NSF-BSF: The role of protein phosphorylation in the mitochondrial matrix in determining mitophagic selectivity

Washington University, Saint Louis MO

Investigators

Abstract

Mitochondria, commonly known as ‘the powerhouses of the cell,’ are organelles found in virtually every cell in the human body and in most eukaryotes. Because of their involvement in the production of high energy compounds, many spurious side reactions can produce toxic radicals that can damage the organelle. To mitigate these toxic effects, cells have evolved various strategies to maintain cellular health. One such strategy is termed mitophagy, which promotes the turnover of whole mitochondria. As this turnover occurs at the organellar level, it has been assumed that most mitochondrial proteins undergoing mitophagy would have similar turnover rates, as they are collectively housed within a single organelle. However, recent data demonstrate significant deviation between turnover rates of specific mitochondrial proteins during mitophagy. This leads to a natural question: how is such selectivity achieved? This project will address this question by studying a well-known cellular modification, protein phosphorylation, and its ties to selective mitochondrial protein turnover. The Broader Impacts of the work include its intrinsic merit because all cells harboring these organelles likely use similar mechanisms and several diseases are known to arise when mitophagy is impaired. Our preliminary studies suggest that disrupting the expression of enzymes involved in protein phosphorylation substantially alters the turnover rates of select mitochondrial proteins. This project seeks to provide a mechanistic understanding of how this occurs and to identify potential regulators of this response from yeast to mammalian systems. We will use isotopic labeling and mass spectrometry to track the turnover rates of mitochondrial proteins to map the mitophagic selectivity and determine how it is altered by dysregulated phosphorylation. In parallel, we will test more focused hypotheses to determine the proteins involved in mitophagic selectivity and the molecular mechanisms by which this process occurs in yeast, cultured cells, and mice. Understanding these mechanisms will bolster our ability to address physiological imbalances in mitochondrial function, which broadly lead to morbidity and disease. This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.