keywords:  Autophagy; Dementia with Lewy bodies; Guanine-rich region; Lysosomes; Neurodegenerative disorder; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.neuint.2026.106137
Mol Cell Biol. 2026 Feb 22. 1-18

p62 Coordinates Autophagy, cAMP Signalling, and Cell-Fate Determination in Dictyostelium discoideum.

Saksham Gautam, Shweta Saran.

  p62/SQSTM1 is a multifunctional adaptor protein playing a central role in the regulation of autophagy and stress response pathways in higher eukaryotes. However, its functional relevance in lower eukaryotes like Dictyostelium remains largely unexplored. In this study, we demonstrate that Dictyostelium p62 is crucial for cAMP-mediated development and autophagy. Loss of p62 alters levels of intracellular glucose, cAMP, ubiquitinated proteins and autophagic flux. These defects result in impaired cell aggregation and abnormal fruiting body formation, accompanied by reduced spore viability. Interestingly, pulsing of p62 null cells with exogenous cAMP could partially rescue the developmental defects, implicating a role of p62 in maintaining the intracellular cAMP levels required for starvation stress-induced development. p62 also influences cell-fate decisions during development as its deletion biases cells toward pre-spore differentiation, whereas overexpression promotes pre-stalk lineage. Mechanistically, p62 also modulates autophagy flux potentially via regulating AMPK levels along with cAMP dynamics. Together, these findings position p62 as an evolutionarily conserved key adaptor protein that provides new insights into the molecular mechanisms underlying multicellular development.

Keywords:  Dictyostelium; autophagy; cAMP; cell differentiation; p62

DOI:  https://doi.org/10.1080/10985549.2026.2627237
Autophagy Rep. 2026 ;5(1): 2629624

Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.

Mariana Joaquim, Maike F Dohrn, Arnaud Chevrollier, Mafalda Escobar-Henriques.

  Mitochondria are central hubs for cellular fitness, empowered by plastic remodeling of their shape, proteome composition, and/or metabolic state. MFN2 (mitofusin 2) mediates mitochondrial fusion and ensures adaptations in response to metabolic changes and stresses. Besides this canonical role, MFN2 serves as a communication hub with other organelles. It tethers mitochondria to the endoplasmic reticulum (ER), lipid droplets, and peroxisomes, regulating calcium buffering, apoptosis, lipid biosynthesis, and lipolysis. Dysfunctional MFN2 causes the hereditary neuropathy Charcot-Marie-Tooth type 2A (CMT2A) and is linked to several metabolic diseases. In a recent publication, we described another fusion-independent role of MFN2 in proteostasis and mitophagy. MFN2 binds the chaperone HSPA8/HSC70 (heat shock protein family A [Hsp70] member 8) and the proteasome, a key function in maintaining mitochondrial and cellular protein quality control, which appears to be lost in the context of CMT2A-associated MFN2 variants.

Keywords:  Charcot–Marie–Tooth type 2A (CMT2A); HSPA8/HSC70; MFN2; protein import; proteasome; VCP/p97; PINK1; apoptosis; mitophagy; proteostasis

DOI:  https://doi.org/10.1080/27694127.2026.2629624
JCI Insight. 2026 Feb 23. pii: e181013. [Epub ahead of print]11(4):

Ubiquitin ligase Nedd4 regulates the abundance and toxicity of mutant huntingtin.

Hyunkyung Jeong, Yiyang Qin, Fangke Xu, Katarina Trajkovic, Myung Jong Kim, Nicolas Marotta, Kana Hamada, Ravi Allada, Su Yang, Dimitri Krainc.

  Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the gene encoding huntingtin. Since accumulation of mutant huntingtin (mHtt) leads to dysfunction of numerous cellular pathways and toxicity, reducing levels of the mutant protein represents a key therapeutic objective in HD. We found that ubiquitination of mHtt by E3 ubiquitin ligase Nedd4 promotes clearance of the mutant protein. Knockdown of Nedd4 increased toxicity of mHtt in mouse primary neurons and in a fly model of HD, suggesting the protective role of Nedd4. Importantly, levels of Nedd4 were decreased in mHtt-expressing neurons through impaired mTORC1 activity, suggesting a feedback loop of mHtt accumulation and Nedd4 reduction that leads to accumulation and, ultimately, toxicity of mHtt. These findings suggest that restoring Nedd4 activity may offer a novel therapeutic opportunity for HD.

