Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration

Abstract

Intervertebral disc degeneration (IDD) is a progressive and dynamic process in which the senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPC) plays a significant role. While impaired chaperone-mediated autophagy (CMA) has been associated with inflammation and cellular senescence, its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood. Through LAMP2A knockout in NPC, we identified a significant upregulation of DYRK1A, a core mediator of premature senescence in Down syndrome. Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC. Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition, elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation, initiating transcriptional activation of cell cycle arrest. Intriguingly, CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC, thereby augmenting their survival fitness. Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis, mediated by decreased glutamine flux via GLUL degradation. Therefore, CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis. This study elucidates CMA’s regulatory role in SASP-mediated senescence amplification circuits, providing novel therapeutic insights for IDD and other age-related pathologies.

References

[1] ReimannM, LeeS, SchmittCA. Cellular senescence: neither irreversible nor reversible. J. Exp. Med., 2024, 221: e20232136

[2] ZhangH, et al.. Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7. Ann. Rheum. Dis., 2022, 81: 676-686

[3] ChenX, et al.. The role of oxidative stress in intervertebral disc degeneration: mechanisms and therapeutic implications. Ageing Res. Rev., 2024, 98 ArticleID: 102323

[4] de MagalhãesJP. Cellular senescence in normal physiology. Science, 2024, 384: 1300-1301

[5] ZingoniA, et al.. The senescence journey in cancer immunoediting. Mol. Cancer, 2024, 23 ArticleID: 68

[6] CoryellPR, DiekmanBO, LoeserRF. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat. Rev. Rheumatol., 2021, 17: 47-57

[7] KangL, et al.. Epigenetic modifications of inflammation in intervertebral disc degeneration. Ageing Res. Rev., 2023, 87 ArticleID: 101902

[8] LiCJ, et al.. Senescent immune cells release grancalcin to promote skeletal aging. Cell Metab., 2021, 33: 1957-1973.e1956

[9] JohmuraY, et al.. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science, 2021, 371: 265-270

[10] SilwalP, et al.. Cellular senescence in intervertebral disc aging and degeneration: molecular mechanisms and potential therapeutic opportunities. Biomolecules, 2023, 13: 686

[11] FanC, et al.. M1 macrophage-derived exosomes promote intervertebral disc degeneration by enhancing nucleus pulposus cell senescence through LCN2/NF-κB signaling axis. J. Nanobiotechnol., 2024, 22 ArticleID: 301

[12] PatilP, et al.. Systemic clearance of p16(INK4a) -positive senescent cells mitigates age-associated intervertebral disc degeneration. Aging Cell, 2019, 18 ArticleID: e12927

[13] WangN, et al.. The Sanbi Decoction alleviates intervertebral disc degeneration in rats through intestinal flora and serum metabolic homeostasis modulation. Phytomedicine, 2024, 127 ArticleID: 155480

[14] CherifH, et al.. Senotherapeutic drugs for human intervertebral disc degeneration and low back pain. eLife, 2020, 9: e54693

[15] FranciscoV, et al.. A new immunometabolic perspective of intervertebral disc degeneration. Nat. Rev. Rheumatol., 2022, 18: 47-60

[16] KelseyR. Targeting NP cell senescence in IVDD. Nat. Rev. Rheumatol., 2024, 20: 197

[17] ChengZ, XiangQ, WangJ, ZhangY. The potential role of melatonin in retarding intervertebral disc ageing and degeneration: a systematic review. Ageing Res. Rev., 2021, 70 ArticleID: 101394

[18] KaushikS, CuervoAM. The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol., 2018, 19: 365-381

[19] DongS, et al.. Chaperone-mediated autophagy sustains haematopoietic stem-cell function. Nature, 2021, 591: 117-123

[20] Madrigal-MatuteJ, et al.. Protective role of chaperone-mediated autophagy against atherosclerosis. Proc. Natl. Acad. Sci. USA, 2022, 119: e2121133119

[21] ChengZ, et al.. Impaired degradation of PLCG1 by chaperone-mediated autophagy promotes cellular senescence and intervertebral disc degeneration. Autophagy, 2025, 21: 352-373

[22] ZhuL, et al.. Chaperone-mediated autophagy degrades Keap1 and promotes Nrf2-mediated antioxidative response. Aging Cell, 2022, 21 ArticleID: e13616

[23] TedescoB, VendredyL, TimmermanV, PolettiA. The chaperone-assisted selective autophagy complex dynamics and dysfunctions. Autophagy, 2023, 19: 1619-1641

