Role of mitochondria-endoplasmic reticulum interaction on maternal inheritance of cardiometabolic syndromes

• Grant number: 20/15412-6
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2021
• End date: March 31, 2024
• 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 researchers: Emerielle Cristine Vanzela ; Fernando Rodrigues de Moraes Abdulkader ; Francisco Rafael Martins Laurindo ; Ricardo Perecin Nociti

Abstract

Growing evidence supports that maternal obesity predispose the offspring to cardiometabolic syndromes. In this respect, previous reports have indicated a possible role for mitochondrial and endoplasmic reticulum (ER) dysfunction in oocytes. In parallel, studies involving humans and mice have found that metabolic disease represses mitofusin 2 (MFN2) expression, further impacting mitochondria-ER contact sites (MERCs) in tissues such as the skeletal muscle and liver. MFN2 is a main regulator of mitochondrial metabolism and insulin signaling, playing a key role in the control of MERCs and mitochondrial dynamics. In our recent work, we have shown that oocyte-specific MFN2 knockout (MFN2 KO) results in offspring with glucose intolerance, which was linked to lower insulinemia and impaired insulin signaling in the liver and skeletal muscle. Furthermore, this offspring phenotype associated to oocytes with abnormal MERCs as well as mitochondrial and ER dysfunction. Given the importance of these findings, here we propose to investigate the impact of maternal obesity on mitochondria-ER interaction in oocytes as well as its consequences to the offspring. Towards this, obesity will be induced in wild-type (WT) and MFN2 KO female mice by use of a high fat diet (HFD). As controls, WT and MFN2 KO females will be fed a normal fat diet (NFD), making up four experimental groups: WT-NFD, WT-HFD, MFN2 KO-NFD e MFN2 KO-HFD. Females will be mated to wild-type males aiming to assess their fertility and analyze progeny as for body weight, food intake, peri-gonadal fat, glucose tolerance, insulin tolerance and cardiac function. Besides, oocytes from progenitor females will be compared as for transcriptome, methylome (nuclear and mitochondrial DNA), lipid droplet content, mitochondria (morphology, number and function), ER (morphology) and MERCs. Further analyses involving gene/protein expression, methylated regions as well as mitochondrial, ER and MERCs function/architecture may be carried out in offspring to explore the molecular mechanism underlying abnormalities. We expect from this work to provide evidence that obesity dysregulates mitochondria-ER interaction in oocytes, which may be linked to the maternal transmission of cardiometabolic disease. (AU)

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)

CHIARATTI, MARCOS R.; CHINNERY, PATRICK F.. Modulating mitochondrial DNA mutations: factors shaping heteroplasmy in the germ line and somatic cells. PHARMACOLOGICAL RESEARCH, v. 185, p. 17-pg., 2022-11-01. (20/15412-6, 17/04372-0)

DOS SANTOS, ANGELICA C.; JOAQUIM, DANIEL C.; NOCITI, RICARDO P.; MACABELLI, CAROLINA H.; SAMPAIO, RAFAEL V.; OLIVEIRA, ALINE S.; PITA, MAICO O.; DE OLIVEIRA, ROBINSON A. M.; DA SILVEIRA, JULIANO C.; MEIRELLES, FLAVIO V.; et al. Micro-vibration results in vitro-derived bovine blastocysts with greater cryotolerance, epigenetic abnormalities, and a massive transcriptional change. Theriogenology, v. 196, p. 13-pg., 2023-01-15. (17/04372-0, 12/50231-6, 20/15412-6)

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)