NAD+/SIRT2途径调节衰老卵母细胞成熟质量的分子机制

doi:10.11843/j.issn.0366-6964.2022.06.001

摘要/Abstract

摘要： 卵母细胞成熟质量不仅是哺乳动物繁殖能力的基础，更能直接决定后代的优劣。卵巢早衰通常引起卵子数量和质量下降，如何提高其成熟质量成为生殖衰老领域的研究热点。近年来，烟酰胺腺嘌呤二核苷酸(NAD+)依赖性去乙酰化酶家族Sirtuins(SIRT1-7)在生殖衰老中的功能愈发受到关注，尤其抗衰老因子SIRT2的乙酰化底物直接与卵母细胞成熟事件相关。本文从乙酰化修饰调控卵母细胞衰老与成熟的全新视角，重点综述了NAD+/SIRT2通过减数分裂、能量代谢、线粒体氧化应激、线粒体质量控制等重要生理环节改善衰老卵母细胞成熟质量的最新研究进展，以期为提高老龄母畜的卵母细胞质量及延长繁殖利用年限提供新思路。

关键词: 烟酰胺腺嘌呤二核苷酸/沉默信息调节因子2, 卵母细胞, 成熟质量, 衰老, 线粒体

Abstract: The maturation quality of oocytes not only is the basis of mammalian reproductive capacity, but also directly determines the quality of offspring. Premature ovarian failure usually causes a decline in the number and quality of oocytes, and how to improve its maturation quality has become a frontier topic in the field of reproductive aging. In recent years, the functions of nicotinamide adenine dinucleotide (NAD+) dependent deacetylase family Sirtuins (SIRT1-7) in reproductive aging have attracted increasing attention. Particularly, the acetylated substrates of the anti-aging factor SIRT2 are directly related to oocyte maturation events. This review focused on the recent research progress of NAD+/SIRT2 in improving the quality of aging oocytes through important physiological processes such as meiosis, energy metabolism, mitochondrial oxidative stress and mitochondrial quality control from a new perspective of acetylation regulating the aging and maturation of oocytes. It is expected to provide new ideas for improving the oocyte quality and prolonging the reproduction period in aged female livestock.

Key words: NAD+/SIRT2, oocyte, maturation quality, aging, mitochondria

中图分类号:

S814.1

徐德军, 赵中权, 赵永聚. NAD+/SIRT2途径调节衰老卵母细胞成熟质量的分子机制[J]. 畜牧兽医学报, 2022, 53(6): 1657-1667.

XU Dejun, ZHAO Zhongquan, ZHAO Yongju. Molecular Mechanism of NAD+/SIRT2 Pathway Regulating Mature Quality of Aged Oocytes[J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(6): 1657-1667.

