bims-auttor 2026-08-09 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–08–09
25 papers selected by
Viktor Korolchuk, Newcastle University

Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.
Exercise-induced lysosomal adaptations in skeletal muscle.
Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.
RAB18-dependent recruitment of OPTN initiates selective lipophagy in osteoblasts.
Small-molecule autophagy modulators: Mechanisms, therapeutic potential, and development challenges in pathological settings.
Cholesterol enhances lysosome-autophagosome fusion for better α-synuclein clearance in GBA L444P-mutated Parkinson disease.
Tankyrase-2 regulates adipocyte differentiation through AMPK/mTOR signaling.
A transposon-derived transcription factor senses ionic stress through phase separation to govern plant autophagy.
PGAM1 rheostat in glycolysis and autophagy.
p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.
The co-regulation of NLRP3 inflammasome and autophagy for cardiovascular diseases.
The role of the HB-EGF-regulated EGFR-mitophagy axis in maintaining cartilage homeostasis and osteoarthritis.
Crosstalk between mitophagy and metabolism in cancer: Mechanisms and therapeutic opportunities.
Targeted Restoration of Mitophagy Reinvigorates Aged Hematopoietic Stem Cells.
Autophagy in ischemic stroke: pathophysiology, therapeutics, and challenges ahead.
Allosteric switching of Ca2+ permeability in the lysosomal ion channel TPC2 underpins biased agonist activation.
Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
The Glial Autophagy-Lysosomal-Inflammation Axis in Alzheimer's Disease: a Unifying Mechanistic Framework.
Microglial SREBP2 regulate cholesterol-related lipid metabolism and inflammatory levels following ischemic stroke via the autophagy pathway.
Sestrin2 alleviates age-related hearing loss through mediating PINK1/Parkin related mitophagy.
TFEB Deficiency Impairs Male Fertility Through Mitochondrial Dysfunction.
Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.
The (European) protein homeostasis network.
A Single-Amino-Acid Ligand for LAT1: A Minimalist and Modular Platform for Lysosome-Targeted Degradation of Membrane Proteins.
Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways.

Autophagy. 2026 Aug 06. 1-17

Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.

F Abrar, D D O Martin.

  SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review will discuss the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy.Abbreviations: ABHD = α/β-hydrolase domain; AD = Alzheimer Disease; ALS = amyotrophic lateral sclerosis; ATG = autophagy related ; CSNK2/CK2 = casein kinase 2; HD = Huntington Disease; HDAC/KDAC = histone deacetylase/lysine deacetylase; HTT = huntingtin; KAT = lysine acetyltransferase; KEAP1 = kelch like ECH associated protein 1; KIR = KEAP1-interacting region; LIR = LC3-interacting region; LYPLA/APT = lysophospholipase/acyl-protein thioesterase; MAP1LC3/LC3 = microtubule associated protein 1 light chain 3; MEF = mouse embryonic fibroblast; mHTT = mutant huntingtin; MTORC1 = MTOR complex 1; NBR1 = NBR1 autophagy cargo receptor; NEDD4 = NEDD4 E3 ubiquitin protein ligase ; NO = nitric oxide; NFE2L2/Nrf2 = nuclear factor erythroid 2-factor 2; PAT = palmitoyl acyltransferase; PB1 = Phox-BEM1 domain; PE = phosphatidylethanolamine; PLEKHM1 = pleckstrin homology and RUN domain containing M1; PLK2 = polo like kinase 2; PRKA/PKA = protein kinase cAMP-activated; PPT1 = palmitoyl-protein thioesterase 1; RB1CC1 = RB1 inducible coiled-coil 1; SNCA/α-synuclein = synuclein alpha; SNO = S-nitrosothiol; SOD1 = superoxide dismutase 1; SQSTM1 = sequestosome 1; TARDBP/TDP-43 = TAR DNA binding protein ; TBK1 = TANK binding kinase 1; TAX1BP1 = Tax1 binding protein 1; TRIM = tripartite motif containing ; UBA = ubiquitin-associated domain; UBE = ubiquitin-conjugating enzyme; ULK1 = unc-51 like autophagy activating kinase 1; UPS =ubiquitin-proteasome system; USP8 = ubiquitin specific peptidase 8; ZDHHC = zDHHC palmitoyltransferase.

Keywords:  Neuroscience; S-acylation; p62; post-translational modifications; sequestosome 1

DOI:  https://doi.org/10.1080/15548627.2026.2711593
Sports Med Health Sci. 2026 Sep;8(5): 487-494

Exercise-induced lysosomal adaptations in skeletal muscle.

Anastasiya Kuznyetsova, David A Hood.

  The adoption of a regular exercise program has immense benefits for whole body health, and for improving the quality of skeletal muscle. This is important as muscle is involved in metabolism, locomotion, and force production, making it a large contributor to the quality of life. The coordinated behavior of several intracellular organelles is responsible for the maintenance of skeletal muscle health, and these organelles are adaptable in response to both acute and chronic exercise. While the adaptations of mitochondria to exercise are well-established, potential alterations in muscle lysosomes are less appreciated. Lysosomes degrade and recycle debris during the terminal step of various forms of autophagy, such as mitophagy, the pathway involved in the removal of dysfunctional mitochondria. This lysosomal activity is important for the maintenance of cellular protein and organelle homeostasis. Recent work has shown that lysosome biogenesis begins with every acute bout of exercise, driven by the nuclear translocation of regulatory transcription factors such as TFEB and TFE3, which mediate the transcription of autophagy and lysosomal genes. These transcription factors also play a role in other pathways such as chaperone-mediated autophagy (CMA) and the regeneration of existing lysosomes through the autophagic-lysosome reformation (ALR) pathway. When performed repeatedly, acute bouts of exercise elicit a longer-term adaptive response, leading to the formation of active lysosomes, which increase lysosomal degradative capacity in skeletal muscle. This review addresses the current knowledge surrounding the effects of acute and chronic exercise on lysosomal adaptations in skeletal muscle, highlighting a novel pathway of muscle plasticity.

