The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn²⁺ trafficking

References

• Vos T, Abajobir AA, Abate KH. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet. 2017;390(10100):1211–1259. doi: 10.1016/S0140-6736(17)32154-2
   PubMed Web of Science ®Google Scholar
• Cieza A, Causey K, Kamenov K, et al. Global estimates of the need for rehabilitation based on the global Burden of disease study 2019: a systematic analysis for the global Burden of disease study 2019. Lancet. 2021;396(10267):2006–2017. doi: 10.1016/S0140-6736(20)32340-0
   PubMed Web of Science ®Google Scholar
• Macdonald J, Stuart E, Rodenberg R. Musculoskeletal low back pain in school-aged children: a review. JAMA Pediatr. 2017;171(3):280–287. doi: 10.1001/jamapediatrics.2016.3334
   PubMed Web of Science ®Google Scholar
• Knezevic NN, Candido KD, Vlaeyen JWS, et al. Low back pain. Lancet. 2021;398(10294):78–92. doi: 10.1016/S0140-6736(21)00733-9
   PubMed Web of Science ®Google Scholar
• Zhao CQ, Wang LM, Jiang LS, et al. The cell biology of intervertebral disc aging and degeneration. Ageing Res Rev. 2007;6(3):247–261. doi: 10.1016/j.arr.2007.08.001
   PubMed Web of Science ®Google Scholar
• Picard M, Shirihai OS. Mitochondrial signal transduction. Cell Metab. 2022;34(11):1620–1653. doi: 10.1016/j.cmet.2022.10.008
   PubMed Web of Science ®Google Scholar
• Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci. 2019;22(3):401–412. doi: 10.1038/s41593-018-0332-9
   PubMed Web of Science ®Google Scholar
• Aman Y, Schmauck-Medina T, Hansen M, et al. Autophagy in healthy aging and disease. Nat Aging. 2021;1(8):634–650. doi: 10.1038/s43587-021-00098-4
   PubMedGoogle Scholar
• Song Y, Lu S, Geng W, et al. Mitochondrial quality control in intervertebral disc degeneration. Exp Mol Med. 2021;53(7):1124–1133. doi: 10.1038/s12276-021-00650-7
   PubMed Web of Science ®Google Scholar
• Zhang W, Li G, Luo R, et al. Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis. Exp Mol Med. 2022;54(2):129–142. doi: 10.1038/s12276-022-00729-9
   PubMed Web of Science ®Google Scholar
• Fleming A, Bourdenx M, Fujimaki M, et al. The different autophagy degradation pathways and neurodegeneration. Neuron. 2022;110(6):935–966. doi: 10.1016/j.neuron.2022.01.017
   PubMed Web of Science ®Google Scholar
• Chan DC. Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol. 2020;15(1):235–259. doi: 10.1146/annurev-pathmechdis-012419-032711
   PubMedGoogle Scholar
• Madhu V, Boneski PK, Silagi E, et al. Hypoxic regulation of mitochondrial Metabolism and mitophagy in nucleus pulposus cells is dependent on HIF-1α-BNIP3 axis. J Bone Miner Res. 2020;35(8):1504–1524. doi: 10.1002/jbmr.4019
   PubMed Web of Science ®Google Scholar
• Lin J, Zhuge J, Zheng X, et al. Urolithin A-induced mitophagy suppresses apoptosis and attenuates intervertebral disc degeneration via the AMPK signaling pathway. Free Radic Biol Med. 2020;150:109–119. doi: 10.1016/j.freeradbiomed.2020.02.024
   PubMed Web of Science ®Google Scholar
• Xu WN, Zheng HL, Yang RZ, et al. Mitochondrial NDUFA4L2 attenuates the apoptosis of nucleus pulposus cells induced by oxidative stress via the inhibition of mitophagy. Exp Mol Med. 2019;51(11):1–16. doi: 10.1038/s12276-019-0331-2
   Web of Science ®Google Scholar
• Huang D, Peng Y, Li Z, et al. Compression-induced senescence of nucleus pulposus cells by promoting mitophagy activation via the PINK1/PARKIN pathway. J Cell Mol Med. 2020;24(10):5850–5864. doi: 10.1111/jcmm.15256
   PubMed Web of Science ®Google Scholar
• Lin Z, Wang H, Song J, et al. The role of mitochondrial fission in intervertebral disc degeneration. Osteoarthritis Cartilage. 2022;31(2):158–166. doi: 10.1016/j.joca.2022.10.020
   PubMed Web of Science ®Google Scholar
• Zhou B, Kreuzer J, Kumsta C, et al. Mitochondrial permeability uncouples elevated autophagy and lifespan extension. Cell. 2019;177(2):299–314.e216. doi: 10.1016/j.cell.2019.02.013
