Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis

Author(s):Show less -

Garcia, Bruna M. ^[1] ; Machado, Thiago S. ^{[1, 2]} ; Carvalho, Karen F. ^[1] ; Nolasco, Patricia ^[3] ; Nociti, Ricardo P. ^[4] ; del Collado, Maite ^[4] ; Capo Bianco, Maria J. D. ^[1] ; Grejo, Mateus P. ^[1] ; Augusto Neto, Jose Djaci ^[1] ; Sugiyama, Fabricia H. C. ^[1] ; Tostes, Katiane ^[1] ; Pandey, Anand K. ^{[1, 5]} ; Goncalves, Luciana M. ^[6] ; Perecin, Felipe ^{[2, 4]} ; Meirelles, V, Flavio ; Ferraz, Jose Bento S. ^[7] ; Vanzela, Emerielle C. ^[6] ; Boschero, Antonio C. ^[6] ; Guimaraes, Francisco E. G. ^[8] ; Abdulkader, Fernando ^[9] ; Laurindo, Francisco R. M. ^[3] ; Kowaltowski, Alicia J. ^[10] ; Chiaratti, Marcos R. ^{[1, 11]}

Affiliation:Show less -

^[1] Univ Fed Sao Carlos, Dept Genet & Evolucao, Rod Washington Luis Km 235, SP 310, BR-13565905 Sao Carlos, SP - Brazil

^[2] Univ Sao Paulo, Fac Med Vet & Zootecnia, Programa Posgrad Anat Anim Domest & Silvestres, BR-05508270 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Coracao, Translat Cardiovasc Biol Unit, BR-05403904 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Zootecnia & Engn Alimentos, Dept Med Vet, BR-13635900 Pirassununga - Brazil

^[5] Lala Lajpat Rai Univ Vet & Anim Sci, Coll Vet Sci, Dept Vet Gynaecol & Obstet, Hisar 125004, Haryana - India

^[6] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, BR-13083865 Campinas - Brazil

^[7] Meirelles, Flavio, V, Univ Sao Paulo, Fac Zootecnia & Engn Alimentos, Dept Med Vet, BR-13635900 Pirassununga - Brazil

^[8] Univ Sao Paulo, Inst Fis Sao Carlos, Dept Fis & Ciencias Mat, BR-13563120 Sao Carlos - Brazil

^[9] Univ Sao Paulo, Inst Ciencias Biomed, Dept Fisiol & Biofis, BR-05508000 Sao Paulo - Brazil

^[10] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508900 Sao Paulo - Brazil

^[11] Meirelles, Flavio, V, Univ Sao Paulo, Fac Med Vet & Zootecnia, Programa Posgrad Anat Anim Domest & Silvestres, BR-05508270 Sao Paulo - Brazil

• Document type: Journal article
• Source: MOLECULAR HUMAN REPRODUCTION; v. 26, n. 12, p. 938-952, DEC 2020.
• Web of Science Citations: 0

Abstract

Offspring born to obese and diabetic mothers are prone to metabolic diseases, a phenotype that has been linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress in oocytes. In addition, metabolic diseases impact the architecture and function of mitochondria-ER contact sites (MERCs), changes which associate with mitofusin 2 (MFN2) repression in muscle, liver and hypothalamic neurons. MFN2 is a potent modulator of mitochondrial metabolism and insulin signaling, with a key role in mitochondrial dynamics and tethering with the ER. Here, we investigated whether offspring born to mice with MFN2-deficient oocytes are prone to obesity and diabetes. Deletion of Mfn2 in oocytes resulted in a profound transcriptomic change, with evidence of impaired mitochondrial and ER function. Moreover, offspring born to females with oocyte-specific deletion of Mfn2 presented increased weight gain and glucose intolerance. This abnormal phenotype was linked to decreased insulinemia and defective insulin signaling, but not mitochondrial and ER defects in offspring liver and skeletal muscle. In conclusion, this study suggests a link between disrupted mitochondrial/ER function in oocytes and increased risk of metabolic diseases in the progeny. Future studies should determine whether MERC architecture and function are altered in oocytes from obese females, which might contribute toward transge-nerational transmission of metabolic diseases. (AU)

• FAPESP's process: 10/51906-1 - Mitochondrial bioenergetics, ion transport, redox state and DNA metabolism
• Grantee: Alicia Juliana Kowaltowski
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/05899-2 - Effect of the knockout of mitofusins on mouse oocyte: implications to fertility and mitochondrial inheritance
• Grantee: Marcos Roberto Chiaratti
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease
• Grantee: Nadja Cristhina de Souza Pinto
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/20028-0 - Does autophagic deficiency increases accumulation of NZB Mitochondrial DNA in the liver?
• Grantee: Katiane Tostes
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 18/06119-3 - Mfn1 knockout in oocytes arrests folliculogenesis in mice through inhibiting the PI3K-Akt pathway
• Grantee: Fabrícia Heloisa Cavicchioli Sugiyama
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 16/11935-9 - Effect of the knockout of mitofusin 2 on mitochondria, endoplasmic reticulum and mitophagy in murine oocytes
• Grantee: Bruna Martins Garcia
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 09/54035-4 - Facility for advanced studies of biosystems and nanostructured materials
• Grantee: Igor Polikarpov
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 12/50231-6 - Molecular basis of mitochondrial inheritance: the role of mitochondrial fusion
• Grantee: Marcos Roberto Chiaratti
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 16/11942-5 - Fertility effect of the knockout of Mitofusin 1 on murine oocytes
• Grantee: Karen Freire Carvalho
• Support Opportunities: Scholarships in Brazil - Master