Browse > Article
http://dx.doi.org/10.5187/jast.2021.e64

Bezafibrate prevents aging in in vitro-matured porcine oocytes  

Kim, Ju-Yeon (Department of Animal Sciences, Chungbuk National University)
Zhou, Dongjie (Department of Animal Sciences, Chungbuk National University)
Cui, Xiang-Shun (Department of Animal Sciences, Chungbuk National University)
Publication Information
Journal of Animal Science and Technology / v.63, no.4, 2021 , pp. 766-777 More about this Journal
Abstract
Bezafibrate, a fibrate drug used as a lipid-lowering agent to treat hyperlipidemia, is a pan-agonist of peroxisome proliferator-activated receptor alpha. It can enhance mitochondrial fatty acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis. After ovulation, oocytes may get arrested at the metaphase II (MII) stage until fertilization beyond optimal timing, which is termed as post-ovulatory aging. Post-ovulatory aging is a disease that degrades DNA, mitochondria, and oxidative system, and has a negative impact on embryo development and quality; however, the impact of bezafibrate during post-ovulatory aging has not been fully defined. In the present study, we assessed the ability of bezafibrate to prevent the progression of aging in in vitro conditions as well as the underlying mechanisms in pigs. An appropriate concentration of this drug (50 µM) was added, and then oxidative stress, reactive oxygen species downstream, mitochondrial biogenesis, and mitochondrial function were analyzed via immunofluorescence staining and real-time polymerase chain reaction. Bezafibrate significantly alleviated reactive oxygen species and ameliorated glutathione production simultaneously in oocytes and embryos. Moreover, it diminished H2A.X and attenuated CASPASE 3 expression produced by oxidative stress in oocytes and embryos. Furthermore, bezafibrate remarkably improved the mitochondrial function and blastocyst quality as well as markedly reduced the mitochondria/TOM20 ratio and mtDNA copy number. The elevated PARKIN level indicated that mitophagy was induced by bezafibrate treatment after post-ovulatory aging. Collectively, these results suggest that bezafibrate beneficially affects against porcine post-ovulatory oocyte aging in porcine by its antioxidant property and mitochondrial protection.
Keywords
Post-ovulatory aging; Bezafibrate; Mitochondria; Oxidative stress; $PGC-1{\alpha}$;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Blesa JR, Prieto-Ruiz JA, Hernandez JM, Hernandez-Yago J. NRF-2 transcription factor is required for human TOMM20 gene expression. Gene. 2007;391:198-208. https://doi.org/10.1016/j.gene.2006.12.024   DOI
2 Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2005;3:28. https://doi.org/10.1186/1477-7827-3-28   DOI
3 Yanagida K, Yazawa H, Katayose H, Suzuki K, Hoshi K, Sato A. Influence of oocyte pre-incubation time on fertilization after intracytoplasmic sperm injection. Hum Reprod. 1998;13:2223-6. https://doi.org/10.1093/humrep/13.8.2223   DOI
4 Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA. 1994;91:10771-8. https://doi.org/10.1073/pnas.91.23.10771   DOI
5 Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001;413:131-8. https://doi.org/10.1038/35093050   DOI
6 Johri A, Calingasan NY, Hennessey TM, Sharma A, Yang L, Wille E, et al. Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease. Hum Mol Genet. 2012;21:1124-37. https://doi.org/10.1093/hmg/ddr541   DOI
7 Bonnefont JP, Bastin J, Behin A, Djouadi F. Bezafibrate for an inborn mitochondrial beta-oxidation defect. N Engl J Med. 2009;360:838-40. https://doi.org/10.1056/NEJMc0806334   DOI
8 Igarashi H, Takahashi T, Nagase S. Oocyte aging underlies female reproductive aging: biological mechanisms and therapeutic strategies. Reprod Med Biol. 2015;14:159-69. https://doi.org/10.1007/s12522-015-0209-5   DOI
9 Miao Y, Zhou C, Cui Z, Zhang M, ShiYang X, Lu Y, et al. Postovulatory aging causes the deterioration of porcine oocytes via induction of oxidative stress. FASEB J. 2018;32:1328-37. https://doi.org/10.1096/fj.201700908R   DOI
10 Lord T, Nixon B, Jones KT, Aitken RJ. Melatonin prevents postovulatory oocyte aging in the mouse and extends the window for optimal fertilization in vitro. Biol Reprod. 2013;88:67. https://doi.org/10.1095/biolreprod.112.106450   DOI