Keywords:  Autophagic lysosome reformation; Chaperone-mediated autophagy (CMA); Exercise training; Macroautophagy; Mitophagy; Skeletal muscle; TFEB; Transcriptional regulation

DOI:  https://doi.org/10.1016/j.smhs.2026.06.001
Aging Dis. 2025 Aug 06. 17(5): 2468-2489

Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.

Khoshnur Jannat, Sang-Bong Lee, Hong-Ryeol Jung, Rengasamy Balakrishnan, Yon-Suk Kim, Mujeeb Ur Rahman, Dong-Kug Choi.

Parkinson's disease is a neurodegenerative condition characterized by the accumulation of misfolded and aggregated α-synuclein in Lewy bodies and neurites. These protein aggregates contribute to neurodegeneration and motor symptoms such as bradykinesia, rigidity, and tremor. While the ubiquitin-proteasome system degrades soluble α-synuclein, aggregated and oligomeric forms are primarily cleared via the autophagy-lysosomal pathway. Mutations of the SNCA gene exacerbate α-synuclein aggregation and significantly impair its clearance, highlighting the importance of targeting toxic α-synuclein species. Strategies such as promoting autophagosome formation via 5'-AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) or facilitating autophagosome maturation via RAB7-a member of the RAS oncogene family-and related effectors, have shown promise in enhancing autophagy and reducing α-synuclein pathology. Pharmacological agents such as rapamycin, trehalose, and nilotinib have demonstrated preclinical efficacy in enhancing α-synuclein clearance and alleviating disease features. Concurrently, immunotherapy approaches, including passive and active immunization, aim to enhance the immune system's ability to recognize and eliminate toxic α-synuclein species. Emerging strategies such as peptide-based therapies aim to inhibit aggregation or promote degradation of α-synuclein. At the same time, nanotechnology enables the targeted delivery of therapeutic agents across the blood-brain barrier with improved efficiency. Additionally, novel AUTOTAC (autophagy-targeting chimera) platforms offer a precision strategy to tag α-synuclein for autophagic degradation. This review explores many advances in autophagy-mediated aggregated α-synuclein clearance, emphasizing its potential as a therapeutic strategy to address the limitations of current symptomatic treatments and slow the progression of Parkinson's disease.

DOI: https://doi.org/10.14336/AD.2025.0642
Autophagy. 2026 Aug 02. 1-17

RAB18-dependent recruitment of OPTN initiates selective lipophagy in osteoblasts.

Chonghao Ji, Lehan Xu, Fu Zheng, Peng Deng, Zuping Wu, Xinyi Fang, Qianming Chen, Misi Si, Xiaoyan Chen.

  Selective lipophagy requires cargo recognition and recruitment of autophagy receptors to lipid droplets (LDs), yet the molecular mechanisms that couple LDs to the core autophagy machinery remain poorly defined. Here, we identified the small GTPase RAB18 (RAB18, member RAS oncogene family) as an upstream initiator of lipophagy that directly recruited the macroautophagy/autophagy receptor OPTN (optineurin) to LDs in osteoblasts. Lipid stress induced RAB18 activation and its localization to LDs, where RAB18 engaged OPTN enabling OPTN-LC3 bridging and lysosomal degradation of LDs. Loss of either RAB18 or OPTN impaired lipophagic flux, resulting in lipid accumulation and defective osteogenic differentiation, whereas OPTN overexpression partially rescued RAB18 deficiency, supporting a hierarchical RAB18-OPTN pathway. Thus, while OPTN acted as a critical effector downstream of RAB18, it did not feed back to promote RAB18 recruitment. In vivo, perturbation of this axis compromised bone regeneration under hyperlipidemic conditions. Together, these findings establish RAB18-dependent recruitment of OPTN as a molecular mechanism for selective lipophagy and reveal lipophagy as a critical metabolic adaptation that sustains osteoblast function during lipid stress.Abbreviations: AAV: adeno-associated virus; ALP: alkaline phosphatase; Baf A1: bafilomycin A1; CC domain 1: coiled-coil domain 1; CCK-8: cell counting Kit-8 kit; Co-IP: co-immunoprecipitation; ER: endoplasmic reticulum; HE: hematoxylin and eosin; IF: immunofluorescence; IHC: immunohistochemistry; KD: knockdown; LDs: lipid droplets; Micro-CT: microscopic computerized tomography; OE: overexpression; OPTN: optineurin; qRT-PCR: quantitative real-time polymerase chain reaction; RAB18: RAB18, member RAS oncogene family; ROI: region of interest; SD: standard deviations; TBK1: TANK binding kinase 1; TEM: transmission electron microscopy; WB: western blot.

Keywords:  Autophagy; high fat; hyperlipidemia; lipid droplet; osteogenesis

DOI:  https://doi.org/10.1080/15548627.2026.2710035
Fundam Res. 2026 Jul;6(4): 2081-2123

Small-molecule autophagy modulators: Mechanisms, therapeutic potential, and development challenges in pathological settings.

Yongya Wu, Jiaxiang Luo, Haolin Tang, Aoxue Wang, Maolin Duan, Jie Liu, Guan Wang, Liang Ouyang.

  Autophagy is an evolutionarily conserved process in eukaryotic cells that delivers intracellular components to lysosomes for degradation and recycling. Increasing evidence has elucidated the regulation of autophagy, highlighting its involvement in cellular metabolism, survival, and development, as well as its association with diverse physiological and pathological processes. There are often mutations in autophagy-regulating genes or abnormal autophagy function in multiple diseases, such as cancer, immune system diseases, and neurodegenerative diseases. Additionally, the regulation of the autophagy process shows potential therapeutic effects for these diseases. Several small molecules have been developed as autophagy regulators based on traditional drug discovery strategies, such as high-throughput screening, structure-activity relationship (SAR) optimization, and computer-aided drug design. Mechanistically, these compounds that bind specifically to such autophagy-related proteins or kinases can act as agonists or antagonists, with downstream consequences on the autophagy process. Several pharmacologic agents that regulate the autophagy process with extraordinary potential in disease treatment have come into clinical use. But most of these molecules still suffer from many obstacles, including low efficacy, low selectivity, poor pharmacokinetic profile, drug resistance, and toxicity. Moreover, some inappropriate and undruggable autophagy-related targets, as well as ubiquitous protein aggregates in neurodegenerative diseases, also bring serious challenges to the identification of small-molecule drugs. In this review, we briefly introduce autophagy and summarize its function and regulatory role in various diseases and disorders, and discuss the possibility of autophagy-targeted therapy in these diseases. The present review highlights current developments regarding the fundamental molecular mechanisms and signaling cascades of autophagy, while also addressing strategies for small-molecule-based therapeutic intervention.

