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Molecular basis of mitochondrial inheritance: the role of mitochondrial fusion

Abstract

Pathologies caused by mutations in the mitocondrial DNA (mtDNA) are a major cause of disease in humans. Nonetheless, due to the unique pattern of mtDNA segregation, it is not yet possible to predict or intervene in the inheritance of these pathologies. This is mainly due to our limited understanding of the molecular basis of mitochondrial inheritance in mammals. Mitochondrial fusion and fission have a major role in organelle function, and may disturb mtDNA segregation by altering the number of organelles in the cell. If mitochondrial fusion and fission play significant roles in somatic tissues, the same occurs in oocytes since throughout oogenesis mitochondria are subjected to profound morphological alterations and to an increase of hundreds to thousands times in mtDNA content. This intense mtDNA replication during oocyte growth contrasts with the absence of replication during early stages of embryonic development, which results in primordial germ cell (PGCs) containing only a few mtDNA copies. The low rate of mitochondrial fusion in oocytes and during early embryonic development might explain the intense segregation of polymorphic mtDNAs between generations. In this case, each mitochondrion would act as a segregative unit to distribute mtDNA molecules among PGCs that will differentiate into oocytes of the next generation. Therefore, the main goal of this proposal is to address the role played by mitochondrial fusion in mtDNA segregation in oocytes during oogenesis and in embryos during early development. In this way, key genes involved in mitochondrial fusion (Mfn1 and Mfn2) will be knocked out exclusively in oocytes (by Zp3 promoter-directed expression of Cre-recombinase) owing two mitochondrial haplotypes (heteroplasmy) to evaluate developmental competence of the female gamete and mitochondria inheritance. It is expected that the knockout of mitochondrial fusion will enhance segregation of the two mitochondrial haplotypes which in turn should result in an increase of heteroplasmy variation between generations. This study should contribute significantly to the knowledge of the molecular basis of mitochondrial inheritance which has implications to the prevention and intervention upon inheritance of severe human pathologies caused by mutations in mtDNA. (AU)

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Scientific publications (7)
(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)
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)
MACHADO, THIAGO S.; MACABELLI, CAROLINA H.; DEL COLLADO, MAITE; MEIRELLES, V, FLAVIO; GUIMARAES, FRANCISCO E. G.; CHIARATTI, MARCOS R.. Evidence of Selection Against Damaged Mitochondria During Early Embryogenesis in the Mouse. FRONTIERS IN GENETICS, v. 11, . (12/50231-6, 13/13869-5, 09/54035-4, 12/12951-7, 17/05899-2, 17/04372-0)
MEIRELLES, FLAVIO VIEIRA; BRESSAN, FABIANA FERNANDES; SMITH, LAWRENCE CHARLES; PERECIN, FELIPE; CHIARATTI, MARCOS ROBERTO; STERMAN FERRAZ, JOSE BENTO. Cytoplasmatic inheritance, epigenetics and reprogramming DNA as tools in animal breeding. LIVESTOCK SCIENCE, v. 166, n. SI, p. 199-205, . (10/09561-7, 12/50231-6, 11/08376-4)
MACHADO, THIAGO SIMOES; MACABELLI, CAROLINA HABERMANN; SANGALLI, JULIANO RODRIGUES; RODRIGUES, THIAGO BITTENCOURT; SMITH, LAWRENCE CHARLES; MEIRELLES, FLAVIO VIEIRA; CHIARATTI, MARCOS ROBERTO. Real-Time PCR Quantification of Heteroplasmy in a Mouse Model with Mitochondrial DNA of C57BL/6 and NZB/BINJ Strains. PLoS One, v. 10, n. 8, . (10/09561-7, 12/50231-6, 12/12951-7, 10/13384-3)
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, 16/11942-5, 16/11935-9, 09/54035-4, 17/04372-0, 16/07868-4, 13/08135-2)
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, . (17/05899-2, 12/50231-6, 16/11942-5, 16/11935-9, 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)

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