Grant: Project Grant

Metabolic flexibility is a key feature of cellular function; it consists in switching back and forth between glucose and fat oxidation, matching the energetic and biosynthetic needs of the cell to the type and amount of nutrients that are available. For the cell, the ability to adapt to metabolic shifts means survival; but for the mitochondrion, which is the powerplant of the cell, this consists in adapting to periodic shifts in carbon combustion rates and to switches between alternative fuels according to nutrients availability. The goal of our research program is to understand how mitochondria secure metabolic flexibility to the cell. The function of the mitochondrion depends on its unique ultrastructure: the cristae and the MERCs, which are the sites of contact with another organelle, the endoplasmic reticulum. Recently, we published a paper in PNAS, the prestigious journal of the US National Academy of Sciences, showing that the cristae and the MERCs change in shape, number, size, and thickness every time that the hepatic metabolism switches gear (which is something that happens after a meal or upon feeling hungry). This study gave us the idea is that when metabolism shifts, a nutrients-sensing pathway instructs mitochondria to adapt their functional output to the needs of the cell by activating a molecular mechanism that simultaneously changes cristae and MERCs structure, which, together, control mitochondrial bioenergetics. In other words, we hypothesize that changes in the organelle's ultrastructure are behind its ability to secure metabolic flexibility to the cell, and failure to do so is central to the development of metabolic syndromes and diseases. To address this model we shall: 1) identify the nutrients-sensing pathway that activates MERCs and cristae remodeling in vivo; 2) reveal the mechanisms governing mitochondrial ultrastructure remodeling during metabolic shifts; 3) link MERCs and cristae dynamics to liver physiology and disease