Keywords:  Cell biology; Neurodegeneration; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.181013
Mol Cell. 2026 Feb 24. pii: S1097-2765(26)00071-7. [Epub ahead of print]

The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.

Dominic A Ritacco, Hamna Shahnawaz, Antonia Oduguwa, Jacob Hawk, Brianna Vizcaino, Donna L Farber, Ryan G Gaudet.

  Lysosomal damage is an endogenous danger signal, but its significance for innate immunity and the specific signaling pathways it engages remain unclear. Here, we uncover an immune-inducible pathway that connects lysosomal damage to mitochondrial DNA (mtDNA) efflux and type I IFN production. We find that transient lysosomal damage elicits sub-lethal mitochondrial outer membrane permeabilization (MOMP) via BAK/BAX macropores; however, the inner mitochondrial membrane (IMM) maintains a barrier against wholesale mtDNA release. Priming with type II IFN (IFN-γ) induced the antibacterial factor APOL3, which, upon sensing lysosomal damage, targets mitochondria undergoing MOMP to selectively permeabilize the IMM, enhance mtDNA release, and potentiate downstream cGAS signaling. Biochemical and cellular reconstitution revealed that, analogous to its bactericidal detergent-like mechanism, APOL3 permeabilized the IMM by solubilizing cardiolipin. Our findings illustrate how cells enlist an antibacterial protein to expedite the breakdown of endosymbiosis and facilitate a heightened response to injury and infection.

Keywords:  DNA; damage; innate immunity; interferon; intracellular bacteria; lysosome; mitochondrion; viruses

DOI:  https://doi.org/10.1016/j.molcel.2026.01.029
Acta Pharmacol Sin. 2026 Feb 25.

TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation.

Chen Chen, Han Lou, An-Ge Hu, Qiang Huang, Ling-Yi Kong, Zhou-Xiu Chen, Heng-Hui Xu, Yong-Chao Chen, Heng Liu, Shu-Qin Duan, Yuan Lin, Li-Min Zhao, Ling Liu, Muneer Ahmed Khoso, Xin Liu, Yong Zhang.

  Lysosomal dysfunction exacerbates cardiomyocyte damage in myocardial infarction (MI) by impairing cellular degradation. However, the precise molecular mechanisms driving this pathologic process remain unclear. Lysosomal transmembrane protein 175 (TMEM175) is critical for regulating lysosomal homeostasis. But its pathophysiological implications in post-infarction cardiac dysfunction are not fully understood. By using both gain and loss of function approaches in vivo and in vitro, we discovered that TMEM175 overexpression conferred cardioprotection in MI models. This was evidenced by reduced infarct size, collagen deposition, and myocardial injury, accompanied by restored lysosomal function characterized by increased biogenesis, normalized pH, enzyme activities, and autophagic flux. Conversely, TMEM175 knockdown exacerbated these pathologies. Under hypoxic stress, TMEM175 overexpression in neonatal mouse cardiomyocytes (NMCMs) improved cell viability and corrected lysosomal dysfunction, whereas its knockdown worsened the aforementioned effects. Mechanistically, the reduction of TMEM175 induced by MI increases mammalian target of rapamycin complex 1 (mTORC1) phosphorylation on lysosomal membranes and suppresses the nuclear translocation of transcription factor EB (TFEB), thereby impairing TFEB's transcriptional regulation of lysosome-associated genes. Meanwhile, TMEM175 restoration reversing this cascade, and restoring lysosomal function and autophagic flux.

Keywords:  TFEB; TMEM175; lysosome; mTORC1; myocardial infarction

DOI:  https://doi.org/10.1038/s41401-026-01749-1
bioRxiv. 2026 Feb 20. pii: 2026.02.19.706635. [Epub ahead of print]

Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.

Tulika Malik, Sam Jones, Olivia Ma, Sahana Mohan, R Michael Burger, Daniel T Babcock.

Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.

DOI: https://doi.org/10.64898/2026.02.19.706635
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00243-2. [Epub ahead of print]203 89-110

Monitoring neuronal mitophagy and locomotion deficits in a C. elegans model of Alzheimer's disease.

Giorgos Garcia Niforos, Eleni Tsakiri, Konstantinos Palikaras.

