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Mfn1 knockout in oocytes arrests folliculogenesis in mice through inhibiting the PI3K-Akt pathway

Grant number: 18/06119-3
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): July 01, 2018
Effective date (End): October 31, 2019
Field of knowledge:Biological Sciences - Genetics - Animal Genetics
Principal Investigator:Marcos Roberto Chiaratti
Grantee:Fabrícia Heloisa Cavicchioli Sugiyama
Home Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
Associated research grant:17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease, AP.TEM
Associated scholarship(s):18/23734-3 - Effects of mitofusin 2 excess during oocyte growth in vitro, BE.EP.IC

Abstract

Mitochondria are organelles essential to oocyte development, characterized by their round shape, small size and increased amount. These characteristics rely on mitochondrial dynamics, which determine organelle activity, transport and degradation. Mitochondrial dynamics is determined by fusion and fission events. Moreover, fusion of the outer mitochondrial membrane is mediated by mitofusins (MFN1 and MFN2). Recently, we found that the conditional knockout (cKO) of Mfn1 led to arrest of folliculogenesis, deficient oocyte growth, decreased content of mitochondrial DNA (mtDNA) and lower level of ATP. On the other hand, double cKO of Mfn1 and Mfn2 partially rescued folliculogenesis as well as oocyte growth, mtDNA content and ATP level. This rescue effect seemed to associate with activation of the PI3K-AKT signaling pathway in oocyte and/or granulosa cells, which was inhibited in Mfn1-cKO oocytes. Herein, we seek to confirm these findings by culturing granulosa cells-oocyte complexes (GOCs) in vitro. If this holds true, we will culture Mfn1-cKO GOCs in the presence of a PI3K agonist (740YP) and a PTEN antagonist (bpV-HOPIC). It is expected that these treatments will rescue development of Mfn1-cKO GOCs, giving evidences of the underlying molecular mechanism implicated in the successful folliculogenesis of double cKO oocytes.