Matthew Googins - VanDemark Lab
"GDAP1 is a sensor of mitochondrial damage"
Friday, January 29, 2021
12:10 PM
Virtual Zoom seminar
Abstract:
Mitochondria form an extensive network across, in most cases, the entire cell. These networks adapt their shape and size in response to their cellular environment due to changes in different factors such as nutrient levels, energy demands, hormone signaling, toxins, and the damaging byproducts of metabolism. To maintain this network, the mitochondria utilize a dynamic balance of fission and fusion events. Mitochondrial fission, a focus of this project, is utilized to regulate mitochondrial number during cellular replication and to facilitate the targeted removal of heavily damaged sections of the mitochondrial network during periods of high cellular stress. My research focuses on a poorly characterized player in mitochondrial fission, the Ganglioside-induced Differentiation Associated Protein 1 (GDAP1), that displays unique regulatory activity despite its initial categorization as a glutathione-s-transferase. My previous work determined the core structure of GDAP1 and revealed that while it shares general structural domains with glutathione-S-transferase enzymes, it is incapable of binding glutathione, the key substrate of glutathione-s-transferase enzymes. Building off these findings, I used purified GDAP1 protein constructs to reveal: 1) GDAP1 interacts with the biomarker of lipid peroxidation 4HNE, 2) The observed interaction between GDAP1 and 4HNE requires the Sensory Loop region of GDAP1, 3) This interaction occurs in a two-step system in which GDAP1 rapidly binds 4HNE then is covalently modified by the peroxidated lipid. These results suggest that GDAP1 regulates mitochondrial morphology by functioning as a sensor protein that detects damage on the mitochondria.