参考文献 80

[1]	LI A, WANG H X, WANG F, et al. Nuclear and cytoplasmic quality of oocytes derived from serum-free culture of secondary follicles in vitro[J]. J Cell Physiol, 2021, 236(7): 5352-5361.
[2]	SOARES M, SOUSA A P, FERNANDES R, et al. Aging-related mitochondrial alterations in bovine oocytes[J]. Theriogenology, 2020, 157: 218-225.
[3]	FANG X H, DU M, LI S, et al. Research progress on the effects of sirtuins on female animal reproduction[J]. Acta Veterinaria et Zootechnica Sinica, 2019, 50(12): 2379-2386. (in Chinese)房晓欢, 杜明, 李飒, 等. Sirtuins对雌性动物生殖的影响研究进展[J]. 畜牧兽医学报, 2019, 50(12): 2379-2386.
[4]	NORTH B J, MARSHALL B L, BORRA M T, et al. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase[J]. Mol Cell, 2003, 11(2): 437-444.
[5]	GOMES P, OUTEIRO T F, CAVADAS C. Emerging role of sirtuin 2 in the regulation of mammalian metabolism[J]. Trends Pharmacol Sci, 2015, 36(11): 756-768.
[6]	MIAO Y L, CUI Z K, GAO Q, et al. Nicotinamide mononucleotide supplementation reverses the declining quality of maternally aged oocytes[J]. Cell Rep, 2020, 32(5): 107987.
[7]	BERTOLDO M J, LISTIJONO D R, HO W H J, et al. NAD+ repletion rescues female fertility during reproductive aging[J]. Cell Rep, 2020, 30(6): 1670-1681.e7.
[8]	DADARWAL D, DIAS F C F, ADAMS G P, et al. Effect of follicular aging on ATP content and mitochondria distribution in bovine oocytes[J]. Theriogenology, 2017, 89: 348-358.
[9]	BABAYEV E, SELI E. Oocyte mitochondrial function and reproduction[J]. Curr Opin Obstet Gynecol, 2015, 27(3): 175-181.
[10]	KIRILLOVA A, SMITZ J E J, SUKHIKH G T, et al. The role of mitochondria in oocyte maturation[J]. Cells, 2021, 10(9): 2484.
[11]	MOGHADAM A R E, MOGHADAM M T, HEMADI M, et al. Oocyte quality and aging[J]. JBRA Assist Reprod, 2022, 26(1): 105-122.
[12]	GRØNDAHL M L, CHRISTIANSEN S L, KESMODEL U S, et al. Effect of women's age on embryo morphology, cleavage rate and competence-A multicenter cohort study[J]. PLoS One, 2017, 12(4): e0172456.
[13]	CHIANG J L, SHUKLA P, PAGIDAS K, et al. Mitochondria in ovarian aging and reproductive longevity[J]. Ageing Res Rev, 2020, 63: 101168.
[14]	MELDRUM D R, CASPER R F, DIEZ-JUAN A, et al. Aging and the environment affect gamete and embryo potential: can we intervene[J]. Fertil Steril, 2016, 105(3): 548-559.
[15]	MAY-PANLOUP P, BOUCRET L, DE LA BARCA J M C, et al. Ovarian ageing: the role of mitochondria in oocytes and follicles[J]. Hum Reprod Update, 2016, 22(6): 725-743.
[16]	MALOTT K F, LUDERER U. Toxicant effects on mammalian oocyte mitochondria[J]. Biol Reprod, 2021, 104(4): 784-793.
[17]	LIM J, LUDERER U. Oxidative damage increases and antioxidant gene expression decreases with aging in the mouse ovary[J]. Biol Reprod, 2011, 84(4): 775-782.
[18]	GAZIEV A I, ABDULLAEV S, PODLUTSKY A. Mitochondrial function and mitochondrial DNA maintenance with advancing age[J]. Biogerontology, 2014, 15(5): 417-438.
[19]	WANG S, ZHENG Y X, LI J Y, et al. Single-cell transcriptomic atlas of primate ovarian aging[J]. Cell, 2020, 180(3): 585-600.e19.
[20]	SEIDLER E A, MOLEY K H. Metabolic determinants of mitochondrial function in oocytes[J]. Semin Reprod Med, 2015, 33(6): 396-400.
[21]	PARK S U, WALSH L, BERKOWITZ K M. Mechanisms of ovarian aging[J]. Reproduction, 2021, 162(2): R19-R33.
[22]	HAMMOND E R, GREEN M P, SHELLING A N, et al. Oocyte mitochondrial deletions and heteroplasmy in a bovine model of ageing and ovarian stimulation[J]. Mol Hum Reprod, 2016, 22(4): 261-271.