   PubMed Web of Science ®Google Scholar
• Knuppertz L, Warnsmann V, Hamann A, et al. Stress-dependent opposing roles for mitophagy in aging of the ascomycete podospora anserina. Autophagy. 2017;13(6):1037–1052. doi: 10.1080/15548627.2017.1303021
   PubMed Web of Science ®Google Scholar
• Kleele T, Rey T, Winter J, et al. Distinct fission signatures predict mitochondrial degradation or biogenesis. Nature. 2021;593(7859):435–439. doi: 10.1038/s41586-021-03510-6
   PubMed Web of Science ®Google Scholar
• Baek A, Son S, Baek YM, et al. KRT8 (keratin 8) attenuates necrotic cell death by facilitating mitochondrial fission-mediated mitophagy through interaction with PLEC (plectin). Autophagy. 2021;17(12):3939–3956. doi: 10.1080/15548627.2021.1897962
   PubMed Web of Science ®Google Scholar
• Song M, Mihara K, Chen Y, et al. Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab. 2015;21(2):273–286. doi: 10.1016/j.cmet.2014.12.011
   PubMed Web of Science ®Google Scholar
• Liang X, Wang S, Wang L, et al. Mitophagy inhibitor liensinine suppresses doxorubicin-induced cardiotoxicity through inhibition of Drp1-mediated maladaptive mitochondrial fission. Pharmacol Res. 2020;157:104846. doi: 10.1016/j.phrs.2020.104846
   PubMed Web of Science ®Google Scholar
• Zhang Y, Yao Y, Qiu X, et al. Listeria hijacks host mitophagy through a novel mitophagy receptor to evade killing. Nat Immunol. 2019;20(4):433–446. doi: 10.1038/s41590-019-0324-2
   PubMed Web of Science ®Google Scholar
• Killackey SA, Bi Y, Soares F, et al. Mitochondrial protein import stress regulates the LC3 lipidation step of mitophagy through NLRX1 and RRBP1. Mol Cell. 2022;82(15):2815–2831.e2815. doi: 10.1016/j.molcel.2022.06.004
   PubMed Web of Science ®Google Scholar
• Lei Y, Wen H, Yu Y, et al. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity. 2012;36(6):933–946. doi: 10.1016/j.immuni.2012.03.025
   PubMed Web of Science ®Google Scholar
• Li S, Zhou Y, Gu X, et al. NLRX1/FUNDC1/NIPSNAP1-2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury. Cell Prolif. 2021;54(3):e12986. doi: 10.1111/cpr.12986
   PubMed Web of Science ®Google Scholar
• Imbeault E, Mahvelati TM, Braun R, et al. Nlrx1 regulates neuronal cell death. Mol Brain. 2014;7(1):90. doi: 10.1186/s13041-014-0090-x
   PubMedGoogle Scholar
• Singh K, Roy M, Prajapati P, et al. NLRX1 regulates TNF-α-induced mitochondria-lysosomal crosstalk to maintain the invasive and metastatic potential of breast cancer cells. Biochim Biophys Acta Mol Basis Dis. 2019;1865(6):1460–1476. doi: 10.1016/j.bbadis.2019.02.018
   PubMed Web of Science ®Google Scholar
• Zhang Q, Cao S, Qiu F, et al. Incomplete autophagy: trouble is a friend. Med Res Rev. 2022;42(4):1545–1587. doi: 10.1002/med.21884
   PubMed Web of Science ®Google Scholar
• Narendra D, Tanaka A, Suen DF, et al. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Bio. 2008;183(5):795–803. doi: 10.1083/jcb.200809125
   PubMed Web of Science ®Google Scholar
• Leber A, Hontecillas R, Zoccoli-Rodriguez V, et al. Su1818 – preclinical efficacy and safety of nx-13: a novel Nlrx1-targeting immunometabolic therapeutic for Crohn’s disease and ulcerative colitis. Gastroenterology. 2019;156(6):S623–S623. doi: 10.1016/S0016-5085(19)38455-0
   PubMed Web of Science ®Google Scholar
• Xu X, Wang D, Zheng C, et al. Progerin accumulation in nucleus pulposus cells impairs mitochondrial function and induces intervertebral disc degeneration and therapeutic effects of sulforaphane. Theranostics. 2019;9(8):2252–2267. doi: 10.7150/thno.30658
   PubMed Web of Science ®Google Scholar
• Wang J, Nisar M, Huang C, et al. Small molecule natural compound agonist of SIRT3 as a therapeutic target for the treatment of intervertebral disc degeneration. Exp Mol Med. 2018;50(11):1–14. doi: 10.1038/s12276-018-0173-3
   Google Scholar