  Neurodegenerative diseases, such as Alzheimer's disease (AD), pose significant socioeconomic and personal burdens due to progressive cognitive and motor decline. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and tau tangles, alongside with emerging evidence linking metabolic dysfunction to its early disease pathogenesis. Impaired mitochondrial selective autophagy (known as mitophagy) and excessive mitochondrial dysfunction have been implicated as key contributors to disease progression. To uncover the mechanistic underpinnings of AD, Caenorhabditis elegans offers a powerful model system providing a fully mapped nervous system, transparency for live imaging, and evolutionary conserved pathways mirroring human pathophysiology. Here, we employ a pan-neuronal Aβ1-42 -expressing C. elegans strain to phenocopy early metabolic disturbances characteristic of AD. Our methodology integrates automated motility tracking with confocal microscopy, utilizing the mitochondria-targeted Rosella biosensor to assess mitophagy dynamics in vivo. This platform enables quantitative assessment of locomotion deficits and spatiotemporal monitoring of mitophagy alterations driven by Aβ1-42-induced toxicity. Our method provides a robust tool for screening genetic and pharmacological interventions aimed at mitigating AD-associated mitochondrial dysfunction and neurodegeneration.

Keywords:  Alzheimer’s disease; Caenorhabditis elegans; Mitochondria; Mitophagy; Motility; Neurodegeneration; Neurons

DOI:  https://doi.org/10.1016/bs.mcb.2025.12.001
bioRxiv. 2026 Feb 13. pii: 2026.02.11.705390. [Epub ahead of print]

TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates.

Ziyan He, Jiechao Zhou, Rongzhen Zhang, Fei Meng, David W Nauen, Juan C Troncoso, Paul F Worley, Wenchi Zhang.

Aberrant protein aggregation is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which share overlapping genetic and pathological features. Similar aggregates are increasingly recognized in Alzheimer's disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, it remains unclear whether a shared molecular pathway drives this pathological aggregation. Here, we report that the E3 ubiquitin ligase TRIM32, together with the shuttle factor UBQLN2 and the autophagy adaptor p62/SQSTM1, form condensates that depend on E3 ligase activity and a network of intermolecular interactions. These condensates act as scaffolds that capture UBQLN2 client proteins, including TDP-43 and ANXA11, and modulate their mobility. A unique hydrophobic loop within TRIM32's substrate-binding domain mimics low-complexity motifs in ANXA11 and TDP-43, enabling selective retention via competitive binding mediated by UBQLN2 STI1 domain. Moreover, TRIM32 condensates promote amyloid aggregation of TDP-43, an effect that is exacerbated by pathogenic UBQLN2 mutation. In brains from individuals with diverse neurodegenerative diseases, TRIM32 co-localizes with pathological phospho-TDP-43 (pTDP-43) inclusions, supporting a model in which TRIM32-driven condensates function as selective proteostasis sorting compartments that broadly contribute to TDP-43 proteinopathy.

DOI: https://doi.org/10.64898/2026.02.11.705390
Innovation (Camb). 2026 Jan 05. 7(1): 100989

Next questions of autophagy in neurodegenerative diseases: From mechanisms to therapeutics.

Rongcan Luo.

Autophagy, a key cellular degradation pathway, is central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Despite progress in understanding its role, critical questions remain. This perspective highlights pressing issues, including cell-type-specific autophagy regulation, interactions with other cellular pathways, and challenges in translating autophagy-modulating therapies to clinical practice. Addressing these questions will advance our understanding of neurodegenerative diseases and pave the way for novel therapeutics.

DOI: https://doi.org/10.1016/j.xinn.2025.100989
Adv Sci (Weinh). 2026 Feb 25. e20441

Coacervate-Mediated Lysosome-Targeting Antibody Delivery for Protein Degradation.

Dingdong Yuan, Yishu Bao, Zhiyi Xu, Zhong Zheng, Yongxu Han, Kai Cheng, Yuan-Di Zhao, Jiang Xia.