[23]	TSAI T S, JOHNSON J, WHITE Y, et al. The molecular characterization of porcine egg precursor cells[J]. Oncotarget, 2017, 8(38): 63484-63505.
[24]	RINE J, STRATHERN J N, HICKS J B, et al. A suppressor of mating-type locus mutations in Saccharomyces cerevisiae: evidence for and identification of cryptic mating-type loci[J]. Genetics, 1979, 93(4): 877-901.
[25]	BURNETT C, VALENTINI S, CABREIRO F, et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila[J]. Nature, 2011, 477(7365): 482-485.
[26]	WATROBA M, SZUKIEWICZ. Sirtuins at the service of healthy longevity[J]. Front Physiol, 2021, 12: 724506.
[27]	MCBURNEY M W, YANG X F, JARDINE K, et al. The mammalian SIR2α protein has a role in embryogenesis and gametogenesis[J]. Mol Cell Biol, 2003, 23(1): 38-54.
[28]	RIEPSAMEN A, WU L, LAU L, et al. Nicotinamide impairs entry into and exit from meiosis I in mouse oocytes[J]. PLoS One, 2015, 10(6): e0126194.
[29]	POLLARD C L, GIBB Z, HAWDON A, et al. Supplementing media with NAD+ precursors enhances the in vitro maturation of porcine oocytes[J]. J Reprod Dev, 2021, 67(5): 319-326.
[30]	AGHAZ F, VAISI-RAYGANI A, KHAZAEI M, et al. Co-encapsulation of tertinoin and resveratrol by solid lipid nanocarrier (SLN) improves mice in vitro matured oocyte/ morula-compact stage embryo development[J]. Theriogenology, 2021, 171: 1-13.
[31]	LI Y, WANG J, ZHANG Z Z, et al. Resveratrol compares with melatonin in improving in vitro porcine oocyte maturation under heat stress[J]. J Anim Sci Biotechnol, 2016, 7: 33.
[32]	KHAN I, KIM S W, LEE K L, et al. Polydatin improves the developmental competence of bovine embryos in vitro via induction of sirtuin 1 (Sirt1)[J]. Reprod Fertil Dev, 2017, 29(10): 2011-2020.
[33]	ALAM F, SYED H, AMJAD S, et al. Interplay between oxidative stress, SIRT1, reproductive and metabolic functions[J]. Curr Res Physiol, 2021, 4: 119-124.
[34]	GONZÁLEZ-FERNÁNDEZ R, MARTÍN-RAMÍREZ R, ROTOLI D, et al. Granulosa-lutein cell sirtuin gene expression profiles differ between normal donors and infertile women[J]. Int J Mol Sci, 2019, 21(1): 295.
[35]	LIU G X, PARK S H, IMBESI M, et al. Loss of NAD-dependent protein deacetylase sirtuin-2 alters mitochondrial protein acetylation and dysregulates mitophagy[J]. Antioxid Redox Signal, 2017, 26(15): 849-863.
[36]	FOURCADE S, MORATÓ L, PARAMESWARAN J, et al. Loss of SIRT2 leads to axonal degeneration and locomotor disability associated with redox and energy imbalance[J]. Aging Cell, 2017, 16(6): 1404-1413.
[37]	XU D J, WU L, JIANG X H, et al. SIRT2 inhibition results in meiotic arrest, mitochondrial dysfunction, and disturbance of redox homeostasis during bovine oocyte maturation[J]. Int J Mol Sci, 2019, 20(6): 1365.
[38]	BISWAS L, TYC K, EL YAKOUBI W, et al. Meiosis interrupted: the genetics of female infertility via meiotic failure[J]. Reproduction, 2021, 161(2): R13-R35.
[39]	WATANABE Y. Geometry and force behind kinetochore orientation: lessons from meiosis[J]. Rev Mol Cell Biol, 2012, 13(6): 370-382.
[40]	MACLENNAN M, CRICHTON J H, PLAYFOOT C J, et al. Oocyte development, meiosis and aneuploidy[J]. Semin Cell Dev Biol, 2015, 45: 68-76.
[41]	YI F, ZHANG Y, WANG Z J, et al. The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis[J]. Sci Adv, 2021, 7(9): eabe5518.