11 Chi MMY, Manchester JK, Yang VC, Curato AD, Strickler RC, Lowry OH. Contrast in levels of metabolic enzymes in human and mouse ova. Biol Reprod. 1988;39:295-307. https://doi.org/10.1095/biolreprod39.2.295   DOI
12 Steele H, Gomez-Duran A, Pyle A, Hopton S, Newman J, Stefanetti RJ, et al. Metabolic effects of bezafibrate in mitochondrial disease. EMBO Mol Med. 2020;12:e11589. https://doi.org/10.15252/emmm.201911589   DOI
13 Tripathi A, Kumar KV, Chaube SK. Meiotic cell cycle arrest in mammalian oocytes. J Cell Physiol. 2010;223:592-600. https://doi.org/10.1002/jcp.22108   DOI
14 Sun QY, Miao YL, Schatten H. Towards a new understanding on the regulation of mammalian oocyte meiosis resumption. Cell Cycle. 2009;8:2741-7. https://doi.org/10.4161/cc.8.17.9471   DOI
15 Lord T, Aitken RJ. Oxidative stress and ageing of the post-ovulatory oocyte. Reproduction. 2013;146:R217-27. https://doi.org/10.1530/REP-13-0111   DOI
16 Mikkelsen AL, Lindenberg S. Morphology of in-vitro matured oocytes: impact on fertility potential and embryo quality. Hum Reprod. 2001;16:1714-8. https://doi.org/10.1093/humrep/16.8.1714   DOI
17 Takahashi T, Takahashi E, Igarashi H, Tezuka N, Kurachi H. Impact of oxidative stress in aged mouse oocytes on calcium oscillations at fertilization. Mol Reprod Dev. 2003;66:143-52. https://doi.org/10.1002/mrd.10341   DOI
18 Grings M, Moura AP, Parmeggiani B, Pletsch JT, Cardoso GMF, August PM, et al. Bezafibrate prevents mitochondrial dysfunction, antioxidant system disturbance, glial reactivity and neuronal damage induced by sulfite administration in striatum of rats: implications for a possible therapeutic strategy for sulfite oxidase deficiency. Biochim Biophys Acta Mol Basis Dis. 2017;1863:2135-48. https://doi.org/10.1016/j.bbadis.2017.05.019   DOI
19 Fujino Y, Ozaki K, Yamamasu S, Ito F, Matsuoka I, Hayashi E, et al. DNA fragmentation of oocytes in aged mice. Hum Reprod. 1996;11:1480-3. https://doi.org/10.1093/oxfordjournals.humrep.a019421   DOI
20 Takai Y, Matikainen T, Jurisicova A, Kim MR, Trbovich AM, Fujita E, et al. Caspase-12 compensates for lack of caspase-2 and caspase-3 in female germ cells. Apoptosis. 2007;12:791-800. https://doi.org/10.1007/s10495-006-0022-z   DOI
21 Baldelli S, Aquilano K, Ciriolo MR. PGC-1α buffers ROS-mediated removal of mitochondria during myogenesis. Cell Death Dis. 2014;5:e1515. https://doi.org/10.1038/cddis.2014.458   DOI
22 Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta Mol Cell Res. 2016;1863:2977-92. https://doi.org/10.1016/j.bbamcr.2016.09.012   DOI
23 Nikolic N, Rhedin M, Rustan AC, Storlien L, Thoresen GH, Stromstedt M. Overexpression of PGC-1α increases fatty acid oxidative capacity of human skeletal muscle cells. Biochem Res Int. 2012;2012:714074. https://doi.org/10.1155/2012/714074   DOI
24 LeBleu VS, O'Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 2014;16:992-1003. https://doi.org/10.1038/ncb3039   DOI
25 Yoshioka K, Suzuki C, Onishi A. Defined system for in vitro production of porcine embryos using a single basic medium. J Reprod Dev. 2008;54:208-13. https://doi.org/10.1262/jrd.20001   DOI
26 Sasaki H, Hamatani T, Kamijo S, Iwai M, Kobanawa M, Ogawa S, et al. Impact of oxidative stress on age-associated decline in oocyte developmental competence. Front Endocrinol. 2019;10:811. https://doi.org/10.3389/fendo.2019.00811   DOI
27 Park SH, Lee AR, Choi K, Joung S, Yoon JB, Kim S. TOMM20 as a potential therapeutic target of colorectal cancer. BMB Rep. 2019;52:712-7. https://doi.org/10.5483/BMBRep.2019.52.12.249   DOI
28 St-Pierre J, Lin J, Krauss S, Tarr PT, Yang R, Newgard CB, et al. Bioenergetic analysis of peroxisome proliferator-activated receptor γ coactivators 1α and 1β (PGC-1α and PGC-1β) in muscle cells. J Biol Chem. 2003;278:26597-603. https://doi.org/10.1074/jbc.M301850200   DOI
29 Cecchino GN, Seli E, Alves da Motta EL, Garcia-Velasco JA. The role of mitochondrial activity in female fertility and assisted reproductive technologies: overview and current insights. Reprod Biomed Online. 2018;36:686-97. https://doi.org/10.1016/j.rbmo.2018.02.007   DOI
30 Narendra DP, Youle RJ. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid Redox Signal. 2011;14:1929-38. https://doi.org/10.1089/ars.2010.3799   DOI
31 St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127:397-408. https://doi.org/10.1016/j.cell.2006.09.024   DOI