Age associated mitochondrial changes in oocytes

• Project/Area Number: 16K07996
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Animal production science
• Research Institution: Tokyo University of Agriculture
• Principal Investigator: IWATA Hisataka 東京農業大学, 農学部, 教授 (50385499)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ミトコンドリア / 加齢 / 肥満 / ゲノムの変異 / 細胞外DNA / ゲノム変異 / 凍結 / 卵子 / エピゲネティクス / 顆粒層細胞

Outline of Final Research Achievements

The present study addressed age and obesity associated low mitochondrial functions and mitochondrial genome mutations and possible countermeasures against the mitochondrial deterioration in oocytes and embryos. DNA sequencing of mitochondrial genome revealed aging associated mitochondrial genome mutations. Obesity induced mitochondrial dysfunctions including hyperacetylation of mitochondrial proteins, which were ameliorated by activation of SIRT1 levels in oocytes. SIRT1 activation helped embryo-recovery from cryopreservation associated mitochondrial dysfunctions through removal of damaged mitochondria and improved quality and pregnancy rate of the post warmed embryos.

Academic Significance and Societal Importance of the Research Achievements

本研究では加齢によって卵子のミトコンドリアのゲノムにどのような異常が蓄積されるのかを明らかにした。また高濃度の脂肪酸存在下ではミトコンドリアのタンパクの高アセチル化が起こり機能が減退することがわかった。凍結などにより物理的に惹起されたミトコンドリア異常の一部はミトコンドリアの品質管理機構をSIRT1の活性化によって活性化させることで、改善できることが分かった。母体の加齢や胚操作に起因するミトコンドリア障害に対する簡便な対抗手段として、本研究の知見は応用が可能である。