• Killackey SA, Bi Y, Philpott DJ, et al. Mitochondria-ER cooperation: NLRX1 detects mitochondrial protein import stress and promotes mitophagy through the ER protein RRBP1. Autophagy. 2022;19(5):1601–1603. doi: 10.1080/15548627.2022.2129763
   PubMed Web of Science ®Google Scholar
• Vargas JNS, Hamasaki M, Kawabata T, et al. The mechanisms and roles of selective autophagy in mammals. Nat Rev Mol Cell Biol. 2023;24(3):167–185. doi: 10.1038/s41580-022-00542-2
   PubMed Web of Science ®Google Scholar
• D’amico D, Olmer M, Fouassier AM, et al. Urolithin a improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis. Aging Cell. 2022;21(8):e13662. doi: 10.1111/acel.13662
   PubMed Web of Science ®Google Scholar
• Liu F, Yuan Y, Bai L, et al. LRRc17 controls BMSC senescence via mitophagy and inhibits the therapeutic effect of BMSCs on ovariectomy-induced bone loss. Redox Biol. 2021;43:101963. doi: 10.1016/j.redox.2021.101963
   PubMed Web of Science ®Google Scholar
• Wang Y, Wang H, Zhuo Y, et al. SIRT1 alleviates high-magnitude compression-induced senescence in nucleus pulposus cells via PINK1-dependent mitophagy. Aging. 2020;12(16):16126–16141. doi: 10.18632/aging.103587
   PubMedGoogle Scholar
• Lan T, Yan B, Guo W, et al. VDR promotes nucleus pulposus cell mitophagy as a protective mechanism against oxidative stress injury. Free Radic Res. 2022;56(3–4):316–327. doi: 10.1080/10715762.2022.2094791
   PubMed Web of Science ®Google Scholar
• Kang L, Liu S, Li J, et al. The mitochondria-targeted anti-oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance. Cell Prolif. 2020;53(3):e12779. doi: 10.1111/cpr.12779
   PubMed Web of Science ®Google Scholar
• Xie C, Shi Y, Chen Z, et al. Apigenin alleviates intervertebral disc degeneration via restoring autophagy flux in nucleus pulposus cells. Front Cell Dev Biol. 2021;9:787278. doi: 10.3389/fcell.2021.787278
   PubMed Web of Science ®Google Scholar
• Twig G, Elorza A, Molina AJ, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27(2):433–446. doi: 10.1038/sj.emboj.7601963
   PubMed Web of Science ®Google Scholar
• Kraus F, Roy K, Pucadyil TJ, et al. Function and regulation of the divisome for mitochondrial fission. Nature. 2021;590(7844):57–66. doi: 10.1038/s41586-021-03214-x
   PubMed Web of Science ®Google Scholar
• Chen Y, Culetto E, Legouis R. A DRP-1 dependent autophagy process facilitates rebuilding of the mitochondrial network and modulates adaptation capacity in response to acute heat stress during C. elegans development. Autophagy. 2021;17(9):2654–2655. doi: 10.1080/15548627.2021.1953821
   PubMed Web of Science ®Google Scholar
• Burman JL, Pickles S, Wang C, et al. Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J Cell Bio. 2017;216(10):3231–3247. doi: 10.1083/jcb.201612106
   PubMed Web of Science ®Google Scholar
• Murata D, Yamada T, Tokuyama T, et al. Mitochondrial safeguard: a stress response that offsets extreme fusion and protects respiratory function via flickering-induced Oma1 activation. EMBO J. 2020;39(24):e105074. doi: 10.15252/embj.2020105074
   PubMed Web of Science ®Google Scholar
• Wai T, García-Prieto J, Baker MJ, et al. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science. 2015;350(6265):aad0116. doi: 10.1126/science.aad0116
   PubMed Web of Science ®Google Scholar
• Yao D, Li Y, Zeng S, et al. Short-form OPA1 is a molecular chaperone in mitochondrial intermembrane space. Sci China Life Sci. 2022;65(2):227–235. doi: 10.1007/s11427-021-1962-0
   PubMed Web of Science ®Google Scholar
• Ban T, Ishihara T, Kohno H, et al. Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin. Nat Cell Biol. 2017;19(7):856–863. doi: 10.1038/ncb3560
   PubMed Web of Science ®Google Scholar
• Acin-Perez R, Lechuga-Vieco AV, Del Mar Muñoz M, et al. Ablation of the stress protease OMA1 protects against heart failure in mice. Sci Transl Med. 2018;10(434). doi: 10.1126/scitranslmed.aan4935
   PubMed Web of Science ®Google Scholar
