Title: GDAP1 links Mitochondrial Morphology to Oxidative Homeostasis
Abstract:
GDAP1 (Ganglioside-induced differentiation-associated protein 1) is a novel member of the GST super family of proteins. These proteins canonically bind and conjugate glutathione to electrophilic substrates to facilitate their removal. This classification was reported due to sequence and structural similarities between GDAP1 and other GSTs, but GDAP1 does not bind glutathione. GDAP1 is anchored to the mitochondrial membrane by a C-terminal transmembrane domain, which makes it unsurprising that GDAP1 knockdown cells have effects on the mitochondrial response to oxidative stress. Additionally, GDAP1 overexpression has been shown to induce mitochondrial fragmentation, and play a cytoprotective role against oxidative stress. These results suggest GDAP1 functions in mitochondrial dynamics and cellular redox states, but to date a molecular mechanism to explain these results remains unelucidated.
Because of GDAP1’s observed effect on oxidative homeostasis, it is of interest to screen ligands linked to oxidative stress for GDAP1 binding partners. To this effect, our lab recently described a binding event between GDAP1 and 4HNE, a biomarker of lipid peroxidation. Lipid peroxidation produces reactive oxidative species, which can induce cascades of redox reactions that in turn produce more free radicals. Because of this, a molecular mechanism to detect 4HNE levels in the lipid-rich mitochondrial membrane is advantageous. Characterizing the 4HNE binding site within GDAP1’s structure is pivotal for the elucidation of GDAP1’s molecular function. Further characterization of 4HNE interaction with GDAP1 will allow us to dissect the role of 4HNE binding in GDAP1-dependent mitochondrial morphology.
Vandemark Lab
Friday, October 6th, 2023
12:00PM
Langley A219B