The Versatile Role of FTO in Mitochondria and Hypoxia.

The FTO (fat mass-and obesity-associated) gene variants are recently found to associate with an increased risk of adult obesity worldwide. The exact effects of these FTO variants are controversial and the function of FTO in human obesity are unclear. FTO is an AlkB-like 2- oxoglutarate-dependent nucleic acid demethylase with strong preference for N6-methyladenosine residues in RNA. The physiological target and functions of FTO are currently unclear. Previous studies have shown that FTO may regulate hypothalamic arcuate nucleus and appetite. Later, studies have shown that FTO are involved in multiple aspects of cellular function and organ physiology, such as RNA demethylation, autophagy, and mRNA translation. Data from our group showed that FTO involves in circadian rhythm control, triglyceride metabolism, and renal fibrosis. The exact mechanism how FTO leads to obesity and its link to cardiovascular diseases are currently unknown. During our previous studies of FTO in adipocytes and kidney, we have observed that FTO would translocate from nucleus to mitochondria after hypoxia or nutrient starvation. We further found that FTO has important roles in mitochondria homeostasis, cardiomyocyte apoptosis, energy expenditure, and hypoxic injury. Cardiomyocyte-specific FTO knockout mice had abnormal mitochondrial function, increased apoptosis, and cardiac dysfunction. Cardiomyocyte-specific FTO deficiency in mice also resulted in increased mortality after myocardial infarction and poor left ventricular ejection fraction compared to control mice. To comprehensively characterize the FTO influences, we performed crosslinking immunoprecipitation-RNA sequencing (CLIP-RNA sequencing) to figure out the FTO binding RNAs in cardiomyocyte. Bioinformatic analysis of these RNAs showed increased enhancement of mitochondrial related RNAs in the FTO targets. Based on these results, we hypothesize that the connections between FTO and myocardial functions could be mitochondria. We propose 3 aims to study these novel findings. In aim 1, we want to study the regulations and alterations of FTO in various cardiac diseases and pathophysiological conditions. We will also use cardiomyocyte-specific FTO knockout mice to study their responses to hypoxia, myocardial infarction, and cardiac hypertrophy. In aim 2, we will investigate the connections between FTO and mitochondria, which are previously unexplored. We will focus on mitochondrial transcription factor A and the complex I of mitochondria, which are targets in CLIP-RNA sequencing study. In aim 3, we want to test whether this novel FTO- mitochondrial axis can be used to change the prognosis after myocardial infarction and rescue the mitochondrial dysfunction in FTO deficiency. We hope to open a new angle to treat myocardial infarction and a novel connection between metabolic syndrome and myocardial infarction with this grant application.

Project ID:PG10603-0116
External Project ID:NHRI-EX106-10617SI