[42]	ZHANG N J, ZHANG Y, WU B Q, et al. Deacetylation-dependent regulation of PARP1 by SIRT2 dictates ubiquitination of PARP1 in oxidative stress-induced vascular injury[J]. Redox Biol, 2021, 47: 102141.
[43]	KANG H J, SONG H Y, AHMED M A, et al. NQO1 regulates mitotic progression and response to mitotic stress through modulating SIRT2 activity[J]. Free Radic Biol Med, 2018, 126: 358-371.
[44]	PANDITHAGE R, LILISCHKIS R, HARTING K, et al. The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility[J]. J Cell Biol, 2008, 180(5): 915-929.
[45]	ZHANG L, HOU X J, MA R J, et al. Sirt2 functions in spindle organization and chromosome alignment in mouse oocyte meiosis[J]. FASEB J, 2014, 28(3): 1435-1445.
[46]	SELESNIEMI K, LEE H J, MUHLHAUSER A, et al. Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies[J]. Proc Natl Acad Sci U S A, 2011, 108(30): 12319-12324.
[47]	LAGIRAND-CANTALOUBE J, CIABRINI C, CHARRASSE S, et al. Loss of centromere cohesion in aneuploid human oocytes correlates with decreased kinetochore localization of the sac proteins Bub1 and Bubr1[J]. Sci Rep, 2017, 7: 44001.
[48]	XU Y, XU C L, XU Z F, et al. Fbf1 regulates mouse oocyte meiosis by influencing Plk1[J]. Theriogenology, 2021, 164: 74-83.
[49]	BAKER D J, JEGANATHAN K B, CAMERON J D, et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice[J]. Nat Genet, 2004, 36(7): 744-749.
[50]	RIRIS S, WEBSTER P, HOMER H. Digital multiplexed mRNA analysis of functionally important genes in single human oocytes and correlation of changes in transcript levels with oocyte protein expression[J]. Fertil Steril, 2014, 101(3): 857-864.
[51]	QIU D H, HOU X J, HAN L S, et al. Sirt2-BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality[J]. Aging Cell, 2018, 17(1): e12698.
[52]	FINNIN M S, DONIGIAN J R, PAVLETICH N P. Structure of the histone deacetylase SIRT2[J]. Nat Struct Biol, 2001, 8(7): 621-625.
[53]	PARK J, YEU S Y, PAIK S, et al. Loss of BubR1 acetylation provokes replication stress and leads to complex chromosomal rearrangements[J]. FEBS J, 2021, 288(20): 5925-5942.
[54]	REN H H, HU F Q, WANG D, et al. Sirtuin 2 prevents liver steatosis and metabolic disorders by deacetylation of hepatocyte nuclear factor 4α[J]. Hepatology, 2021, 74(2): 723-740.
[55]	AKIN N, VON MENGDEN L, HERTA A C, et al. Glucose metabolism characterization during mouse in vitro maturation identifies alterations in cumulus cells[J]. Biol Reprod, 2021, 104(4): 902-913.
[56]	MARIN D F D, DA COSTA N N, DI PAULA BESSA SANTANA P, et al. Importance of lipid metabolism on oocyte maturation and early embryo development: can we apply what we know to buffalo?[J]. Anim Reprod Sci, 2019, 211: 106220.
[57]	TANG F, PAN M H, WAN X, et al. Kif18a regulates Sirt2-mediated tubulin acetylation for spindle organization during mouse oocyte meiosis[J]. Cell Div, 2018, 13: 9.
[58]	ZHANG B J, PAN Y D, XU L, et al. Berberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting deacetylase SIRT3[J]. Endocrine, 2018, 62(3): 576-587.
[59]	LAMAS-TORANZO I, PERICUESTA E, BERMEJO-ÁLVAREZ P. Mitochondrial and metabolic adjustments during the final phase of follicular development prior to IVM of bovine oocytes[J]. Theriogenology, 2018, 119: 156-162.
[60]	MANNING B D, TOKER A. AKT/PKB signaling: navigating the network[J]. Cell, 2017, 169(3): 381-405.
