Effect of genetic and metabolic alterations on mitochondrial function in oocytes

• Grant number: 25/13891-8
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2025
• End date: October 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Marcos Roberto Chiaratti
• Grantee: Marcos Roberto Chiaratti
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Associated research grant: 23/02226-8 - Bilateral BBSRC-FAPESP: molecular mechanisms shaping the germ-line transmission of mtDNA variants, AP.TEM

Abstract

During folliculogenesis, the maternal gamete (oocyte) undergoes important changes needed for conclusion of meiosis, fertilization and embryogenesis. Among these changes we highlight a significant alteration in mitochondrial dynamics, resulting in extensive fragmentation of the mitochondrial network and, thereby, segregation of mitochondrial DNA (mtDNA) molecules across thousands of mitochondria present in the gamete at the end of follicle development. This process, also known as mitochondrial meiosis, results from an increase in the rate of mitochondrial fission, in relation to fusion, which minimizes mitochondrial complementation and favors the removal of dysfunctional mitochondria, for instance, by autophagy. The relevance of these events has been demonstrated by the use of mouse models harboring a mixture of wild-type and mutant mtDNAs (condition termed heteroplasmy), where mitochondrial meiosis promotes the propagation of wild-type over mutant molecules. On the other hand, disturbs affecting oocyte homeostasis, resulting from genetic or metabolic origins, lead to mitochondrial damage that accumulates in the gamete and is transmitted to subsequent generations, contributing to the onset of diseases in offspring. In this regard, the aim of the present proposal is to investigate how dysfunctions of genetic (e.g., mutant mtDNA) or metabolic (e.g., obesity and diabetes) origin affect oocyte mitochondria and if this effect relies on the action of autophagy. To that aim, we considered two experimental models. In a first proposal, we will take advantage of a heteroplasmic mouse model transmitting the non-sense mutation m.8069G>A, which results in the knockout of the mt-Atp6 gene and mitochondrial dysfunction. The second proposal will be based on a high-fat diet associated with streptozotocin (STZ) treatment to induce a phenotype similar to obesity and type 2 diabetes. Our aim with these proposals is to investigate how mitochondrial dysfunctions of genetic (e.g., mutant mtDNA) or metabolic (e.g., obesity and diabetes) origins affect oocyte mitochondria. More specifically, our hypothesis is that the m.8069G>A mutation will result in mitochondria with heterogeneous membrane potential, while the obesity and diabetes model will affect mitochondrial membrane potential more homogeneously across organelles in the gamete. Also, we will investigate the effect of these two models on Atg7-knockout mice seeking to assess how autophagy deficiency impacts the mitochondrial network in oocytes. We expect to contribute to the understanding of the mechanism associated with transmission of dysfunctional organelles, which potentially leads to the onset of diseases in offspring. (AU)