[24] LeeW, et al.. SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation. Theranostics, 2022, 12: 2351-2369

[25] RoviraM, et al.. The lysosomal proteome of senescent cells contributes to the senescence secretome. Aging Cell, 2022, 21 ArticleID: e13707

[26] Gómez-SintesR, AriasE. Chaperone-mediated autophagy and disease: implications for cancer and neurodegeneration. Mol. Asp. Med., 2021, 82, ArticleID: 101025

[27] Moreno-BlasD, Gorostieta-SalasE, Castro-ObregónS. Connecting chaperone-mediated autophagy dysfunction to cellular senescence. Ageing Res. Rev., 2018, 41: 34-41

[28] ZhangJ, et al.. Inflammation-induced inhibition of chaperone-mediated autophagy maintains the immunosuppressive function of murine mesenchymal stromal cells. Cell Mol. Immunol., 2021, 18: 1476-1488

[29] ChoiYJ, et al.. Chaperone-mediated autophagy dysregulation during aging impairs hepatic fatty acid oxidation via accumulation of NCoR1. Mol. Metab., 2023, 76 ArticleID: 101784

[30] FlemingA, et al.. The different autophagy degradation pathways and neurodegeneration. Neuron, 2022, 110: 935-966

[31] QiaoL, et al.. Deficient chaperone-mediated autophagy promotes inflammation and atherosclerosis. Circ. Res., 2021, 129: 1141-1157

[32] WuJ, et al.. Self-amplifying loop of NF-κB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration. Mol. Ther., 2022, 30: 3241-3256

[33] NieT, et al.. Chaperone-mediated autophagy controls the turnover of E3 ubiquitin ligase MARCHF5 and regulates mitochondrial dynamics. Autophagy, 2021, 17: 2923-2938

[34] NovaisEJ, et al.. Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat. Commun., 2021, 12 ArticleID: 5213

[35] LimS, et al.. Local delivery of senolytic drug inhibits intervertebral disc degeneration and restores intervertebral disc structure. Adv. Health. Mater., 2022, 11, ArticleID: e2101483

[36] MatjusaitisM, ChinG, SarnoskiEA, StolzingA. Biomarkers to identify and isolate senescent cells. Ageing Res. Rev., 2016, 29: 1-12

[37] WuZ, et al.. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc. Natl. Acad. Sci. USA, 2019, 116: 2996-3005

[38] LiuC, et al.. Glia maturation factor-β induces ferroptosis by impairing chaperone-mediated autophagic degradation of ACSL4 in early diabetic retinopathy. Redox Biol., 2022, 52 ArticleID: 102292

[39] YuanJ, OfengeimD. A guide to cell death pathways. Nat. Rev. Mol. Cell Biol., 2024, 25: 379-395

[40] LeNT. Metabolic regulation of endothelial senescence. Front. Cardiovasc. Med., 2023, 10 ArticleID: 1232681

[41] PanC, LocasaleJW. Targeting metabolism to influence aging. Science, 2021, 371: 234-235

[42] JiangB, et al.. Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis. Mol. Cell, 2022, 82: 1821-1835.e1826

[43] Auzmendi-IriarteJ, MatheuA. Impact of chaperone-mediated autophagy in brain aging: neurodegenerative diseases and glioblastoma. Front. Aging Neurosci., 2020, 12 ArticleID: 630743

[44] DelabarJM, et al.. EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a down syndrome model. Eur. J. Med. Chem., 2024, 265 ArticleID: 116098

[45] YangY, et al.. Function and inhibition of DYRK1A: emerging roles of treating multiple human diseases. Biochem. Pharm., 2023, 212 ArticleID: 115521

[46] KargboRB. Selective DYRK1A inhibitor for the treatment of neurodegenerative diseases: Alzheimer, Parkinson, Huntington, and Down syndrome. ACS Med. Chem. Lett., 2020, 11: 1795-1796

[47] LiuT, et al.. DYRK1A inhibitors for disease therapy: current status and perspectives. Eur. J. Med. Chem., 2022, 229 ArticleID: 114062

[48] LanC, et al.. Inhibition of DYRK1A, via histone modification, promotes cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction. EBioMedicine, 2022, 82 ArticleID: 104139

[49] LitovchickL, et al.. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev., 2011, 25: 801-813

[50] WuY, et al.. Identification of key genes and transcription factors in aging mesenchymal stem cells by DNA microarray data. Gene, 2019, 692: 79-87

