Role of mitochondria-endoplasmic reticulum interaction on maternal inheritance of cardiac dysfunction

Abstract

Cardiopathies are a major determinant of deaths worldwide and several studies support that maternal obesity predisposes the offspring to cardiovascular diseases. Among the factors contributing to this maternal effect, growing evidence indicates a possible role for mitochondrial and endoplasmic reticulum (ER) dysfunction in oocytes. For instance, obese mice harbor oocytes with mitochondrial and ER dysfunction, alterations which are passed on to the next generation and associate with cardiometabolic diseases. In addition, studies in humans and mice have found that metabolic diseases repress mitofusin 2 (MFN2) expression, further impacting mitochondria-ER contact sites (MERCs) in various tissues. MFN2 is a main regulator of mitochondrial metabolism, playing a key role in the regulation of MERCs, calcium signaling and mitochondrial dynamics. Cardiomyocyte-specific MFN2 deficiency leads to pleiomorphic, swollen and dysfunctional mitochondria, which is followed by deterioration of cardiac function involving cardiomyocyte hypertrophy, higher left ventricular mass and altered systolic function. In our recent work, we have shown that oocyte-specific MFN2 knockout (MFN2 KO) results in offspring with glucose intolerance, which was linked to oocytes with abnormal MERCs as well as mitochondrial and ER dysfunction. In the present work, we propose to investigate the impact of maternal obesity on cardiac function of offspring born to MFN2 KO female mice. 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, body mass index, food intake and cardiac function. Further cardiac analyses involving epigenetic marks, gene/protein expression as well as mitochondrial, ER and MERCs function/architecture will be carried out in offspring. We expect from this work to provide evidence that obesity, associated with impaired mitochondria-ER interaction in oocytes, leads to cardiac dysfunction in the offspring.