Maternal inheritance of mitochondrial and endoplasmic reticulum abnormalities

Abstract

Growing evidence suggests that maternal obesity predisposes offspring to cardiometabolic disorders. In this context, previous studies point to a possible role of mitochondrial and endoplasmic reticulum (ER) dysfunction in the oocyte. In parallel, human and mouse studies report that metabolic diseases mitigate mitofusin2 (MFN2) expression, impacting mitochondria-ER contact sites (MERCs) in skeletal muscle and liver. MFN2 is a potent modulator of the mitochondrial metabolism and insulin signaling, playing a key role in the regulation of MERCs and mitochondrial dynamics. In a previous work, oocyte-specific knockout of MFN2 resulted in progeny with glucose intolerance, which linked to reduced insulinemia and deficient insulin signaling in liver and skeletal muscle. Furthermore, this phenotype was associated in the progenitor oocytes with changes in MERCs as well as mitochondrial and ER dysfunction. Given the importance of these findings, the present work aims to investigate the impact of maternal obesity and oocyte-specific MFN2 deletion on mitochondria and ER in the skeletal muscle of the progeny. Therefore, wild-type (WT) and oocyte-specific MFN2 knockout (MFN2 KO) females will be induced to obesity by use of a high-fat diet (HFD). As a control, 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 and MFN2 KO-HFD. Females will be mated to WT males for analysis by transmission electron microscopy of progeny gastrocnemius muscle regarding the architecture of mitochondria and MERCs. Quantitative PCR and western blotting will also be used for analysis of mitochondrial abundance and the expression of factors implicated in the regulation of mitochondrial dynamics and MERCs. Functional analyses of mitochondria will be carried out depending on the results found. We expect from this work to provide evidence that maternal obesity results in mitochondrial and ER abnormalities in the progeny skeletal muscle, possibly contributing to the development of cardiometabolic diseases.