Keywords:  Autophagy; Disease therapy; Drug discovery; Signal transduction; Small molecules

DOI:  https://doi.org/10.1016/j.fmre.2026.04.015
Cell Rep. 2026 Aug 06. pii: S2211-1247(26)00878-8. [Epub ahead of print]45(8): 117800

Cholesterol enhances lysosome-autophagosome fusion for better α-synuclein clearance in GBA L444P-mutated Parkinson disease.

Mingjia Chen, Fengtao Liu, Yujie Yang, Ruibo Chen, Linhua Gan, Yimin Sun, Yuchen Yan, Sisi Xie, Chenwei Zhu, Xiaoting Sun, Yang Li, Shun Zhu, Wen Liu, Ji Zuo, Yunlong Yang, Jian Wang.

  Mutations in lysosomal enzyme glucocerebrosidase (GBA), the most common genetic risk factor for Parkinson disease (PD), exacerbate α-synuclein pathology through unclear mechanisms. Here, we report, in a large cohort, that GBA-mutated PD patients exhibit lower serum cholesterol levels. By introducing the most common GBA variant in our cohort, L444P, into human α-synuclein knock-in mice, we noted that the mice exhibited behavioral and molecular pathological PD features at 12 months of age. Mechanistically, lysosomal proteomics identified the loss of lysosome-cytoplasmic vesicle interactions and cholesterol-containing lipid microdomains in both PD patients and mice. Autophagic flux monitoring revealed impaired autophagosome-lysosome fusion in GbaL444P/+ neurons. Gain- and loss-of-function experiments uncovered cholesterol synthesis impairment via glycosphingolipid-reduced SREBP2 levels. Importantly, cholesterol supplementation was found to enhance the autophagic flux and mitigate α-synuclein accumulation in vitro, whereas AAV-Srebp2 delivery increased α-synuclein clearance in GbaL444P/+ mice. Our study provides animal models and mechanistic insights into GBA-associated PD and offers a therapeutic paradigm by facilitating cholesterol-associated α-synuclein autophagic clearance.

Keywords:  CP: metabolism; CP: neuroscience; GBA; PD; Parkinson disease; autophagy; cholesterol; glucocerebrosidase; mouse model; α-synuclein

DOI:  https://doi.org/10.1016/j.celrep.2026.117800
FEBS J. 2026 Aug 06.

Tankyrase-2 regulates adipocyte differentiation through AMPK/mTOR signaling.

Boglarka Rauch, Gyula Ujlaki, Szilard Poliska, Nakayi Murahwa, Patrik Kovacs, Aladar Pettko-Szandtner, Karen Uray, Peter Bai.

  Although tankyrases (TNKSs) were originally described as enzymes safeguarding genome integrity, TNKSs are also associated with metabolism and are involved in the differentiation of multiple cell lineages including adipocytes. Here we aimed to understand the role of TNKSs specifically in adipocyte differentiation. We found that the deletion of TNKS1 or TNKS2 decreased the rate of adipocyte differentiation. Furthermore, the loss of TNKs induced a multi-pronged cellular adaptation characterized by changes in cellular proteostasis centered around the inhibition of autophagy, AMPK activation and the suppression of mTORC1 activity. Deleting TNKSs also induced mitochondrial oxidative phosphorylation and glycolytic flux. Interestingly, the fraction of oligomycin-resistant respiration decreased, suggesting more coupled OXPHOS. However, the lower differentiation rate of TNKS2 knockout cells was salvaged by pharmacological activation of autophagy (by NV-5138) and the pharmacological inhibition of LKB1 (by HY-10371), an upstream suppressor of the mTOR system. Finally, TNKS2 can ADP-ribosylate LKB1, rendering it susceptible for ubiquitinylation that appears to be a key step towards committing adipocytes to differentiation. Together this data validates the use of TNK inhibitors for managing metabolic diseases and raises the possibility that TNK inhibition can influence tumor or immunometabolism and amplify the effects of other treatments.

Keywords:  MARUbylation; autophagy; metabolic adaptation; metabolic flexibility; oxidative phosphorylation; tankyrase

DOI:  https://doi.org/10.1111/febs.70676
Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2617665123

A transposon-derived transcription factor senses ionic stress through phase separation to govern plant autophagy.

Yang Shao, Songyang Wang, Li Liang, Biao Gong, Aurore Johary, Benhui Shi, Linyang Zhang, Yanqun Xu, Zoé Joly-Lopez, Zisheng Luo, Thomas E Bureau, Jiaqi Sun.

  Salt stress severely impairs plant growth through two distinct cellular insults: osmotic stress caused by water limitation and ionic toxicity resulting from excessive Na+ accumulation. Although plant osmosensors have been identified, the mechanisms underlying ionic stress perception remain elusive. Salt stress also activates autophagy, a conserved degradation pathway that removes damaged organelles and protein aggregates to promote stress tolerance. In animals, master regulators such as transcription factor EB (TFEB) coordinate this response by activating autophagy genes across the pathway, but no analogous regulator has been identified in plants. Here, we show that MUSTANG4 (MUG4), a transcription factor derived from Mutator-like element (MULE) transposons, functions as an ionic stress sensor and the primary transcriptional driver of salt-induced autophagy in Arabidopsis. MUG4 responds to elevated monovalent cation concentrations, but not chloride anions or osmotic stress, thereby distinguishing ionic from osmotic stress. Ionic stress compacts the intrinsically disordered region (IDR) of MUG4 and drives liquid-liquid phase separation of the full-length protein, as demonstrated by Förster resonance energy transfer-fluorescence lifetime imaging, in vitro assays, and coarse-grained molecular dynamics simulations. Genome-wide in vivo CUT&Tag sequencing and RNA sequencing reveal that MUG4 directly and coordinately activates autophagy genes spanning multiple functional stages of the pathway. IDR deletion abolishes phase separation, reduces autophagy gene activation and autophagic flux, and prevents the truncated protein from rescuing the salt-sensitive phenotype of mug4 mutants. These findings identify a dedicated plant ionic stress sensor and establish a mechanistic link between exapted transposable elements, phase separation, and transcriptional stress responses, thereby integrating ionic stress perception with autophagy activation.

