HSP70 attenuates compression-induced apoptosis of nucleus pulposus cells by suppressing mitochondrial fission via upregulating the expression of SIRT3
0
조회
0
다운로드
1
인용
0
참고문헌
초록
Compression-induced apoptosis of nucleus pulposus (NP) cells plays a pivotal role in the pathogenesis of intervertebral disc degeneration (IVDD). Recent studies have shown that the dysregulation of mitochondrial fission and fusion is implicated in the pathogenesis of a variety of diseases. However, its role in and regulatory effects on compression-induced apoptosis of NP cells have not yet been fully elucidated. Heat shock protein 70 (HSP70) is a major cytoprotective heat shock protein, but its physiological role in IVDD, especially its effect on mitochondrial fission and fusion, is still unknown. Herein, we found that compression could induce mitochondrial fission, which ultimately trigger apoptosis of NP cells via the mitochondrial apoptotic pathway. In addition, we identified the cytoprotective effects of HSP70 on NP cells, and we found that promoting the expression of HSP70 could protect NP cells from abnormal mechanical loading in vitro and in vivo. Finally, we showed that HSP70 inhibited compression-induced mitochondrial fission by promoting SIRT3 expression, thereby attenuating mitochondrial dysfunction and the production of reactive oxygen species and ultimately inhibiting the mitochondrial apoptotic pathway in NP cells. In conclusion, our results demonstrated that HSP70 could attenuate compression-induced apoptosis of NP cells by suppressing mitochondrial fission via upregulating SIRT3 expression. Promoting the expression of HSP70 might be a novel strategy for the treatment of IVDD.
Abstract
Compression-induced apoptosis of nucleus pulposus (NP) cells plays a pivotal role in the pathogenesis of intervertebral disc degeneration (IVDD). Recent studies have shown that the dysregulation of mitochondrial fission and fusion is implicated in the pathogenesis of a variety of diseases. However, its role in and regulatory effects on compression-induced apoptosis of NP cells have not yet been fully elucidated. Heat shock protein 70 (HSP70) is a major cytoprotective heat shock protein, but its physiological role in IVDD, especially its effect on mitochondrial fission and fusion, is still unknown. Herein, we found that compression could induce mitochondrial fission, which ultimately trigger apoptosis of NP cells via the mitochondrial apoptotic pathway. In addition, we identified the cytoprotective effects of HSP70 on NP cells, and we found that promoting the expression of HSP70 could protect NP cells from abnormal mechanical loading in vitro and in vivo. Finally, we showed that HSP70 inhibited compression-induced mitochondrial fission by promoting SIRT3 expression, thereby attenuating mitochondrial dysfunction and the production of reactive oxygen species and ultimately inhibiting the mitochondrial apoptotic pathway in NP cells. In conclusion, our results demonstrated that HSP70 could attenuate compression-induced apoptosis of NP cells by suppressing mitochondrial fission via upregulating SIRT3 expression. Promoting the expression of HSP70 might be a novel strategy for the treatment of IVDD.