[61]	PANAJATOVIC M, SINGH F, DUTHALER U, et al. Role of PGC-1-alpha-associated mitochondrial biogenesis in statin-induced myotoxicity[J]. Eur Cardiol, 2020, 15: e35.
[62]	JING E X, GESTA S, KAHN C R. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation[J]. Cell Metab, 2007, 6(2): 105-114.
[63]	TANG X Q, CHEN X F, WANG N Y, et al. SIRT2 Acts as a cardioprotective deacetylase in pathological cardiac hypertrophy[J]. Circulation, 2017, 136(21): 2051-2067.
[64]	RAMAKRISHNAN G, DAVAAKHUU G, KAPLUN L, et al. Sirt2 deacetylase is a novel AKT binding partner critical for AKT activation by insulin[J]. J Biol Chem, 2014, 289(9): 6054-6066.
[65]	LIEMBURG-APERS D C, WAGENAARS J A L, SMEITINK J A M, et al. Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR-RAPTOR[J]. J Cell Sci, 2016, 129(23): 4411-4423.
[66]	LOMBARD D B, ALT F W, CHENG H L, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation[J]. Mol Cell Biol, 2007, 27(24): 8807-8814.
[67]	HOCAOGLU H, WANG L, YANG M Y, et al. Heritable shifts in redox metabolites during mitochondrial quiescence reprogramme progeny metabolism[J]. Nat Metab, 2021, 3(9): 1259-1274.
[68]	DE BIE J, MAREI W F A, MAILLO V, et al. Differential effects of high and low glucose concentrations during lipolysis-like conditions on bovine in vitro oocyte quality, metabolism and subsequent embryo development[J]. Reprod Fertil Dev, 2017, 29(11): 2284-2300.
[69]	WANG Y P, ZHOU L S, ZHAO Y Z, et al. Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress[J]. EMBO J, 2014, 33(12): 1304-1320.
[70]	XU Y P, LI F L, LV L, et al. Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase[J]. Cancer Res, 2014, 74(13): 3630-3642.
[71]	WANG F, TONG Q. SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARγ[J]. Mol Biol Cell, 2009, 20(3): 801-808.
[72]	XU K X, ZHU W Y, XU A Y, et al. Inhibition of FOXO1-mediated autophagy promotes paclitaxel-induced apoptosis of MDA-MB-231 cells[J]. Mol Med Rep, 2022, 25(2): 72.
[73]	FISKUS W, COOTHANKANDASWAMY V, CHEN J G, et al. SIRT2 deacetylates and inhibits the peroxidase activity of peroxiredoxin-1 to sensitize breast cancer cells to oxidant stress-inducing agents[J]. Cancer Res, 2016, 76(18): 5467-5478.
[74]	LEMOS V, DE OLIVEIRA R M, NAIA L, et al. The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes[J]. Hum Mol Genet, 2017, 26(21): 4105-4117.
[75]	INOUE T, NAKAYAMA Y, LI Y Z, et al. SIRT2 knockdown increases basal autophagy and prevents postslippage death by abnormally prolonging the mitotic arrest that is induced by microtubule inhibitors[J]. FEBS J, 2014, 281(11): 2623-2637.
[76]	NIE H, CHEN H Y, HAN J, et al. Silencing of SIRT2 induces cell death and a decrease in the intracellular ATP level of PC12 cells[J]. Int J Physiol Pathophysiol Pharmacol, 2011, 3(1): 65-70.
[77]	GAL J, BANG Y, CHOI H J. SIRT2 interferes with autophagy-mediated degradation of protein aggregates in neuronal cells under proteasome inhibition[J]. Neurochem Int, 2012, 61(7): 992-1000.
[78]	TRISCIUOGLIO D, DEGRASSI F. The tubulin code and tubulin-modifying enzymes in autophagy and cancer[J]. Cancers (Basel), 2022, 14(1): 6.
[79]	FUKUI K, MASUDA A, HOSONO A, et al. Changes in microtubule-related proteins and autophagy in long-term vitamin E-deficient mice[J]. Free Radic Res, 2014, 48: 649-658.
[80]	XU D J, JIANG X H, HE H S, et al. SIRT2 functions in aging, autophagy, and apoptosis in post-maturation bovine oocytes[J]. Life Sci, 2019, 232: 116639.