Keywords:  autophagy; ionic sensing; phase separation; salt stress; transposable elements

DOI:  https://doi.org/10.1073/pnas.2617665123
Nat Cell Biol. 2026 Aug 07.

PGAM1 rheostat in glycolysis and autophagy.

Kay F Macleod.

DOI: https://doi.org/10.1038/s41556-026-02033-4
J Biol Chem. 2026 Aug 07. pii: S0021-9258(26)02282-9. [Epub ahead of print] 113410

p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.

Nunzia Pastore, Sergio Attanasio, Francesco Annunziata, Claudia D'Agostino, Veronica Maffia, Rita Colonna, Teresa Giuliano, Rosa Ferriero, Iolanda Boffa, Donna Palmer, Philip Ng, Rossella De Cegli, Massimo D'Agostino, Florian Rosenberger, Pavel Strnad, Joseph E Chambers, Stefan J Marciniak, Jeffrey Teckman, Pasquale Piccolo, Nicola Brunetti-Pierri.

Liver disease in Alpha-1 antitrypsin deficiency (AATD) is caused by the toxic accumulation of mutant Z alpha-1 antitrypsin (Z-AAT) within the endoplasmic reticulum (ER) of hepatocytes. Livers from PiZ transgenic mice expressing the human Z-AAT and AATD patients were both found to have increased p62/SQSTM1, a multifunctional protein involved in protein homeostasis, consistent with previous reports. However, whether p62/SQSTM1 is a marker of Z-AAT globules or plays an active role in Z-AAT proteostasis is unclear. The goal of this study was to elucidate the involvement of p62/SQSTM1 in the formation of Z-AAT globules that are responsible for liver injury in AATD. In the present study, we found that p62/SQSTM1 decorated ubiquitin-positive, Periodic-Acid Shiff-diastase-resistant Z-AAT globules and interacted with Z-AAT at the ER-cytosol interface. Genetic ablation of p62/SQSTM1 in PiZ mice (PiZ;p62-/-) led to marked reduction in hepatic Z-AAT globules and polymers, and decreased serum Z-AAT, highlighting a central role for p62/SQSTM1 in disease pathogenesis. Moreover, hepatocyte-specific somatic deletion of the ubiquitin-association (UBA) domain of p62/SQSTM1 reduced Z-AAT aggregation. Furthermore, KEAP1 was identified as a binding partner of p62/SQSTM1-Z-AAT complex, leading to nuclear translocation and activation of NRF2. Inhibition of KEAP1-p62/SQSTM1 interaction reduced the abundance of p62 and phosphorylated p62, decreased intracellular Z-AAT, and redistributed NRF2 to the cytoplasm. In conclusion, this study identifies p62/SQSTM1 as a regulator of Z-AAT proteostasis and link Z-AAT/p62 accumulation to KEAP1 sequestration and NRF2 pathway activation in liver disease due to Z-AAT.

DOI: https://doi.org/10.1016/j.jbc.2026.113410
Pharmacology. 2026 Aug 03. 1-29

The co-regulation of NLRP3 inflammasome and autophagy for cardiovascular diseases.

Shuxin Zheng, Huaqian Dou, Xiao Feng Zhang, Renshan Chen, Yunjing Wang, Anran Zheng, Liangyan Lu, Muhammad Rafiq, Qing Xiao, Xiuhui Chen.

Cardiovascular diseases (CVDs) represent a significant global public health challenge. Activation of the NLRP3 inflammasome contributes to CVD pathogenesis, while autophagy mitigates the condition by eliminating harmful metabolites. Furthermore, NLRP3 inflammasome and autophagy co-regulate CVDs by enhancing autophagic processes, inhibiting inflammasome activity, and reducing inflammatory responses, thus playing a pivotal role in the disease's pathophysiology. Certain pharmacological agents have been shown to inhibit NLRP3 inflammasome activity by promoting autophagy, thereby ameliorating disease pathology. This review underscores the critical roles of NLRP3 inflammasome and autophagy in CVDs and examines the regulatory effects of specific drugs on these processes.

DOI: https://doi.org/10.1159/000549572
J Mol Histol. 2026 Aug 04. pii: 256. [Epub ahead of print]57(4):

The role of the HB-EGF-regulated EGFR-mitophagy axis in maintaining cartilage homeostasis and osteoarthritis.

JunHua Wang, ChiShou Mo, Qiang Wang, Jia Qin, Yong Li, WuXun Peng.

  This study investigates the mechanism by which heparin-binding epidermal growth factor (HB-EGF) maintains cartilage homeostasis in osteoarthritis (OA) through the epidermal growth factor receptor (EGFR)-mitochondrial autophagy axis. Given the challenges in OA treatment and the critical role of impaired mitochondrial autophagy in disease progression, this research first identified key regulators using transcriptomic data from human OA cartilage and GEO databases. An in vitro OA model was established via IL-1β induction in chondrocytes, through which HB-EGF was found to reverse the IL-1β-induced metabolic imbalance by downregulating catabolic markers (Mmp13, Adamts5) and upregulating anabolic markers (Acan, Col2a1). Further analysis revealed that HB-EGF enhanced mitophagy, as indicated by increased levels of Pink1, Parkin, and Lc3-II alongside decreased P62. These protective effects were attenuated by the mitophagy inhibitor Mdivi-1, confirming the dependence on this pathway. In conclusion, HB-EGF activates EGFR signaling to promote PINK1/ PARKIN-mediated mitophagy, which facilitates the clearance of damaged mitochondria and improves mitochondrial function, thereby restoring chondrocyte metabolic balance and delaying OA progression, suggesting the EGFR-mitophagy axis as a potential therapeutic target for OA.

