Grant: Project Grant

The mitochondrion is best known for energy metabolism, including respiration, but these functions have been lost many times in anaerobic parasites, resulting in structurally and functionally reduced, but still essential, relict organelles. Most apicomplexans, like the malaria agent Plasmodium, retain normal mitochondrial metabolism; the human pathogen Cryptosporidium is an exception, with reduced mitochondria and anaerobic metabolism that are currently the most promising target for therapeutic interventions. Recently, we showed that many more apicomplexans also have reduced mitochondrial metabolism. These reductions took place multiple times in parallel, and resulted in diverse functional outcomes, which we will use to address fundamental questions about mitochondrial function in these parasites using the following two approaches. (1) We will map the distribution of all known mitochondrial proteins of model apicomplexans across the whole tree of apicomplexans, including parasites with a range of mitochondrial metabolism, and correlate these genomic predictions with observations of ETC activity in live cells. This will identify the factors driving functional reduction and create a clear picture of the implications of the loss of energy metabolism, with the ultimate goal of developing a model for the stepwise loss of function that applies to other reduced parasites. (2) We will create high-resolution 3D structural models of mitochondria with a range of functional reduction, to test correlations between morphology and function and identify cases that defy current models of mitochondrial biogenesis. Overall, this work will relate functional and structural reduction of a key drug target in Cryptosporidium, and provide fundamental insights into the process of mitochondrial biogenesis and metabolic adaptation in a range of anaerobic parasites.