Peroxisomal fatty acid metabolism in genetic and age-related disorders

Project summary/Abstract Fatty acid oxidation occurs in various compartments of the cell and is a vital source of metabolic energy. One of such cellular compartments- peroxisomes, are central to α- and β- oxidation of fatty acids. Peroxisomes are ubiquitous eukaryotic organelles that form a focal point for multiple metabolic pathways. Lipid metabolism, and in particular, fatty acid transport related to it, depend heavily on peroxisomal membrane proteins that have specifically evolved for such purposes. The ATP-dependent cassette (ABC) transporters of ‘D’ subfamily’ reside in the peroxisomal membrane and are responsible for fatty acid import into the peroxisomes, defects in which process are related to various metabolic disorders. Mutations in ABCD1 cause X-linked adrenoleukodystrophy (X-ALD) which manifests as mild to severe central nervous system (CNS) demyelination. Dysfunction of ABCD3 and/or peroxisome biogenesis factors (PEXs) may cause Zellweger syndrome (ZS), a heterogeneous group of peroxisome assembly disorders. In addition to inherited diseases, reduced peroxisomal function is associated with aging and pathogenesis of age-related acquired diseases like diabetes, neurodegenerative disorders. Key gaps in understanding the function of peroxisomal ABC transporters and their protein-protein interactions in metabolism and disease are due to lack of sufficient structural details, particularly of their conformational plasticity during substrate transport, and how this is compromised during aging and disease. Our goal is to understand the participation of peroxisomal fatty acid metabolism in aging and age-related neurodegenerative diseases, specifically Alzheimer’s disease. This proposal utilizes biochemistry, structural, and cell biology tools to examine changes in levels of peroxisomal fatty acid oxidation, expression of proteins involved, and peroxisome morphology at scales in aging and diseases.