Pho88, a protein at the crossroads of phosphate transport, mitochondrial dynamics and mitophagy
Description: Mitochondria are central organelles that provide eukaryotic cells with the chemical energy required for life sustaining metabolism. As such, mitochondria govern cellular life and death, and dysfunctional mitochondrial dynamics have been linked to numerous human diseases, e.g., cancer, neurodegeneration and metabolic disorders. Mitochondria are dynamic organelles that constantly move, divide and fuse in response to changing cellular requirements. The remodeling of mitochondrial architecture facilitated by division and fusion is critical for proper mitochondrial function, such as the inheritance of organelles during cytokinesis, bioenergetic oxidative phosphorylation reactions, cellular metabolism, and the execution of programmed cell death. Dynamin-related GTPases have been identified as the central and evolutionary conserved components of the molecular machinery governing mitochondrial dynamics. However, there remain large holes in our understanding of these fundamental cellular processes.
We have preliminary data that demonstrates a link between phosphate homeostasis and mitochondrial dynamics. We have identified the phosphate transporter Pho88 to be able to shift the balance between mitochondrial division and fusion, and have shown that it is required for mitophagy, the selective degradation of mitochondria via autophagy. The main goal of this project is to understand how Pho88 re-localizes from the endoplasmic reticulum to mitochondria, and how this re-localization impacts mitochondrial architecture, mitophagy and cell death. Our experiments will test the hypothesis that Pho88 represents a molecular bridge between mitochondrial dynamics and phosphate homeostasis and/or phosphate availability. We will employ the simple and genetically tractable yeast Saccharomyces cerevisiae, which is a well-characterized and major model organism to study mitochondrial dynamics. Using a combination of cell biology, genetics, biochemistry, proteomics and lipidomics, our data will reveal molecular mechanisms that are not only important for basic science but also add to our understanding of human disease.
Funder: Vetenskapsrådet
Amount: SEK 3,200,000
Funding type: research
Funder scheme: Project grant
Start date: 2016-01-01
End date: 2019-12-31
Investigator: Sabrina Büttner
Institution: Stockholm University
Funded outputs count: 23
Funder award ID: 2015-05468
OpenAlex ID: G383845785