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Effect of the knockout of mitofusin 2 on mitochondria, endoplasmic reticulum and mitophagy in murine oocytes

Grant number: 16/11935-9
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): December 01, 2016
Effective date (End): August 31, 2018
Field of knowledge:Biological Sciences - Genetics - Animal Genetics
Principal Investigator:Marcos Roberto Chiaratti
Grantee:Bruna Martins Garcia
Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
Associated scholarship(s):17/11143-8 - Role of Mfn2 and LRRK2 on endoplasmic reticulum-mitochondrial tethering, BE.EP.MS


Mitofusins 1 (Mfn1) and 2 (MFN2) are transmembrane GTPases present in the outer mitochondrial membrane and being involved in the regulation of mitochondrial fusion. Since Mfn2 is also present in the membrane of the endoplasmic reticulum (ER), it is also responsible for regulating the morphology and the interaction of ER with the mitochondrion. Thus, there are increasing evidences that Mfn2 plays a key role in the regulation of mitochondrial and ER function as well as autophagy. However, little is known about its role in the oocyte. Recently, it was observed that the conditional knockout of Mfn2 in murine oocyte does not affect fertility, but results in hyperglycemia in the offspring. Furthermore, suppression of Mfn2 expression prevents elimination of mutant mitochondrial DNA (mtDNA) in the oocyte, resulting in higher levels of this mutation in the progeny. Thus, the aim of this study is to investigate the molecular mechanisms that result in these phenotypes. The effects of the Mfn2 knockout in the oocyte will be evaluated considering the mitochondria and ER function as well as the occurrence of mitophagy. Therefore, wild type and knockout oocytes containing >45% mutant mtDNA will be compared as to the expression of genes involved in the glycolytic pathway, ß-oxidation, mitochondrial function, mitochondrial dynamics, ER function, mitophagy pathway and oocytes developmental competence. Using transmission electron microscopy, fluorescence microscopy and western blot, it will also be analyzed whether these oocytes differ as to the mitochondrial activity, the production of reactive oxygen species, the content of lipid droplets and activation of mitophagy. It is expected that these analyses clarify the molecular pathways connecting Mfn2 and the phenotype observed in the mouse model containing Mfn2-null oocytes. (AU)

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CHIARATTI, MARCOS ROBERTO; GARCIA, BRUNA MARTINS; CARVALHO, KAREN FREIRE; MACHADO, THIAGO SIMOES; DA SILVA RIBEIRO, FERNANDA KARINA; MACABELLI, CAROLINA HABERMANN. The role of mitochondria in the female germline: Implications to fertility and inheritance of mitochondrial diseases. Cell Biology International, v. 42, n. 6, SI, p. 711-724, . (12/50231-6, 16/11935-9, 17/05899-2, 16/11942-5, 16/07868-4)
CARVALHO, KAREN F.; MACHADO, THIAGO S.; GARCIA, BRUNA M.; ZANGIROLAMO, AMANDA F.; MACABELLI, CAROLINA H.; SUGIYAMA, FABRICIA H. C.; GREJO, MATEUS P.; NETO, J. DJACI AUGUSTO; TOSTES, KATIANE; RIBEIRO, FERNANDA K. S.; et al. Mitofusin 1 is required for oocyte growth and communication with follicular somatic cells. FASEB JOURNAL, v. 34, n. 6, . (12/50231-6, 16/11935-9, 09/54035-4, 13/08135-2, 17/04372-0, 16/11942-5, 16/07868-4)
CHIARATTI, MARCOS R.; GARCIA, BRUNA M.; CARVALHO, KAREN F.; MACABELLI, CAROLINA H.; DA SILVA RIBEIRO, FERNANDA KARINA; ZANGIROLAMO, AMANDA F.; SARAPIAO, FABIANA D.; SENEDA, MARCELO M.; MEIRELLES, FLAVIO V.; GUIMARAES, FRANCISCO E. G.; et al. Oocyte mitochondria: role on fertility and disease transmission. ANIMAL REPRODUCTION, v. 15, n. 3, p. 231-238, . (16/07868-4, 17/05899-2, 12/50231-6, 16/11942-5, 16/11935-9)
GARCIA, BRUNA M.; MACHADO, THIAGO S.; CARVALHO, KAREN F.; NOLASCO, PATRICIA; NOCITI, RICARDO P.; DEL COLLADO, MAITE; CAPO BIANCO, MARIA J. D.; GREJO, MATEUS P.; AUGUSTO NETO, JOSE DJACI; SUGIYAMA, FABRICIA H. C.; et al. Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis. MOLECULAR HUMAN REPRODUCTION, v. 26, n. 12, p. 938-952, . (10/51906-1, 17/05899-2, 17/04372-0, 18/20028-0, 18/06119-3, 16/11935-9, 09/54035-4, 12/50231-6, 16/11942-5)

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