Summary of Broad Institute MLPCN Small Molecule Modulators for Redox Regulation in the Mitochondrial Intermembrane Space Project
Keywords: Mitochondria, biogenesis, protein import, intermembrane space, FAD, sulfhydryl oxidase, ALR, Erv1 ..more
Keywords: Mitochondria, biogenesis, protein import, intermembrane space, FAD, sulfhydryl oxidase, ALR, Erv1
Carla Koehler,UCLA,Los Angeles,CA,firstname.lastname@example.org,310-794-4834
Deepa Dabir,UCLA,Los Angeles,CA,email@example.com
Samuel Hasson,UCLA,Los Angeles,CA,firstname.lastname@example.org
Defects in mitochondrial assembly impact a wide range of diseases from degenerative muscle and neural diseases to cancer. The mitochondrion is not only important for the production of energy but plays an important role in other aspects such as intermediary metabolism and signaling. The mitochondrion contains an inner membrane and outer membrane that separate the matrix from the intermembrane space. The intermembrane space is an important compartment because it houses molecules such as cytochrome c and apoptosis inducing factor (AIF) that are released during apoptosis. Recently, the intermembrane space has been implicated in diseases such as Parkinson's disease by the presence of the kinase PINK1. In addition, we continue to make new discoveries about the function of this compartment. Specifically, we have identified a new import pathway in the intermembrane space that is redox regulated, indicating that oxidation-reduction reactions are unexpectedly housed in this compartment. Key components include the sulfhydryl oxidase Erv1 and cytochrome c, which form a complex in the intermembrane space. A recent study has demonstrated a role of ALR, the human Erv1 homolog, in Autosomal-Recessive Myopathy. Both Erv1 and ALR belong to a class of FAD dependent sulfhydryl oxidases that have essential roles in the mitochondrion.
The goal of this project is to develop small molecule modulators that affect the mitochondrial sulfhydral oxidase pathways by using purified components, specifically ALR, in an in vitro assay.