  Selective recognition of cancer-associated proteins (CAPs) by antibodies, followed by their delivery into the intracellular organelle, the lysosome, results in targeted degradation of CAPs and suppresses the growth of cancer cells. Translocating the antibody-CAP complex across the plasma membrane is, however, nontrivial. Phase-separating molecules are known to form membrane-translocating coacervates that can encapsulate proteins and transport them into the cytoplasm. Nevertheless, these coacervates generally lack the ability to guide the cargo to the lysosome. Here, we seal this gap and develop lysosome-targeting coacervates by tailoring a tetrapeptide into a phase-separating, coacervate-forming peptide. In the aqueous solution, the peptide derivative forms microdroplets, or coacervates, through liquid-liquid phase separation (LLPS), which spontaneously enter cells and colocalize with the lysosome; hence, these coacervates are referred to as Lysosome-Sorting Peptide Coacervates or LSP-Coa. We show that LSP-Coa can encapsulate proteins, facilitate the translocation of antibody-CAP complexes to the lysosome, and enable the degradation of membrane-bound CAPs - a mechanism we call Coacervate-mediated Lysosome-targeting Protein Degradation, or CoaLPD. Using the CoaLPD technology, we successfully degraded HER2 and EGFR in cancer cells and in tumor-bearing mice, showcasing its potential use as an anticancer treatment. The LSP-Coa system also increases the efficacy of PROTAC degradation through enhanced lysosomal uptake. Taken together, we present the design of lysosomal-targeting coacervates and demonstrate their use as vehicles for lysosome-specific antibody delivery and for the selective degradation of CAPs, thereby validating the CoaLPD strategy as a potential anticancer treatment.

Keywords:  intracellular delivery; lysosome‐targeting delivery; peptide coacervates; phase separation; targeted protein degradation

DOI:  https://doi.org/10.1002/advs.202520441
Ageing Res Rev. 2026 Feb 21. pii: S1568-1637(26)00054-1. [Epub ahead of print]117 103062

Linking mitochondrial DNA release to neurodegeneration and cognitive decline.

Zongwei Fang, Catarina Barbosa, Daniela Marinho, Rita Peixoto, Ildete Luísa Ferreira, João Laranjinha, A Cristina Rego.

  Mitochondrial DNA (mtDNA) has been recognized as a key link between mitochondrial dysfunction and neuroinflammation in neurodegenerative diseases. Beyond being a vulnerable target of oxidative damage, mtDNA can act as a damage-associated molecular pattern when released from mitochondria, triggering innate immune signaling pathways in the nervous system. This review synthesizes current evidence on the mechanisms regulating mtDNA escape from mitochondria into the cytosol and its subsequent intracellular and extracellular effects, reframing mtDNA as an active driver of inflammatory processes rather than a passive by-product of mitochondrial injury. We discuss how defects in mitochondrial quality control, particularly impaired mitophagy and macroautophagy, promote the accumulation of damaged mtDNA, including its release via mitochondria-derived vesicles, exosomes or as cell-free mtDNA. By integrating mitochondrial dysfunction, immune activation, and clearance pathways, this review highlights the mitochondria-immune axis as a central contributor to neurodegeneration and cognitive decline, identifying upstream molecular targets with potential for therapeutic intervention.

Keywords:  Damage-associated molecular patterns (DAMPs); Inflammation; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Neurodegenerative diseases; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.arr.2026.103062
Biochem Biophys Res Commun. 2026 Feb 19. pii: S0006-291X(26)00271-8. [Epub ahead of print]809 153507

Muscle-specific expression of Atg2 and high-fat diet influence age-related deterioration of skeletal muscle in aged drosophila via the ATGL/Sirt1/PGC-1α pathway.

Jingfeng Wang, Nijia Meng, Dengtai Wen.

  Atg2 plays a vital role in regulating the ageing process. Autophagy and lysosomal repair depend on the lipid transport function of Atg2. The molecular mechanisms of the muscle Atg2 gene resistance to high-fat diet (HFD)-induced age-related damages of skeletal muscle are not known. In this study, we achieved overexpression and knockdown of the muscle Atg2 gene in drosophila by constructing the Atg2UAS/MhcGal4 system. Drosophila was subjected to an HFD intervention for three weeks. The findings demonstrated that an HFD markedly reduced climbing endurance and speed, down-regulated muscle Atg2, Atg8a (a mammalian ortholog of LC3 and an autophagy marker), ATGL, Sirt1, and PGC-1α gene expression, and raised MDA and TG in elderly drosophila. Age-related muscle degeneration caused by a high-fat diet was worsened by knocking down muscle Atg2. In contrast, age-related muscle degeneration brought on by a high-fat diet was avoided by overexpressing the Atg2 gene in muscles. Therefore, the present findings demonstrated that the muscle Atg2 gene was essential for skeletal muscle resistance against age-related damages caused by a high-fat diet by controlling the activity of the ATGL/Sirt1/PGC-1α pathway, oxidative balance, and lipid metabolism.

