As you read this, most cells in your body are involved in some form of metabolism – the set of life-sustaining chemical reactions that allow us to digest food, grow, and reproduce. Elegantly, the key chemicals involved in metabolism, referred to as metabolites, are largely conserved across organisms – from the bacteria E. coli to an elephant. These metabolites are produced and consumed dynamically within a cell; however, their excess accumulation can be detrimental to our cells, increasing the risk of disorders such as atherosclerosis, Parkinson, Alzheimer’s, and Cancer.
A recent study published in Journal of Biological Chemistry identifies a novel detoxifier that helps cells get rid of excess of a critical but toxic metabolite – methylgloxal (MG). This detoxifier keeps in check the cellular levels of reactive oxygen species (ROS) – chemically reactive oxygen molecules, which are crucial in cellular signalling, but whose higher levels can damage cell’s structures and biomolecules. “Previous studies have identified other detoxifiers and antioxidants, but their levels are themselves limited when they are needed the most, i.e. in conditions of high ROS. Our study identifies how smart the cells are! They have a backup plans to detoxify themselves, thereby maintaining our health,” says Dr. Patrick D’Silva, the lead author and the team lead to the study, is an Associate Professor at the Biochemistry Department, Indian Institute of Science, Bangalore.
The novel detoxifier identified is named Hsp31, and it protects cells against ‘oxidative stress’ – a cellular imbalance in the levels of ROS against those of detoxifiers – by two mechanisms. First, it maintains the levels of antioxidant GSH and NADPH, both are required to protect the cells against oxidative stress in the cytosol as well as in the mitochondria by reducing the levels of ROS and the toxic metabolite MG. Second, it enters the mitochondria (cell's energy-producing machines) and prevents impending damage to its structure under oxidative stress conditions.
“Hsp1 is a protein found in S. cerevisiae (Baker’s yeast). Later, we also found that DJ-1, a human protein belonging to the similar family as Hsp31, combats oxidative stress in the yeast cells that lacks Hsp31; thereby indicating the functional conservation of this family of proteins,” says K. Bankapalli, the first author on the study.
“We found that similar to yeast Hsp31; human DJ-1 also known to enter the mitochondria under high oxidative stress. Genetic alteration in DJ-1 is known to be involved in development of familial form of Parkinson disease. Our results connect the dots between these two aspects of DJ-1, and offer functional insights as well as a new model system to further-explore the role of DJ-1 in Parkinson disease progression,” says Dr. D’Silva
Another recent study that appeared in Journal of Biological Chemistry found that Hsp31 interferes in the protein folding process, and prevents aggregation of misfolded protein is a hallmark of many neurodegenerative diseases such as Parkinson and Alzheimer’s. “Taken together, these two studies establish how the ThiJ/DJ-1/PfpI family of proteins, of which Hsp31 is a member, resist oxidative stress and prevent protein misfolding, both of which are implicated in neurodegenerative diseases, added K. Bankapalli.
Overall, the authors not only highlight the significance of the ThiJ/DJ-1/PfpI family in oxidative stress resistance in yeast, but also elucidate, for the first time, the underlying molecular mechanisms of the same. Such mechanistic insights pave the way for a better understanding of homeostasis of ROS levels in the cells, and are crucial in charting out an integrated network of proteins that are continuously detoxifying our cells.
Dr Patrick D' Silva is an Assiatant Professor at the Department of Biochemistry, Indian Institute of Science, Bengaluru. He can be contacted at +91-80-2293 2821.