Sex-specific modulators of mitochondrial function

• Antragstellerin: Professorin Dr. Vera Regitz-Zagrosek
• Fachliche Zuordnung: Kardiologie, Angiologie
• Förderung: Förderung von 2008 bis 2016
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 60843499

Female mice develop more physiological myocardial hypertrophy than males in response to exercise. Our project investigates the mechanisms leading to these sex differences. We have identified target mitochondrial genes/proteins (PGC-1a, MEF2A, NRF1/2, TFAM) and pathways (PI3K/AKT and p38-MAPK) that are activated only in the hearts of female running mice or in in-vitro studies with cardiomyocytes in the presence of estrogen (E2). The preliminary results suggest that female sex and/or E2/estrogen receptors (ER) strongly influence mitochondrial biogenesis and function. To test this hypothesis, we will analyze the sex-specific regulation of nuclear and mitochondrial key enzymes involved in mitochondrial biogenesis and respiratory function (oxygen consumption, and ATP-content) in a mouse model of exercise-induced myocardial hypertrophy. To analyze the molecular mechanisms by which E2-activated ER regulates mitochondrial biogenesis and function, we will determine the activation of PI3K/AKT and p38-MAPK pathways, and its downstream molecule, peroxisome proliferator-activated receptor-y (PPAR-y) coactivator 1a (PGC-1a), in cultured cells. We will test the transcriptional regulation of myocyte enhancer factor-2 (MEF2A), nuclear respiratory factor (NRF1/2), and mitochondrial transcription factor A (TFAM) that are regulated by PGC-1a. We will investigate the import of nuclear-encoded gene products into the mitochondria. Finally, we will clarify the specific role of ERa and ERß on metabolic changes during the development of myocardial hypertrophy in mouse models with heartspecific deletion of ERa and ERß, respectively. This study will give significant new insight into the protective mechanism of female sex and/or E2/ER on mitochondrial biogenesis and function in HF.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 1054: Sex-specific mechanisms in myocardial hypertrophy
• Beteiligte Person: Dr. Shokoufeh Mahmoodzadeh