[51] KumarK, et al.. Development of kinase-selective, harmine-based DYRK1A inhibitors that induce pancreatic human β-cell proliferation. J. Med. Chem., 2018, 61: 7687-7699

[52] KrupkovaO, et al.. An inflammatory nucleus pulposus tissue culture model to test molecular regenerative therapies: validation with epigallocatechin 3-gallate. Int. J. Mol. Sci., 2016, 17: 1640

[53] LiuL, et al.. Injectable pathological microenvironment-responsive anti-inflammatory hydrogels for ameliorating intervertebral disc degeneration. Biomaterials, 2024, 306 ArticleID: 122509

[54] LiY, et al.. DYRK1a mediates BAFF-induced noncanonical NF-κB activation to promote autoimmunity and B-cell leukemogenesis. Blood, 2021, 138: 2360-2371

[55] JuC, et al.. Inhibition of Dyrk1A attenuates LPS-induced neuroinflammation via the TLR4/NF-κB P65 signaling pathway. Inflammation, 2022, 45: 2375-2387

[56] WangP, et al.. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat. Med., 2015, 21: 383-388

[57] WangP, et al.. Combined inhibition of DYRK1A, SMAD, and trithorax pathways synergizes to induce robust replication in adult human beta cells. Cell Metab., 2019, 29: 638-652.e635

[58] HilleS, et al.. Dyrk1a regulates the cardiomyocyte cell cycle via D-cyclin-dependent Rb/E2f-signalling. Cardiovasc. Res., 2016, 110: 381-394

[59] SchneiderJL, SuhY, CuervoAM. Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation. Cell Metab., 2014, 20: 417-432

[60] ZhangY, et al.. Glutamine suppresses senescence and promotes autophagy through glycolysis inhibition-mediated AMPKα lactylation in intervertebral disc degeneration. Commun. Biol., 2024, 7: 325

[61] FengS, et al.. Filament formation drives catalysis by glutaminase enzymes important in cancer progression. Nat. Commun., 2024, 15 ArticleID: 1971

[62] GuoCJ, WangZX, LiuJL. Structural basis for activation and filamentation of glutaminase. Cell Res., 2024, 34: 76-79

[63] XieW, et al.. Chaperone-mediated autophagy prevents apoptosis by degrading BBC3/PUMA. Autophagy, 2015, 11: 1623-1635

[64] ChaibS, TchkoniaT, KirklandJL. Cellular senescence and senolytics: the path to the clinic. Nat. Med., 2022, 28: 1556-1568

[65] FranceschiC, CampisiJ. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci., 2014, 69(Suppl. 1): S4-S9

[66] FarrJN, et al.. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med., 2017, 23: 1072-1079

[67] XuM, et al.. Senolytics improve physical function and increase lifespan in old age. Nat. Med., 2018, 24: 1246-1256

[68] Mohd IsaIL, et al.. Intervertebral disc degeneration: biomaterials and tissue engineering strategies toward precision medicine. Adv. Health. Mater., 2022, 11, ArticleID: e2102530

[69] BourdenxM, et al.. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell, 2021, 184: 2696-2714.e2625

[70] Madrigal-MatuteJ, CuervoAM, SluimerJC. Chaperone-mediated autophagy protects against atherosclerosis. Autophagy, 2022, 18: 2505-2507

[71] ByrnesK, et al.. Therapeutic regulation of autophagy in hepatic metabolism. Acta Pharm. Sin. B, 2022, 12: 33-49

[72] XuX, et al.. Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model. Protein Cell, 2021, 12: 769-787

[73] YaoR, ShenJ. Chaperone-mediated autophagy: molecular mechanisms, biological functions, and diseases. MedComm, 2023, 4: e347

[74] WangL, et al.. Palmitoylation prevents sustained inflammation by limiting NLRP3 inflammasome activation through chaperone-mediated autophagy. Mol. Cell, 2023, 83: 281-297.e210

[75] YangS, et al.. ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3. Autophagy, 2025, 21: 338-351

[76] ZhangW, et al.. Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration. J. Clin. Invest., 2024, 134: e165140

[77] JiML, et al.. Preclinical development of a microRNA-based therapy for intervertebral disc degeneration. Nat. Commun., 2018, 9 ArticleID: 5051

[78] PierceBG, HouraiY, WengZ. Accelerating protein docking in ZDOCK using an advanced 3D convolution library. PLoS One, 2011, 6: e24657

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82172497)

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