Keywords:  ATGL/Sirt1/PGC-1α; Atg2; Autophagy; High-fat diet; Skeletal muscle aging

DOI:  https://doi.org/10.1016/j.bbrc.2026.153507
Biomedicines. 2026 Feb 05. pii: 376. [Epub ahead of print]14(2):

Metformin for Longevity and Sarcopenia: A Therapeutic Paradox in Aging.

Song-Yi Han, Mukesh Kumar Yadav, Jing-Hua Wang.

  Metformin is a first-line oral antidiabetic agent that has attracted increasing interest as a potential geroprotective therapy due to its ability to improve metabolic homeostasis, reduce oxidative stress, and attenuate chronic inflammation. However, its role in skeletal muscle aging and sarcopenia remains controversial. Observational and epidemiological studies suggest that metformin use is associated with a lower prevalence of sarcopenia, particularly in metabolically compromised or insulin-resistant older populations, where improvements in systemic metabolism and inflammatory burden may indirectly support muscle quality and function. In contrast, randomized interventional trials in metabolically healthy older adults indicate that metformin can blunt resistance exercise-induced muscle hypertrophy and protein synthesis, likely through sustained activation of AMP-activated protein kinase (AMPK) and consequent suppression of mammalian target of rapamycin complex 1 (mTORC1) signaling. This perspective argues that these apparently opposing outcomes reflect a con-text-dependent therapeutic paradox rather than inconsistent evidence. Metformin may provide metabolic protection in frail, insulin-resistant individuals, yet limit anabolic adaptations in physically active older adults. These findings emphasize the necessity for precision geropharmacological strategies to balance metabolic longevity with preservation of musculoskeletal health in aging populations.

Keywords:  AMPK; aging; frailty; mTORC1; metformin; resistance training; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3390/biomedicines14020376
bioRxiv. 2026 Feb 14. pii: 2026.02.13.705749. [Epub ahead of print]

Tubulin acetylation governs organelle remodeling and lysosomal reformation during neuronal differentiation.

Chih-Hsuan Hsu, Alexander Josiah Kinrade, Maria Clara Zanellati, Sarah Cohen.

A functional nervous system depends on neuronal morphology established during differentiation. The microtubule (MT) cytoskeleton supports neuronal differentiation by organizing organelle positioning and facilitating transport. The dynamics and properties of MTs are regulated by a variety of post-translational modifications (PTMs), with many organelle interactions occurring preferentially on modified MTs. Here we find that tubulin acetylation is enriched at specific subcellular locations during differentiation of human induced neurons. We apply a quantitative multispectral imaging pipeline to simultaneously analyze eight membrane-bound organelles and define how tubulin acetylation reshapes organelle architecture and interaction networks during neuronal differentiation. We find that loss of tubulin acetylation broadly alters organelle morphology, spatial distribution, and inter-organelle interactions, with lysosome-organelle interactions most affected. Loss of acetylated MTs leads to enlarged, highly acidified lysosomes, impaired lysosomal fission, and accumulation of autolysosomes, consistent with defective lysosomal reformation. Super-resolution microscopy further reveals that lysosome-endoplasmic reticulum (ER) contacts preferentially associate with acetylated MTs. Together, our data support a model in which tubulin acetylation coordinates lysosome-ER interactions to facilitate lysosome remodeling and turnover. This work establishes tubulin acetylation as a key cytoskeletal regulator that links organelle interactions to organelle homeostasis important for neuronal differentiation.

DOI: https://doi.org/10.64898/2026.02.13.705749
Cells. 2026 Feb 12. pii: 335. [Epub ahead of print]15(4):

Precise Mapping of the Proteasome Interaction Region (PIR) of p62/SQSTM1: Decoupling Condensate Formation from Proteasome Recruitment.