Keywords:  Chondrocytes; EGFR; HB-EGF; Mitochondrial autophagy; Osteoarthritis; Synthesis and catabolism

DOI:  https://doi.org/10.1007/s10735-026-10916-x
Free Radic Biol Med. 2026 Aug 03. pii: S0891-5849(26)00985-8. [Epub ahead of print]255 573-590

Crosstalk between mitophagy and metabolism in cancer: Mechanisms and therapeutic opportunities.

Jingyi Cheng, Ting Xiao, Zhangui Tang, Yuhan Chen.

  Mitophagy is a highly selective autophagic process that eliminates dysfunctional mitochondria to enforce stringent cellular quality control, acting as a context-dependent modulator of stress adaptation in cancer cells. Concurrently, to thrive in hostile microenvironments, cancer cells undergo extensive metabolic reprogramming to fulfill the immense bioenergetic and anabolic demands of rapid proliferation. Rather than operating independently, mitophagy and metabolism are intrinsically coupled to form a highly sophisticated and bidirectional regulatory circuit. Metabolic disturbances trigger mitophagy, while mitophagy reciprocally remodels metabolic landscape. This crosstalk functions as a critical metabolic rheostat, equipping cancer cells with the dynamic plasticity required to cope with the dynamic physicochemical stresses. Furthermore, this mitophagy-metabolism crosstalk extends beyond cancer cells into the tumor microenvironment, orchestrating systemic metabolic symbiosis and driving immune evasion. In this review, we summarize the molecular mechanisms underpinning this crosstalk, and highlight how therapeutic targeting of these vulnerabilities offer opportunities for overcoming therapeutic resistance and improving clinical outcomes.

Keywords:  Cancer; Metabolic reprogramming; Mitophagy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.004
Antioxid Redox Signal. 2026 Aug 05. 15230864261475098

Targeted Restoration of Mitophagy Reinvigorates Aged Hematopoietic Stem Cells.

Jin Liu, Aiwei Wu, Jieyu Ling, Liquan Hong, Mingwei Wang, Xinyi Chen, Jianpin Zhou, Zhenyu Ju, Yue Sheng, Hongguang Xia, Hu Wang.

   AIMS: Aging-related functional decline in hematopoietic stem cells (HSCs) is closely associated with mitochondrial dysfunction and impaired mitophagy. This study aimed to investigate whether targeted restoration of mitophagy via the myeloid cell leukemia 1 (MCL-1)/light chain 3A pathway could rejuvenate aged HSCs and improve their regenerative capacity.
RESULTS: We identified MCL-1 as the most highly expressed mitophagy receptor in aged HSCs. Treatment with UMI-77, a selective MCL-1 agonist, significantly enhanced mitophagy, reduced mitochondrial mass, improved mitochondrial membrane potential, and reduced reactive oxygen species levels in aged HSCs both in vitro and in vivo. Single-cell RNA sequencing revealed that UMI-77 upregulated mitophagy-related genes (Sqstm1, Fundc1, Bnip3) and restored stemness signatures in long-term HSCs. Transplantation assays demonstrated that UMI-77-treated aged HSCs exhibited superior hematopoietic reconstitution capacity compared with those from control mice. However, this intervention also increased the proportion of myeloid-biased CD150high HSCs, a hallmark of aging.
CONCLUSION: Targeted mitophagy restoration via MCL-1 activation improves mitochondrial fitness and stemness in aged HSCs but does not reverse myeloid bias. These findings highlight mitophagy enhancement as a viable therapeutic approach, while suggesting combinatorial strategies may be needed to fully restore lineage balance in aging hematopoiesis. Antioxid. Redox Signal. 00, 000-000.

Keywords:  MCL-1; UMI-77; aging; hematopoietic stem cells; mitophagy

DOI:  https://doi.org/10.1177/15230864261475098
Front Stroke. 2026 ;5 1769395

Autophagy in ischemic stroke: pathophysiology, therapeutics, and challenges ahead.

Tshibambe N Tshimbombu, Arsene Daniel Nyalundja, Gates Mulume Iragi, Josué Aganze Mwambali, Samira Braimah Shardow, Melissa Ewurakua Amoako, Kyle E Thurmann, Daniel I Gonzalez, Paige Banyas, Judea Wiggins, Supreet Kaur.

  Autophagy is a fundamental cellular homeostatic process that exerts a dual, context-dependent influence on the pathophysiology of ischemic stroke. Functioning as both a neuroprotective survival mechanism and a neurotoxic pathway, autophagy presents a complex therapeutic challenge as well as a potential target for molecular intervention. This narrative review synthesizes preclinical and emerging clinical evidence to summarize key mechanisms regulating autophagy in ischemic injury, evaluate therapeutic strategies, and identify promising molecular pathways and druggable targets for translational development. In the early ischemic phase, moderate autophagic activation facilitates neuronal survival by clearing damaged mitochondria and protein aggregates, thereby reducing oxidative stress and modulating neuroinflammation. This protective response is primarily mediated by regulators such as Beclin-1, the conversion of LC3-I to LC3-II, and the energy-sensing AMP-activated protein kinase pathway. Conversely, sustained or excessive autophagy, particularly during late-stage reperfusion, exacerbates neuronal injury through impaired lysosomal fusion, autophagosome accumulation, and the triggering of autophagic cell death and ferroptosis. Preclinical evidence highlights a critical Goldilocks zone of activation, suggesting that therapeutic success hinges on maintaining autophagic flux within narrow physiological limits. Advancing these therapies into clinical practice requires precise spatiotemporal modulation, potentially as an adjunct to mechanical thrombectomy, as well as the development of robust, real-time biomarkers. A comprehensive understanding of the molecular and genetic determinants of autophagy, including sex-specific responses, is essential to bridge the translational gap and establish autophagy as a viable target for precision stroke medicine.

