Does autophagic deficiency increases accumulation of NZB Mitochondrial DNA in the liver?

• Grant number: 18/20028-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2019
• End date: January 31, 2020
• Field of knowledge: Biological Sciences - Genetics - Animal Genetics
• Principal Investigator: Marcos Roberto Chiaratti
• Grantee: Katiane Tostes
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Associated research grant: 17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease, AP.TEM

Abstract

Mitochondrial dynamics regulates several characteristics of mitochondria such as architecture, activity, transport, interaction with other organelles, inheritance and degradation. Important defects in mitochondrial dynamics typical of aging, for example in the autophagic pathway, result in the accumulation of damaged mitochondria and development of pathologies in mice and humans. This is especially relevant for postmitotic tissues with elevated metabolism and mitochondrial turnover, such as the liver. As a consequence, hepatic mitochondria accumulate damage and mutations in mitochondrial DNA (mtDNA) with aging. Some hypotheses have already been elaborated in an attempt to explain this phenotype, but still lack evidence. In this sense, the main goal of this project is to evaluate the role of autophagy in the accumulation of mutant mtDNA in the liver. For this, heteroplasmic mice containing mtDNA of two mouse lineages, C57BL/6 (B6) and NZB/BINJ (NZB) will be used. It is known that mtDNA NZB results in mitochondrial dysfunction, and when present in heteroplasmy it causes cognitive and behavioral disorders. In addition, the level of mtDNA NZB increases in the liver with age. To investigate the role of autophagy in NZB mtDNA accumulation, we will perform a knock out of the Atg7 gene, which regulates a fundamental stage of autophagic activation. Due to the perinatal lethality of Atg7 deletion, we will carry out the conditional knockout of this gene in the liver by use of floxed Atg7 mice and cre recombinase expression regulated by the Alb (albumin) gene promoter. Hepatic levels of mtDNA NZB from animals with 35-37 and 100-102 days of age, from the wild type and the knockout groups, will be compared to the NZB mtDNA levels in the tail (10-12 days of age). With this, we expect to investigate the hypothesis that autophagy regulates the accumulation of mutant mtDNA in the liver.

Scientific publications

(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, DEC 2020. (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)

TOSTES, KATIANE; DOS SANTOS, ANGELICA C.; ALVES, LINDOMAR O.; BECHARA, LUIZ R. G.; MARASCALCHI, RACHEL; MACABELLI, CAROLINA H.; GREJO, MATEUS P.; FESTUCCIA, WILLIAM T.; GOTTLIEB, ROBERTA A.; FERREIRA, JULIO C. B.; et al. Autophagy deficiency abolishes liver mitochondrial DNA segregation. AUTOPHAGY, v. 18, n. 10, p. 12-pg., 2022-02-27. (19/25049-9, 16/07868-4, 17/04372-0, 18/20028-0, 17/05899-2, 12/50231-6, 20/15412-6)