Grant: Discovery Grants Program - Individual

Iron is a transition metal with critical biological functions. In mammals, most of body iron is present in hemoglobin of red blood cells and mediates oxygen transport. Significant amounts of iron are also present within myoglobin of skeletal muscle cells. Other cell types require smaller quantities of iron for utilization by several metalloproteins. Moreover, four out of five complexes in the mitochondrial electron transport chain contain hemoproteins (such as cytochromes) or iron-sulfur cluster proteins. Thus, iron is essential for cellular energy metabolism. However, while iron is an essential nutrient, in excess it may also become a potent biohazard by promoting oxidative stress and endoplasmic reticulum stress. We have also shown that iron regulates autophagy. Short-term iron overload stimulates autophagy induction through inhibition of the mammalian target of rapamycin complex 1 protein (mTORC1). However, chronic iron overload impairs autophagic flux via attenuating autophagosome lysosome reformation (ALR). Thus, careful control of cellular iron content is critical, and an excess of labile iron has numerous adverse cellular consequences. The work is based on the hypothesis that excess labile iron regulates cellular stress related processes in skeletal muscle which have important metabolic consequences. Specific aims will be: 1. Investigation of the effect of iron overload on mitochondrial dysfunction and insulin resistance and mechanistic role of autophagy/mitophagy and NLRP3 inflammasome activation and 2. Translation of mechanistic cellular analyses to an animal model of iron overload and assessment of the functional consequences of iron-induced changes in autophagy/mitophagy and NLRP3 inflammasome activation in muscle. Both will involve examination of insulin signaling and action, mitochondrial structure and function (fission, fusion, biogenesis), autophagy (in particular mitophagy), oxidative stress and NLRP3 inflammasome. To achieve our goals, both molecular and pharmacological gain and loss of function of key mechanistic targets in each of these processes will be used. The principal biological outcome is insulin resistance and metabolic dysfunction. In summary, iron is an essential trace element required for various critical biological processes. On the other hand, too much iron induces detrimental cellular effects. This research program will examine the iron-induced crosstalk between cellular stress pathways and their functional significance. It provides an excellent framework for trainees to gain research experience and feasibility is outstanding, with a likelihood of several strong manuscript publications. New knowledge resulting from this research program over the next 5 years will have potential implications for the well-being of a large percentage of our Canadian population.