Fedor Lipskerov, Victoria Cohen-Kaplan, Aaron Ciechanover.

  p62/SQSTM1 is a multifunctional scaffold protein central to selective autophagy and, more recently, recognized as a regulator of ubiquitin-proteasome system-mediated degradation of intracellular proteins. Within phase-separated condensates, p62 has been shown to recruit and sequester the proteasome, yet the molecular basis for this interaction has remained largely unknown. Our previous study demonstrated that the 'PB1' domain (residues 1-123) of p62 is necessary for proteasome binding. However, this long stretch is also responsible for other functions of p62, such as condensate assembly and signal transduction. Thus, it was important to define more precisely the region responsible for interaction with the proteasome. In this study, we used systematic deletion variants of p62 and biochemical assays to delineate the minimal sequence within the PB1 domain responsible for proteasome binding. Our analyses revealed a small stretch of six amino acids (residues 84-89) that bind the proteasome and are distinct from the region responsible for condensate formation. Such a precise variant can serve as a useful tool to dissect how p62-proteasome interaction affects selective degradation and probably stress response, separating it from other p62 functions. Overall, this work advances our understanding of the structural determinants underlying p62's dual role in autophagy and UPS regulation.

Keywords:  LLPS; PB1 domain; UPS; p62/SQSTM1; selective proteolysis

DOI:  https://doi.org/10.3390/cells15040335
Biomol Ther (Seoul). 2026 Mar 01. 34(2): 264-278

Skin Organoids in Proteostasis Research: Early Insights into Aging.

Muhammad Kamal Hossain, Hyung-Ryong Kim.

  The decline of proteostasis is a central hallmark of aging, the earliest manifestations of which have remained difficult to capture in human tissues with conventional model systems. The skin is a continuously renewing and environmentally exposed organ offering a uniquely accessible window into aging biology. Skin organoid technologies allow for long-term culturing of human epidermal and full-thickness skin-like tissues that accurately recapitulate important aspects of cellular heterogeneity, spatial organization, and stem cell dynamics. In this perspective, we discuss how skin organoids are beginning to reveal early proteostasis alterations-encompassing impaired protein folding, reduced proteasomal activity, and autophagy dysfunction-that precede overt structural and functional hallmarks of skin aging, with particular emphasis on underexplored regulators- sebaceous gland and sebocyte-specific proteostasis, autophagy, and inflammaging. We also highlight emerging insights, conceptual challenges, and experimental limitations, and outline future directions for integrating skin organoids with skin-on-a-chip, single-cell proteomics, and stress-reporting approaches to advance proteostasis-targeted interventions in skin aging.

Keywords:  Autophagy dysfunction; Inflammaging; Proteostasis decline; Sebocyte-specific proteostasis; Skin organoids; Skin-on-a-chip

DOI:  https://doi.org/10.4062/biomolther.2025.268
Brain Pathol. 2026 Feb 24. e70088

The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease.

Sanaz Gabery, Sofia Bergh, Chrisovalantou Huridou, Rachel Y Cheong, Barbara Baldo, Paul Günther Scheunemann, Marie-Louisa Schoebel, Linda Holmquist Mengelbier, Elisabet Englund, Catriona McLean, Carsten Saft, Deniz Kirik, Maria Björkqvist, Glenda Halliday, Elisabeth Petrasch-Parwez, Huu Phuc Nguyen, Jonasz Jeremiasz Weber, Åsa Petersén.

  The pathogenic mechanisms leading to neurodegeneration in Huntington disease (HD) are not fully understood but involve accumulation of toxic mRNA and protein products in the brain. Recent studies described an unconventional autophagic pathway involving DNA and RNA degradation through DNautophagy and RNautophagy that is regulated by the lysosomal protein SID1 transmembrane family member 2 (SIDT2). Interestingly, SIDT2 has been shown to bind to the expanded CAG repeat in the mutant huntingtin (mHTT) transcript and lower mHTT in vitro. The aim of the present study was to determine whether SIDT2 levels are altered in HD and whether manipulation of SIDT2-mediated RNautophagy can alter HD pathology. We demonstrate a significant reduction of SIDT2 protein levels in the striatum and in the lateral hypothalamic area in postmortem HD brains compared to control cases without effects on SIDT2 mRNA levels. In frontal cortical postmortem HD tissue, we show a CAG-repeat-length-dependent increase in the frequency of SIDT2-immunoreactive intranuclear inclusions. In postmortem tissue of an HD case with Vonsattel grade 0, we demonstrate SIDT2- and mHTT-immunoreactive inclusions not only in the frontal cortex, but also in the striatum and the lateral hypothalamic area. In the R6/2 mouse model of HD, we show that SIDT2 inclusions form at later stages than mHTT inclusions. Overexpression of SIDT2 using adeno-associated viral vectors injected into the hypothalamus of R6/2 mice led to a reduction of mHTT inclusions in the lateral hypothalamic area. Similarly, in a neuronal cell model, overexpression of SIDT2 reduced soluble and insoluble mHTT exon 1 protein levels. Taken together, our results reveal novel pathology in clinical HD cases and in experimental models, characterized by the accumulation of SIDT2-immunoreactive inclusions, while demonstrating the efficacy of overexpressing SIDT2 for lowering detrimental mHTT species. Targeting SIDT2-mediated RNautophagy may offer a potential strategy to ameliorate the molecular pathology in HD.