• Guo H, Wang Q, Ghneim K, et al. Multi-omics analyses reveal that HIV-1 alters CD4(+) T cell immunometabolism to fuel virus replication. Nat Immunol. 2021;22(4):423–433. doi: 10.1038/s41590-021-00898-1
   PubMed Web of Science ®Google Scholar
• Singh K, Sripada L, Lipatova A, et al. NLRX1 resides in mitochondrial RNA granules and regulates mitochondrial RNA processing and bioenergetic adaptation. Biochim Biophys Acta, Mol Cell Res. 2018;1865(9):1260–1276. doi: 10.1016/j.bbamcr.2018.06.008
   PubMed Web of Science ®Google Scholar
• Shin HJ, Kim SH, Park HJ, et al. Nucleotide-binding domain and leucine-rich-repeat-containing protein X1 deficiency induces nicotinamide adenine dinucleotide decline, mechanistic target of rapamycin activation, and cellular senescence and accelerates aging lung-like changes. Aging Cell. 2021;20(7):e13410. doi: 10.1111/acel.13410
   PubMed Web of Science ®Google Scholar
• Peng J, Pan J, Wang H, et al. Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1. J Neuroinflammation. 2022;19(1):87. doi: 10.1186/s12974-022-02453-7
   PubMed Web of Science ®Google Scholar
• Yin H, Yang Q, Cao Z, et al. Activation of NLRX1-mediated autophagy accelerates the ototoxic potential of cisplatin in auditory cells. Toxicol Appl Pharmacol. 2018;343:16–28. doi: 10.1016/j.taap.2018.02.007
   PubMed Web of Science ®Google Scholar
• Rensvold JW, Shishkova E, Sverchkov Y, et al. Defining mitochondrial protein functions through deep multiomic profiling. Nature. 2022;606(7913):382–388. doi: 10.1038/s41586-022-04765-3
   PubMed Web of Science ®Google Scholar
• Cho HM, Ryu JR, Jo Y, et al. Drp1-Zip1 interaction regulates mitochondrial quality surveillance System. Mol Cell. 2019;73(2):364–376.e368. doi: 10.1016/j.molcel.2018.11.009
   PubMed Web of Science ®Google Scholar
• Ma T, Zhao L, Zhang J, et al. A pair of transporters controls mitochondrial Zn(2+) levels to maintain mitochondrial homeostasis. Protein Cell. 2022;13(3):180–202. doi: 10.1007/s13238-021-00881-4
   PubMed Web of Science ®Google Scholar
• Li F, Munsey TS, Sivaprasadarao A. TRPM2-mediated rise in mitochondrial Zn(2+) promotes palmitate-induced mitochondrial fission and pancreatic β-cell death in rodents. Cell Death Differ. 2017;24(12):1999–2012. doi: 10.1038/cdd.2017.118
   PubMed Web of Science ®Google Scholar
• Olgar Y, Tuncay E, Turan B. Mitochondria-targeting antioxidant provides cardioprotection through regulation of Cytosolic and mitochondrial Zn(2+) levels with re-distribution of Zn(2+)-transporters in Aged rat Cardiomyocytes. Int J Mol Sci. 2019;20(15):3783. doi: 10.3390/ijms20153783
   PubMed Web of Science ®Google Scholar
• Zhang H, Yang N, He H, et al. The zinc transporter ZIP7 (Slc39a7) controls myocardial reperfusion injury by regulating mitophagy. Basic Res Cardiol. 2021;116(1):54. doi: 10.1007/s00395-021-00894-4
   PubMed Web of Science ®Google Scholar
• Jones E, Gaytan N, Garcia I, et al. A threshold of transmembrane potential is required for mitochondrial dynamic balance mediated by DRP1 and OMA1. Cell Mol Life Sci. 2017;74(7):1347–1363. doi: 10.1007/s00018-016-2421-9
   PubMed Web of Science ®Google Scholar
• Onishi M, Yamano K, Sato M, et al. Molecular mechanisms and physiological functions of mitophagy. EMBO J. 2021;40(3):e104705. doi: 10.15252/embj.2020104705
   PubMed Web of Science ®Google Scholar
• Terešak P, Lapao A, Subic N, et al. Regulation of PRKN-independent mitophagy. Autophagy. 2022;18(1):24–39. doi: 10.1080/15548627.2021.1888244
   PubMed Web of Science ®Google Scholar
• Song Y, Li S, Geng W, et al. Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration. Redox Biol. 2018;19:339–353. doi: 10.1016/j.redox.2018.09.006
   PubMed Web of Science ®Google Scholar
• Valente AJ, Maddalena LA, Robb EL, et al. A simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture. Acta Histochem. 2017;119(3):315–326. doi: 10.1016/j.acthis.2017.03.001
   PubMed Web of Science ®Google Scholar