Keywords:  autophagy; ischemia-reperfusion injury; ischemic stroke; neuroprotection; therapeutic targets

DOI:  https://doi.org/10.3389/fstro.2026.1769395
EMBO J. 2026 Aug 07.

Allosteric switching of Ca2+ permeability in the lysosomal ion channel TPC2 underpins biased agonist activation.

Qianru Mu, Ryo Saito, Franceska Ozola, Dawid Jaślan, Pak Nin Chu, Afroditi-Maria Zaki, Marcos Rubio-Alarcon, Marco Keller, Yu Yuan, Alan Greig, Virginia Silio, Franz Bracher, Philip C Biggin, Gabriela C Brailoiu, Eugen Brailoiu, Jonathan S Marchant, Christian Grimm, Eric J Lambie, Taufiq Rahman, Sandip Patel.

Ion channels possess selectivity filters that are hardwired to ensure the selective passage of ions. Lysosomal two-pore channels are unusual as they are able to switch their cation selectivity in an agonist-specific manner, allowing differential control of organellar activity. TPC2 is permeable to Ca2+ when activated by the calcium-mobilizing messenger NAADP, but largely Na+-selective when activated by the signaling lipid PI(3,5)P2. Co-stimulation increases Ca2+ but not Na+ permeability; however, the molecular basis for these specificity switches is not well understood. Here we show that mutation of TPC2 residues within the distal cytosolic linker, which connects the first voltage-sensing-like domain to the pore, rendered TPC2 largely unable to discriminate its agonists and highly calcium-permeable, even in the presence of PI(3,5)P2. This mutation induced a co-activated-like state by disrupting a network of residues that connects the linker to the activation gate. Such deregulated agonist action increased lysosomal Ca2+ flux and compromised locomotion and viability when expressed in C. elegans. A proximal disease-linked mutation perturbed agonist action in a similar way both in vitro and in vivo. Biased signaling through TPC2 thus proceeds through molecular determinants that are remote from the selectivity filter, affecting Ca2+ permeability, endo-lysosomal integrity and disease.

DOI: https://doi.org/10.1038/s44318-026-00882-1
Nat Commun. 2026 Aug 07. pii: 8011. [Epub ahead of print]17(1):

Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.

Jonathan Kölschbach, Hormos S Dafsari, Emily Baum, Anna Löhrke, Chun Kew, Ivan Dikic, Wenming Huang, Adam Antebi.

mRNA splicing represents a fundamental level of gene regulation that alters proteomic diversity and cellular state. Its dysfunction can profoundly rewire metabolism, yet underlying mechanisms remain elusive. Here, we investigate Verheij syndrome, caused by mutations in core splicing factor PUF60, using a Caenorhabditis elegans model, human cell lines, and patient-derived samples. We demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, impairing S-adenosylmethionine/S-adenosylhomocysteine cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental growth defects. Vitamin B12 supplementation restores metabolic balance by reactivating S-adenosylmethionine-dependent phospholipid remodeling and mTORC1 activity, effectively rescuing Verheij-like phenotypes. Similar responses arise from perturbing another splicing factor, PRP-19. Mechanistically, intron retention of nhr-114/HNF4 transcription factor drives these phenotypes, while restoring its splicing rescues them. Our findings implicate vitamin B12-dependent one-carbon metabolism as a metabolic modulator with therapeutic potential to mitigate Verheij syndrome and other spliceosomopathies.

DOI: https://doi.org/10.1038/s41467-026-76295-9
Mol Neurobiol. 2026 Aug 01. pii: 801. [Epub ahead of print]63(1):

The Glial Autophagy-Lysosomal-Inflammation Axis in Alzheimer's Disease: a Unifying Mechanistic Framework.

Fengge Yang, Wei Gao, Junting Wang, Honglin Li.

  Recent studies suggest that impairment of the glial autophagy-lysosomal pathway (ALP) critically contributes to the sustained neuroinflammatory response and neurodegenerative processes in Alzheimer's disease (AD). Glial cells, comprising microglia, astrocytes, oligodendrocytes, and ependymal cells, serve as key immune regulators in the central nervous system, where they are essential for maintaining ALP homeostasis, promoting proteostasis, and modulating neuroinflammatory responses. Here, we systematically review the regulatory roles of glial ALP in AD pathology, emphasizing its involvement in amyloid accumulation, tau hyperphosphorylation, synaptic impairment, white matter damage, and mitochondrial as well as other organelle dysfunction, and provide an in-depth analysis of key signaling pathways including TFEB, mTOR, and NLRP3. Furthermore, we outline therapeutic strategies aimed at restoring lysosomal function, regulating autophagic flux, and suppressing inflammation, along with a discussion of the multi-target regulatory potential of acupuncture and natural bioactive agents. We also highlight emerging ALP-associated biomarkers and their potential utility in early diagnosis and treatment response assessment. The objective of this review is to uncover the mechanistic interplay between glial ALP dysregulation and the pathological cascade of AD, offering a conceptual framework for the development of novel therapeutics that integrate neuroprotection with immune modulation.

Keywords:  Alzheimer’s disease; Autophagy–lysosomal pathway; Biomarkers; Glial cells; Neuroinflammation; Therapeutic strategy

DOI:  https://doi.org/10.1007/s12035-026-06098-y
Free Radic Biol Med. 2026 Aug 05. pii: S0891-5849(26)00989-5. [Epub ahead of print]

Microglial SREBP2 regulate cholesterol-related lipid metabolism and inflammatory levels following ischemic stroke via the autophagy pathway.

Wei Wei, Yi Lei, Yongli Pan, Jiacong Tan, Zhongnan Hao, Lin Zhang, Xiaoyue Luo, Meihua Li, Zhipeng Xiao, Wenqiang Xin.

