IMPC: Investigation into the function of pyrroline 5-carboxylate reductase 1 (PYCR1) in metabolic homeostasis

The metabolism of cells is tightly controlled so that nutrients taken up from the outside are used efficiently, and only when necessary. This level of control requires checks and balances that link different metabolic activities - for example the metabolism of sugars and amino acids - ensuring normal cell function. One key aspect of metabolism that is critical for normal cell function is known as redox homeostasis - the balance of pro- and anti-oxidants. An aberrant redox status in a cell can lead to its malfunction and drive changes that may result in disease. Some diseases known to be linked to changes in redox homeostasis are cancer, diabetes and chronic inflammation.

We have recently discovered that our understanding of how the enzyme known as pyrroline 5-carboxylate reductase 1 (PYCR1) functions, may be incorrect. This enzyme is responsible for making an amino acid called proline, but in doing so, it influences the redox state of the cell. Although we've previously thought that the main function of this enzyme was to make proline, it may actually be to react to changes in cell redox to try and keep the metabolism of the cell healthy.

This proposal will provide the first physiological information to support our hypothesis - that PYCR1 is a critical enzyme in the response to changes in the redox environment of cell. The data that comes out of this research will provide the building blocks - both data and animal model - for a bigger grant application to investigate this hypothesis more fully.

Maintaining physiological redox homeostasis is essential for a long health span. Both acute and chronic perturbations in this homeostasis manifest as diseases such as cancer, diabetes and morbidities such as premature ageing. Although some mechanisms of maintaining cellular redox homeostasis are well-described, there are significant fundamental systems that are as yet unclear.

Pyrroline 5-carboxylate reductase 1 (PYCR1) is a mitochondrial enzyme that synthesises proline with the concomitant oxidation of NADH. Preliminary data leading to this application suggest that through its contribution to maintenance of the mitochondrial NAD+:NADH ratio, PYCR1 forms part of the cellular response to redox stress. There are also initial data to suggest that loss of Pycr1 may alter glucose and lipid homeostasis in normal conditions. However, there are currently insufficient data currently to support a strong hypothesis-driven project to define the function of Pycr1 in health and disease.

The investigations in this project will define the overall physiology of the Pycr1 knock-out mouse, physiological metabolic parameters (e.g. food/water intake, oxygen consumption), the cardiorespiratory response to changes in oxygen tension, and the biochemistry of the blood. Additionally, we will perform initial studies to determine whether loss of Pycr1 alters the physiology of major metabolic tissues, including muscle, liver and adipose tissue. Through these studies, this pump priming award will provide fundamental metabolic information to support a future grant application to the BBSRC to investigate the function of PYCR1 in maintaining 'healthy' redox homeostasis.