Keywords:  SIDT2; aggregation; huntingtin; huntingtin lowering; inclusions; neuropathology

DOI:  https://doi.org/10.1111/bpa.70088
Nat Commun. 2026 Feb 24.

Bnip3lb-driven mitophagy maintains fate of the embryonic hematopoietic stem cell pool.

Eleanor Meader, Morgan T Walcheck, Mindy R Leder, Patrice Delaney, Marcelo Falchetti, Ran Jing, Christopher Li, Netra K Kambli, Paul J Wrighton, Wade W Sugden, Mohamad A Najia, Isaac M Oderberg, Vivian M Taylor, Zachary C LeBlanc, Eleanor D Quenzer, Sung-Eun Lim, Thorsten Schlaeger, George Q Daley, Wolfram Goessling, Trista E North.

Embryonic hematopoietic stem and progenitor cells (HSPCs) have the clinically valuable ability to undergo substantial proliferative expansion while maintaining multipotency, which remains difficult to replicate in culture. Here, we show that newly specified HSPCs achieve this unique state by precise spatio-temporal regulation of reactive oxygen species (ROS) via Bnip3lb-associated developmentally-programmed mitophagy, a distinct autophagic regulatory mechanism from that of adult HSPCs. While ROS drives HSPC specification in the dorsal aorta, scRNAseq and live-imaging of mitophagy-reporter zebrafish indicate that mitophagy initiates during endothelial-to-hematopoietic transition and colonization of secondary niches. Knockdown of bnip3lb reduces mitophagy and HSPC numbers in the caudal hematopoietic tissue by promoting myeloid-biased differentiation and apoptosis, which can be rescued by antioxidant exposure. Conversely, chemical or genetic induction of mitophagy enhances embryonic HSPC and lymphoid progenitor numbers. Significantly, compound-mediated mitophagy activation improves ex vivo function of HSPCs derived from human-induced pluripotent stem cells, enhancing serial-replating hematopoietic colony forming potential.

DOI: https://doi.org/10.1038/s41467-026-69593-9
Cell Death Discov. 2026 Feb 21. pii: 104. [Epub ahead of print]12(1):

Novel mechanism of neuronal hypoxia response: HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against neuronal injury.

Yuning Li, Zirui Xu, Zhengming Tian, Mengyuan Guo, Qianqian Shao, Yingxia Liu, Yakun Gu, Feiyang Jin, Xunming Ji, Jia Liu.

Hypoxic stress contributes to brain disorders by causing neuronal injury, making it crucial to understand neuronal hypoxic response mechanisms for disease resistance. In the early stage of stress, neurons initiate a series of compensatory pathways to resist cell damage, but the underlying mechanisms have not been fully elucidated. In this study, we found that hypoxia transiently activates PTEN-induced kinase 1 (PINK1)-dependent mitophagy in the early stage before cell damage and neurological dysfunction. When PINK1-dependent mitophagy is inhibited, neuronal injury begins to exacerbate. Under hypoxia, overexpression of PINK1 can resist neuronal injury, while knockdown of PINK1 aggravates neuronal injury, revealing that PINK1-dependent mitophagy plays a key role in neuronal compensatory hypoxia response. Mechanistically, in the early stage of hypoxia, the nuclear translocation of HIF-1α increases, mediating the transcription of its downstream target molecule STOML2. STOML2 translocates to the outer mitochondrial membrane and participates in the cleavage of PGAM5. These processes initiate PINK1-dependent mitophagy. Knockdown of HIF-1α, STOML2, or PGAM5 inhibits mitophagy and worsens hypoxia-induced dysfunction, highlighting this pathway's importance. Intermittent hypoxia, a conditioning strategy, stimulates endogenous protection. Notably, it activates the HIF-1α/STOML2 axis, inducing PINK1-dependent mitophagy and protecting neurons. In conclusion, our study reveals a new "self-protection" mechanism of neurons against hypoxic stress and discovers that intermittent hypoxia can effectively activate this pathway to resist neuronal injury, providing new insights into the mechanisms and interventions of hypoxia-related nerve injury.

