Evidence of Selection Against Damaged Mitochondria During Early Embryogenesis in the Mouse

Author(s)

Machado, Thiago S. ^{[1, 2]} ; Macabelli, Carolina H. ^[2] ; Del Collado, Maite ^[3] ; Meirelles, V, Flavio ; Guimaraes, Francisco E. G. ^[4] ; Chiaratti, Marcos R. ^{[2, 5]}

Affiliation

^[1] Univ Sao Paulo, Fac Med Vet & Zootecnia, Sao Paulo - Brazil

^[2] Univ Fed Sao Carlos, Dept Genet & Evolucao, Sao Carlos - Brazil

^[3] V, Univ Sao Paulo, Fac Zootecnia & Engn Alimentos, Pirassununga - Brazil

^[4] Univ Sao Paulo, Inst Fis Sao Carlos, Sao Carlos - Brazil

^[5] Meirelles, Flavio, V, Univ Sao Paulo, Fac Med Vet & Zootecnia, Sao Paulo - Brazil

• Document type: Journal article
• Source: FRONTIERS IN GENETICS; v. 11, JUL 15 2020.
• Web of Science Citations: 0

Abstract

There is evidence of a purifying filter acting in the female germline to prevent the expansion of deleterious mutations in the mitochondrial DNA (mtDNA). Given our poor understanding of this filter, here we investigate the competence of the mouse embryo to eliminate dysfunctional mitochondria. Toward that, mitochondria were damaged by photoirradiation of NZB/BINJ zygotes loaded with chloromethyl-X-rosamine (CMXRos). The resultant cytoplasm was then injected into C57BL/6J zygotes to track the levels of NZB/BINJ mtDNA during the preimplantation development. About 30% of NZB/BINJ mtDNA was present after injection, regardless of using photoirradiated or non-photoirradiated cytoplasmic donors. Moreover, injection of photoirradiated-derived cytoplasm did not impact development into blastocysts. However, lower levels of NZB/BINJ mtDNA were present in blastocysts when comparing injection of photoirradiated (24.7% +/- 1.43) versus non-photoirradiated (31.4% +/- 1.43) cytoplasm. Given that total mtDNA content remained stable between stages (zygotes vs. blastocysts) and treatments (photoirradiated vs. non-photoirradiated), these results indicate that the photoirradiated-derived mtDNA was replaced by recipient mtDNA in blastocysts. Unexpectedly, treatment with rapamycin prevented the drop in NZB/BINJ mtDNA levels associated with injection of photoirradiated cytoplasm. Additionally, analysis of mitochondria-autophagosome colocalization provided no evidence that photoirradiated mitochondria were eliminated by autophagy. In conclusion, our findings give evidence that the mouse embryo is competent to mitigate the levels of damaged mitochondria, which might have implications to the transmission of mtDNA-encoded disease. (AU)

• 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: 13/13869-5 - Induced pluripotent stem cells derived from patients with mitochondrial diseases as a model for studying mitochondrial inheritance
• Grantee: Carolina Habermann Macabelli
• 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: 12/12951-7 - Transplantation of cytoplasm subjected to oxidative stress as a model for study of mitochondrial disease inheritance
• Grantee: Thiago Simões Machado
• Support Opportunities: Scholarships in Brazil - Master
• 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