참고문헌 (54)
- Luoma, K., "Low back pain in relation to lumbar disc degeneration", Spine, 25, pp.487~492 (2000)
- Tang, P., "Honokiol alleviates the degeneration of intervertebral disc via suppressing the activation of TXNIP-NLRP3 inflammasome signal pathway", Free Radic. Biol. Med, 120, pp.368~379 (2018)
- Ding, F., "Cell death in intervertebral disc degeneration", Apoptosis, 18, pp.777~785 (2013)
- Smith, L. J., "Degeneration and regeneration of the intervertebral disc : lessons from development", Dis. Model. Mech, 4, pp.31~41 (2011)
- Ding, F., "Role of mitochondrial pathway in compression-induced apoptosis of nucleus pulposus cells", Apoptosis, 17, pp.579~590 (2012)
- Chen, S., "Critical contribution of RIPK1 mediated mitochondrial dysfunction and oxidative stress to compression-induced rat nucleus pulposus cells necroptosis and apoptosis", Apoptosis, 23, pp.299~313 (2018)
- Westermann, B., "Mitochondrial fusion and fission in cell life and death", Nat. Rev. Mol. Cell Biol, 11, pp.872~884 (2010)
- Youle, R. J., "Mitochondrial fission, fusion, and stress", Science, 337, pp.1062~1065 (2012)
- Eisner, V., "Mitochondrial dynamics in adaptive and maladaptive cellular stress responses", Nat. Cell Biol, 20, pp.755~765 (2018)
- Jin, Q., "DUSP1 alleviates cardiac ischemia", reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways, 2018, pp.14, 576~587
- Archer, S. L., "Mitochondrial dynamics–mitochondrial fission and fusion in human diseases", N. Engl. J. Med, 369, pp.2236~2251 (2013)
- Chan, D. C., "Mitochondrial dynamics and its involvement in disease", Annu. Rev. Pathol, 15, pp.235~259 (2020)
- Lin, H., "Drp1 mediates compression-induced programmed necrosis of rat nucleus pulposus cells by promoting mitochondrial translocation of p53 and nuclear translocation of AIF", Biochem. Biophys. Res. Commun, 487, pp.181~188 (2017)
- Kang, L., "The mitochondria-targeted anti-oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance", Cell Prolif, 53, pp.e12779~ (2020)
- Finkel, T., "Recent progress in the biology and physiology of sirtuins", Nature, 460, pp.587~591 (2009)
- Anderson, K. A., "SnapShot: mammalian sirtuins", Cell, 159, pp.956~956.e951 (2014)
- Zhang, J., "Mitochondrial sirtuin 3 : new emerging biological function and therapeutic target", Theranostics, 10, pp.8315~8342 (2020)
- Zhou, J., "Sirtuin 3 inhibition induces mitochondrial stress in tongue cancer by targeting mitochondrial fission and the JNK-Fis1 biological axis", Cell Stress Chaperone, 24, pp.369~383 (2019)
- Yi, X., "SIRT3-dependent mitochondrial dynamics remodeling contributes to oxidative stress-induced melanocyte degeneration in vitiligo", Theranostics, 9, pp.1614~1633 (2019)
- Wang, Q., "Sirt3 modulate renal ischemia-reperfusion injury through enhancing mitochondrial fusion and activating the ERK-OPA1 signaling pathway", J. Cell. Physiol, 234, pp.23495~23506 (2019)
- Jianle Wang, "Small molecule natural compound agonist of SIRT3 as a therapeutic target for the treatment of intervertebral disc degeneration", Experimental and Molecular Medicine, 50, pp.1~14 (2018), 생화학분자생물학회
- Mayer, M. P., "Hsp70 chaperones : cellular functions and molecular mechanism", Cell. Mol. Life Sci, 62, pp.670~684 (2005)
- Kim, J. Y., "The 70-kDa heat shock protein(Hsp70)as a therapeutic target for stroke", Expert Opin. Ther. Targets, 22, pp.191~199 (2018)
- Song, Y. J., "Heat shock protein 70 : a promising therapeutic target for myocardial ischemia-reperfusion injury", J. Cell. Physiol, 234, pp.1190~1207 (2019)
- Takao, T., "A comparative study of localization of heat shock protein 27and heat shock protein 72 in the developmental and degenerative intervertebral discs", Spine, 27, pp.361~368 (2002)
- Gogate, S. S., "Tonicity enhancer binding protein(TonEBP)and hypoxia-inducible factor(HIF)coordinate heat shock protein 70(Hsp70)expression in hypoxic nucleus pulposus cells : role of Hsp70 in HIF-1α degradation", J. Bone Miner. Res, 27, pp.1106~1117 (2012)
- Tsai, T. T., "TonEBP", OREBP is a regulator of nucleus pulposus cell function and survival in the intervertebral disc, 2006, pp.281, 25416~25424
- Chooi, W. H., "Compression loading-induced stress responses in intervertebral disc cells encapsulated in 3D collagen constructs", Sci. Rep, 6, pp.26449~ (2016)