   BACKGROUND: Dysregulated lipid metabolism and inflammation exacerbate brain injury, with abnormal cholesterol metabolism playing a role in stroke condition. SREBPs are key transcription factors regulating lipid synthesis, and their activation is linked to autophagy. It remains unclear whether autophagy clears lipids and modulates inflammation after ischemic stroke, and whether SREBP2 affect cholesterol metabolism and inflammation via autophagy. This study aims to investigate the role of SREBPs and the mediating mechanism of autophagy in post-ischemic stroke lipid dysregulation and inflammation.
METHODS: In vivo mice models of ischemic stroke (middle cerebral artery occlusion, MCAO) and in vitro neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) models were employed. Through interfering with SREBP2, combined with autophagy inhibitor/activator treatment, we detected cholesterol and cholesteryl ester in microglia and brain tissue, the expression levels of inflammatory factors, and the expression changes of autophagy-related proteins (LC3, p62) and SREBP downstream lipid metabolism-related genes.
RESULTS: After ischemic stroke, the expression of SREBP2 in brain tissue was significantly upregulated, the autophagy pathway was activated, accompanied by cholesterol and lipid accumulation and increased expression of inflammatory factors. Interfering with SREBP2 expression significantly inhibited the excessive activation of the autophagy pathway, reduced the content of cholesterol-related lipids in brain tissue and neurons, decreased the release of inflammatory factors, and alleviated cerebral ischemia-reperfusion injury. In microglia-neuron co-culture experiments, SREBPs interference in microglia significantly improved the survival rate of OGD/R-induced injured neurons and reduced neuronal apoptosis, while behavioral tests revealed that SREBP2 interference remarkably promoted neural function recovery in MCAO mice.
CONCLUSION: SREBP2 regulate the autophagy pathway to affect the balance of cholesterol-related lipid metabolism and the intensity of inflammatory responses after ischemic stroke, thereby participating in the pathophysiological process of cerebral ischemic injury, which provides a new target and theoretical basis for the treatment of ischemic stroke.

Keywords:  Ischemic stroke; SREBP2; autophagy; lipid metabolism; microglia; neuroinflammation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.008
Nagoya J Med Sci. 2026 May;88(2): 297-311

Sestrin2 alleviates age-related hearing loss through mediating PINK1/Parkin related mitophagy.

Liwen Wang, Yuenong Jiao, Tianqi Nie, Linlan Jiang, Shuyi Gao, Jinyu Wang.

  Age-related hearing loss (ARHL) is closely linked to mitochondrial dysfunction in cochlear hair cells; however, its molecular regulation remains unclear. Sestrin2 (SESN2), a stress-inducible protein crucial for regulating energy metabolism, has not been comprehensively studied in the context of ARHL. To investigate SESN2's role, cochlea-specific SESN2 overexpression and knockout mouse models were established via adeno-associated virus 9 (AAV9) delivery through posterior semicircular canal injection. These models, combined with an H2O2-induced accelerated-aging paradigm and H2O2-treated House Ear Institute-organ of Corti 1 (HEI-OC1) cellular oxidative injury system, were systematically evaluated using auditory brainstem response (ABR), immunofluorescence (IF), mitochondrial membrane potential assays, western blotting, and other methods. Analysis of ARHL mouse cochleae revealed downregulation of SESN2 in hair cells, accompanied by mitochondrial membrane disruption and increased apoptosis. In aged mice, SESN2 overexpression significantly improved low-frequency hearing thresholds (p < 0.01). Mechanistically, SESN2 reduced oxidative stress, restored mitochondrial function, and suppressed excessive PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy, thereby maintaining mitochondrial quality control. This study is the first to show that SESN2 protects against ARHL through a tripartite cascade: antioxidant defense, mitochondrial functional restoration, and dynamic mitophagy regulation. These findings highlight SESN2's pivotal role in auditory preservation and identify it as a promising new therapeutic target for age-related hearing deterioration.

Keywords:  SESN2; Sestrin2; age-related hearing loss; mitochondrial function; mitophagy

DOI:  https://doi.org/10.18999/nagjms.88.2.297
FASEB J. 2026 Aug 15. 40(15): e72185

TFEB Deficiency Impairs Male Fertility Through Mitochondrial Dysfunction.

Hongxia Li, Guoqing Zhao, Ruojun Zong, Jia Liu, Liwei Huang, Juan Xiong, Xiaolong Pan, Lijuan Huang, Lili Wang, Danna Jia, Yiyan Zhao, Xiaoyuan Zhang, Pengkang Song, Le Zhao, Xuanqi Yu, Junyao Zhang, Huimin Lv, Xiaoyu Li, Hongyong Zhang, Ruigao Song.

  Transcription Factor EB (TFEB) is widely recognized as a key transcription factor regulating lysosomal biogenesis and autophagy. Although the TFEB gene is highly expressed in the testes, the mechanism by which it affects male fertility remains unclear. Here, we report that spermatogonia-specific deletion of TFEB in mice results in a multifaceted reproductive phenotype, including impaired fertility, compromised sperm motility, and attenuated androgen production. Immunofluorescence results showed a significant decrease in the expression levels of TNP1, a marker for spermiogenesis. Under electron microscopy, we observed abnormalities in the mitochondria of the testes and sperm. Integrated transcriptomic and biochemical analyses identified a cluster of mitochondrial-associated genes, including Star, Slc25a48, Gss, and ROMO1, with functional enrichment pinpointing disruptions in steroidogenic flux and calcium homeostasis. In summary, our study identifies TFEB as a pivotal regulator of mitochondrial integrity in the testes, the loss of which drives male subfertility through metabolic and hormonal dysregulation.

Keywords:  androgens; fertility; male; mitochondria; testis

DOI:  https://doi.org/10.1096/fj.202601937RR
Immunity. 2026 Aug 03. pii: S1074-7613(26)00307-9. [Epub ahead of print]

Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.

Christopher D Balak, Johannes C M Schlachetzki, Addison J Lana, Elizabeth West, Christine Hong, Jordan DuGal, Yi Zhou, Benjamin Li, Nathanael J Spann, Payam Saisan, Vishal Sarsani, Kilian L Kleemann, Xiaoming Zhang, Martina P Pasillas, Sydney O'Brien, Juliette A Bokor, Philip L S M Gordts, Oleg Butovsky, Beth Stevens, Fredrik Kamme, Christopher K Glass.

  Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice. Further investigation identified dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors. Features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency were also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer's disease patients. These findings reveal common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.

Keywords:  ChIP-seq; MITF; MPS-IIIA; TFE3; disease-associated microglia; epigenetics; lysosomal storage disorder; lysosome; microglia; neurodegeneration

DOI:  https://doi.org/10.1016/j.immuni.2026.07.008
FEBS J. 2026 Aug 05.

The (European) protein homeostasis network.

Eric Chevet.

  Proteostasis, the cellular network that governs protein synthesis, folding, trafficking, and degradation, is essential for maintaining cellular and organismal homeostasis. This review series highlights the breadth and impact of European research in the field of proteostasis, spanning fundamental mechanisms, organelle-specific quality control pathways, and emerging therapeutic opportunities. Contributions from leading laboratories across Europe examine key components of the proteostasis network, including translational regulation, molecular chaperones, ubiquitin-dependent protein degradation, organelle communication, and adaptive stress responses. Particular emphasis is placed on proteostasis mechanisms operating within the endoplasmic reticulum and mitochondria as well as on their roles in aging, inflammation, neurodegeneration, and other human diseases. The series also showcases the collaborative efforts that have strengthened the European proteostasis community through major networking initiatives and training programs. Together, these articles provide a comprehensive overview of current advances in proteostasis research and underscore its growing importance as a framework for understanding cellular adaptation and developing innovative therapeutic strategies.

Keywords:  cellular signaling network; protein degradation; protein folding; protein quality control; protein synthesis; proteostasis; stress response; ubiquitin

DOI:  https://doi.org/10.1111/febs.70663
Adv Sci (Weinh). 2026 Aug 03. e76862

A Single-Amino-Acid Ligand for LAT1: A Minimalist and Modular Platform for Lysosome-Targeted Degradation of Membrane Proteins.

Liquan Zhu, Ke Liu, Haotian Liu, Chaoqi He, Xiaozhen Liu, Xin Zeng, Misha Mao, Yuxiao Mu, Ying Li, Qinghui Zheng, Hongchao Tang, Da Qian, Xuli Meng.

  Targeted degradation of membrane proteins via the lysosomal pathway holds great therapeutic promise, yet existing platforms rely on bulky ligands such as glycopolymers, antibodies, or protein nanocages, which complicate synthesis and limit tissue penetration. Here, we repurpose L‑type amino acid transporter 1 (LAT1)-a nutrient transporter overexpressed in diverse cancers-as a lysosomal targeting receptor. Taking advantage of LAT1's natural substrate preference, we design a minimalist chemical handle: a single phenylalanine derivative that serves as a high‑affinity LAT1 ligand. This ligand is conjugated via bioorthogonal chemistry to various warheads (antibodies or small molecules) to generate modular degraders termed LAT1-mediated lysosome-targeting chimeras (LA‑LYTAC). These chimeras efficiently internalize and route oncogenic membrane proteins-including PD‑L1, EGFR, and integrins-to lysosomes for degradation. The platform operates through a LAT1‑dependent, lysosomal mechanism and suppresses downstream signaling pathways. In a syngeneic mouse model of triple‑negative breast cancer, a PD‑L1‑targeting LA‑LYTAC reduces tumor growth by more than 60%, enhances CD8+ T cell infiltration, and shows no overt toxicity. This work establishes a synthetically accessible, truly modular, and tumor‑selective degradation platform driven by a single amino acid, offering a streamlined alternative to existing lysosome‑targeting technologies.

Keywords:  LAT1; amino acid ligand; lysosome‐targeting chimera; membrane protein degradation; modular degradation platform; targeted protein degradation

DOI:  https://doi.org/10.1002/advs.76862
Brain Res. 2026 Aug 05. pii: S0006-8993(26)00349-5. [Epub ahead of print] 150487

Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways.

Shanshan Shi, Ruyue Liu, Chang Liu, Yuyao Chen, Yujun Pan, Chunyan Wang.

   BACKGROUND: Mitochondrial dysfunction and neuroinflammation drive dopaminergic neuron loss in Parkinson's disease (PD). While BMSC-derived small extracellular vesicles (BMSC-Exo) are neuroprotective, their ability to repair mitochondrial deficits is limited. We engineered mitochondrial-enriched sEVs (Exo-Mito) to evaluate their effects on microglia-neuron interactions in a PD-relevant model.
METHODS: BMSC-Exo-Mito were characterized via TEM, NTA, and immunoblotting. Their therapeutic efficacy was assessed using an MPP + -induced BV2/SH-SY5Y transwell co-culture model. Assessments included ROS levels, mitochondrial membrane potential, ATP quantification, mitophagy flux, and signaling pathway analysis.
RESULTS: Exo-Mito significantly restored mitochondrial homeostasis by reducing ROS, preserving membrane potential, and increasing ATP production. Mechanistically, Exo-Mito enhanced PINK1/Parkin-dependent mitophagy and PGC-1alpha/TFAM-mediated biogenesis. In BV2 microglia, Exo-Mito suppressed the NF-kappaB/NLRP3 axis, reduced proinflammatory cytokines, and promoted M2 polarization. In SH-SY5Y cells with dopaminergic phenotype, Exo-Mito was associated with reactivated PI3K/Akt/mTOR signaling, preserved tyrosine hydroxylase expression, and inhibited apoptosis. Functionally, Exo-Mito improved SH-SY5Y cell and restored microglial migratory capacity, showing superior efficacy to unmodified BMSC-Exo.
CONCLUSION: Mitochondria-enriched BMSC sEVs protect SH-SY5Y cells by coordinating mitochondrial quality control and modulating neuroinflammation. These findings support Exo-Mito as a promising cell-free therapeutic strategy for Parkinson's disease.

Keywords:  Mesenchymal stem cells; Mitochondria; Mitophagy; Neuroinflammation; PI3K/Akt/mTOR; Parkinson’s disease; Small extracellular vesicles

DOI:  https://doi.org/10.1016/j.brainres.2026.150487