DOI: https://doi.org/10.1038/s41420-026-02960-z
Cells. 2026 Feb 13. pii: 345. [Epub ahead of print]15(4):

The Role of Autophagy-Lysosomal Pathways in Photoreceptor Death in the rd10 Mouse Model of Inherited Retinal Degeneration.

Kirstan A Vessey, Nadia Hosseini Naveh, Ophelia Ehrlich, Allegra Glover, Joshua Lee, Ursula Greferath, Andrew I Jobling, Erica L Fletcher.

  Inherited retinal degenerations, such as retinitis pigmentosa, are a leading cause of irreversible vision loss, yet broadly effective treatments remain elusive. Impaired cellular waste clearance via autophagy-lysosomal pathways have been implicated in photoreceptor death, but the spatiotemporal dynamics of these processes during degeneration remain poorly understood. Using the rd10 mouse model of retinitis pigmentosa, we characterised autophagy-lysosomal dysfunction at key stages of photoreceptor degeneration (postnatal day P17, P22, P35) through super-resolution imaging of RFP-EGFP-LC3 reporter mice, Western blot, and bulk RNA sequencing. Autophagosome and autolysosome numbers were significantly elevated across all photoreceptor compartments (inner/outer segments, outer nuclear layer, outer plexiform layer) at P17, prior to significant photoreceptor nuclei loss. Autophagosome and autolysosome size progressively increased from P22 onwards, suggesting accumulation of unprocessed intracellular waste. Molecular analyses revealed downregulation of mTOR protein, upregulation of autophagy-related genes, and increased lysosomal processes from P17. These histological and molecular findings are consistent with early autophagy induction followed by overwhelmed degradative capacity. Our findings identify autophagy-lysosomal change as an early event in photoreceptor loss in the rd10 model, revealing a critical therapeutic window for mutation-independent interventions targeting cellular clearance pathways in inherited retinal degenerations.

Keywords:  LC3; autophagy; cell death; cellular waste clearance; inherited retinal disease; lysosome; photoreceptor degeneration; rd10 mouse; retinitis pigmentosa

DOI:  https://doi.org/10.3390/cells15040345
Science. 2026 Feb 26. 391(6788): eady2822

A cellular basis for the mammalian nocturnal-diurnal switch.

Andrew D Beale, Matthew J Christmas, Nina M Rzechorzek, Andrei Mihut, Aiwei Zeng, Christopher Ellis, Nathan R James, Nicola J Smyllie, Violetta Pilorz, Rose Richardson, Mads F Bertelsen, Shaline V Fazal, Zanna Voysey, Kevin Moreau, Jerry Pelletier, Priya Crosby, Sew Y Peak-Chew, Rachel S Edgar, Madeline A Lancaster, Roelof A Hut, John S O'Neill.

Early mammals were nocturnal while dinosaurs dominated the daytime. Mammalian transition to daytime activity accelerated after the Cretaceous-Paleogene extinction, but the underlying mechanisms remain unclear. We identified a conserved cell-intrinsic, thermodynamic mechanism that likely facilitated this shift. In cells from diurnal mammals, protein synthesis, phosphorylation, and circadian timing were less sensitive to temperature changes than were cells from nocturnal mammals. Comparative genomics revealed accelerated evolution within essential signaling pathways, including mechanistic target of rapamycin (mTOR), that increase the robustness of diurnal cellular clocks to thermal and osmotic perturbation. In nocturnal mice, mTOR inhibition shifted cells, tissues, and behavior toward diurnal activity. These findings uncover a genetic and biochemical basis for nocturnal-diurnal switching, emphasizing how cellular signaling networks can encode complex phenotypes such as temporal niche selection.

DOI: https://doi.org/10.1126/science.ady2822