- Kawai, A., "Loss of the mitochondrial Hsp70functions causes aggregation of mitochondria in yeast cells", J. Cell Sci, 114, pp.3565~3574 (2001)
- Law, I. K., "Identification and characterization of proteins interacting with SIRT1 and SIRT3 : implications in the anti-aging and metabolic effects of sirtuins", Proteomics, 9, pp.2444~2456 (2009)
- Liu, S., "Over-expression of heat shock protein 70 protects mice against lung ischemia", reperfusion injury through SIRT1, eNOS pathway, pp.Am. J. Transl. Res, 2016[DOI]
- Pfirrmann, C. W., "Magnetic resonance classification of lumbar intervertebral disc degeneration", Spine, 26, pp.1873~1878 (2001)
- Chen, S., "RIPK1", RIPK3, Apoptosis, pp.2017, 22[DOI]
- Hu, B., "Inhibiting heat shock protein 90 protects nucleus pulposus-derived stem", progenitor cells from compression-induced necroptosis and apoptosis, 2020, pp.8, 685~
- Jensen, E. C., "Quantitative analysis of histological staining and fluorescence using ImageJ", Anat. Rec, 296, pp.378~381 (2013)
- Mohanan, A., "Delayed intervention in experimental stroke with TRC051384–a small molecule HSP70 inducer", Neuropharmacology, 60, pp.991~999 (2011)
- Allende, M., "Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis without increased bleeding risk", Cardiovasc. Res, 110, pp.309~318 (2016)
- Masuda, K., "A novel rabbit model of mild, reproducible disc degeneration by an anulus needle puncture : correlation between the degree of disc injury and radiological and histological appearances of disc degeneration", Spine, 30, pp.5~14 (2005)
- Hartman, R., "Age-dependent changes in intervertebral disc cell mitochondria and bioenergetics", Eur. Cells Mater, 36, pp.171~183 (2018)
- Madhu, V., "Hypoxic Regulation of mitochondrial metabolism and mitophagy in nucleus pulposus cells is dependent on HIF-1α-BNIP3 axis", J. Bone Miner. Res, 35, pp.1504~1524 (2020)
- Xu, D., "Hydrogen sulfide protects against endoplasmic reticulum stress and mitochondrial injury in nucleus pulposus cells and ameliorates intervertebral disc degeneration", Pharmacol. Res, 117, pp.357~369 (2017)
- Wu, W., "Drp1-mediated mitochondrial fission is involved in oxidized low-density lipoprotein-induced AF cella poptosis", J. Orthop. Res, 39, pp.1496~1504 (2020)
- Imoto, Y., "Molecular basis of mitochondrial and peroxisomal division machineries", Int. J. Mol. Sci, 21, pp.5452~ (2020)
- Chen, Y., "Mfn2 is involved in intervertebral disc degeneration through autophagy modulation", Osteoarthr. Cartil, 28, pp.363~374 (2020)
- Zhou, H., "Melatonin protects cardiac microvasculature against ischemia", reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTPmitophagy axis, 2017, pp.63, e12413~
- Zhou, H., "Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia", reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2, J. Am. Heart Assoc, pp.2017, 6[DOI]
- Yan, H., "NR4A1-induced increase in the sensitivity of a human gastric cancer line to TNFα-mediated apoptosis is associated with the inhibition of JNK", Parkindependent mitophagy, 2018, pp.52, 367~378
- Zhou, H., "BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways", Angiogenesis, 21, pp.599~615 (2018)
- Zhou, H., "NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mffrequired mitochondrial fission by CK2α", Basic Res. Cardiol, 113, pp.23~ (2018)
- Hu, C., "Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progresses in mammals", Int. J. Mol. Sci, 18, pp.144~ (2017)
- Silver, J. T., "Regulation of survival gene hsp70", Cell Stress Chaperone, 17, pp.1~9 (2012)
- Takao, T., "A comparative study of localization of heat shock protein 27and heat shock protein 72 in the developmental and degenerative intervertebral discs", Spine, 27, pp.361~368 (2002)
- Siebelt, M., "Hsp90 inhibition protects against biomechanically induced osteoarthritis in rats", Arthritis Rheum, 65, pp.2102~2112 (2013)
- Liu, J., "Effects of heat shock protein 70 activation by metabolic inhibition preconditioning or kappa-opioid receptor stimulation on Ca2+ homeostasis in rat ventricular myocytes subjected to ischemic insults", J. Pharmacol. Exp. Ther, 310, pp.606~613 (2004)