Research Products

• [Journal Article] Cell-free DNA in medium is associated with the maturation ability of <i>in vitro</i> cultured oocytes (2019)
  • Author(s): MUNAKATA Yasuhisa、SHIRASUNA Koumei、KUWAYAMA Takehito、IWATA Hisataka
  • Journal Title: Journal of Reproduction and Development Volume: 65 Issue: 2 Pages: 171-175
  • DOI: 10.1262/jrd.2018-123
  • NAID: 130007630933
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Open Access
• [Journal Article] Addition of granulosa cells collected from differential follicle stages supports development of oocytes derived from porcine early antral follicles. (2018)
  • Author(s): Ishiguro A, Munakata Y, Shirasuna K, Kuwayama T, Iwata H.
  • Journal Title: Reprod Med Biol. Volume: 18 Issue: 1 Pages: 65-71
  • DOI: 10.1002/rmb2.12248
  • Peer Reviewed / Open Access
• [Journal Article] Resveratrol enhances the clearance of mitochondrial damage by vitrification and improves the development of vitrified-warmed bovine embryos. (2018)
  • Author(s): Hara T, Kin A, Aoki S, Nakamura S, Shirasuna K, Kuwayama T, Iwata H.
  • Journal Title: PLoS One Volume: 13 Issue: 10 Pages: e0204571-e0204571
  • DOI: 10.1371/journal.pone.0204571
  • Peer Reviewed / Open Access
• [Journal Article] Follicular factors determining granulosa cell number and developmental competence of porcine oocytes (2018)
  • Author(s): Munakata Yasuhisa、Ueda Manami、Kawahara-Miki Ryoka、Kansaku Kazuki、Itami Nobuhiko、Shirasuna Koumei、Kuwayama Takehito、Iwata Hisataka
  • Journal Title: Journal of Assisted Reproduction and Genetics Volume: 35 Issue: 10 Pages: 1809-1819
  • DOI: 10.1007/s10815-018-1247-9
  • Peer Reviewed
• [Journal Article] Short-term heat stress induces mitochondrial degradation and biogenesis and enhances mitochondrial quality in porcine oocytes (2018)
  • Author(s): Itami N, Shirasuna K, Kuwayama T, Iwata H
  • Journal Title: Journal of Thermal Biology Volume: 74 Pages: 256-263
  • DOI: 10.1016/j.jtherbio.2018.04.010
  • Peer Reviewed
• [Journal Article] Palmitic acid induces ceramide accumulation, mitochondrial protein hyperacetylation, and mitochondrial dysfunction in porcine oocytes (2018)
  • Author(s): Itami N, Shirasuna K, Kuwayama T, Iwata H.
  • Journal Title: Biology of Reproduction Volume: 97 Issue: 5 Pages: 644-653
  • DOI: 10.1093/biolre/ioy023
  • Peer Reviewed
• [Journal Article] Mitochondrial dysfunction in cumulus-oocyte complexes increases cell-free mitochondrial DNA (2018)
  • Author(s): Kansaku K, Munakata Y, Itami N, Shirasuna K, Kuwayama T, Iwata H.
  • Journal Title: Journal of Reproduction and Development Volume: 64 Issue: 3 Pages: 261-266
  • DOI: 10.1262/jrd.2018-012
  • NAID: 130007409988
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Open Access
• [Journal Article] Non-esterified fatty acid-associated ability of follicular fluid to support porcine oocyte maturation and development. (2018)
  • Author(s): Ogawa K, Itami N, Ueda M, Kansaku K, Shirasuna K, Kuwayama T, Iwata H
  • Journal Title: Reproductive Medicine and Biology Volume: 17 Issue: 2 Pages: 155-163
  • DOI: 10.1002/rmb2.12084
  • Peer Reviewed / Open Access
• [Journal Article] Maternal aging affects oocyte resilience to carbonyl cyanide-m-chlorophenylhydrazone -induced mitochondrial dysfunction in cows. (2017)
  • Author(s): Kansaku K, Takeo S, Itami N, Kin A, Shirasuna K, Kuwayama T, Iwata H.
  • Journal Title: PLoS One Volume: 12 Issue: 11 Pages: e0188099-e0188099
  • DOI: 10.1371/journal.pone.0188099
  • Peer Reviewed / Open Access
• [Journal Article] Differential effects of mitochondrial inhibitors on porcine granulosa cells and oocytes. (2017)
  • Author(s): Kansaku K, Itami N, Kawahara-Miki R, Shirasuna K, Kuwayama T, Iwata H
  • Journal Title: Theriogenology Volume: 103 Pages: 98-103
  • DOI: 10.1016/j.theriogenology.2017.07.049
  • Peer Reviewed
• [Journal Article] Effect of aging on telomere lengths in bovine oocytes and granulosa cells (2017)
  • Author(s): Kin A, Kansaku K, Sumiya M, Itami N, Sirasuna K, Kuwayama T, Iwata H
  • Journal Title: Journal of Mammalian Ova Research Volume: 34
  • NAID: 40021179880
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Polyacrylamide gel as a culture substrate improves in vitro oocyte growth from porcine early (2017)
  • Author(s): Munakata Y, Kawahara-Miki R, Shirasuna K, Kuwayama T, Iwata H.
  • Journal Title: Mol Reprod Dev Volume: 84 Issue: 1 Pages: 44-54
  • DOI: 10.1002/mrd.22758
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Low oxygen level increases proliferation and metabolic changes in bovine granulosa cells. (2016)
  • Author(s): Shiratsuki S, Hara T, Munakata Y, Shirasuna K, Kuwayama T, Iwata H.
  • Journal Title: Mol Cell Endocrinol. Volume: 437 Pages: 75-85
  • DOI: 10.1016/j.mce.2016.08.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Promotion of glucose utilization by insulin enhances granulosa cell proliferation and developmental competence of porcine oocyte grown in vitro. (2016)
  • Author(s): Itami N, Munakata Y, Shirasuna K, Kuwayama T, Iwata H
  • Journal Title: Zygote Volume: 13 Issue: 1 Pages: 1-10
  • DOI: 10.1017/s0967199416000356
  • Peer Reviewed
• [Journal Article] Addition of granulosa cell mass to the culture medium of oocytes derived from early antral follicles increases oocyte growth, ATP content, and acetylation of H4K12. (2016)
  • Author(s): Sugiyama M, Sumiya M, Shirasuna K, Kuwayama T, Iwata H.
  • Journal Title: Zygote Volume: 25 Issue: 6 Pages: 248-256
  • DOI: 10.1017/s0967199416000198
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Relationship between the number of cells surrounding oocytes and energy states of oocytes. (2016)
  • Author(s): Munakata Y, Ichinose T, Ogawa K, Itami N, Tasaki H, Shirasuna K, Kuwayama T, Iwata H
  • Journal Title: Theriogenology Volume: 86 Issue: 7 Pages: 1789-1798
  • DOI: 10.1016/j.theriogenology.2016.05.036
  • Peer Reviewed
• [Presentation] 卵子発育を支えるマイクロRNA (2019)
  • Author(s): 岩田 尚孝
  • Organizer: 第19回日本生殖工学会
  • Int'l Joint Research / Invited
• [Presentation] Telomere lengths in oocytes and granulosa cells derived from aged cows Kin A, Kansaku K (2017)
  • Author(s): Kin A, Kansaku K, Ueno Y, Shirasuna K, Kuwayama T, Iwata H
  • Organizer: 4ｔｈ World congress of reproductive biology
  • Int'l Joint Research
• [Presentation] Aged-associated increases in mitochondrial DNA mutation in bovine oocytes (2017)
  • Author(s): Kin A, Kansaku K, Kawahara-Miki R, Shirasuna K, Kuwayama T, Iwata H
  • Organizer: The 11th Congress of the Pacific Society for Reproductive Medicine
  • Int'l Joint Research
• [Presentation] Granulosa cell number and oocyte growth (2017)
  • Author(s): Iwata Hisataka
  • Organizer: 4ｔｈ World congress of reproductive biology
  • Int'l Joint Research / Invited
• [Remarks] 東京農業大学 家畜繁殖学研究室
  • URL: https://www.facebook.com/nodai.c613/?fref=ts