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Principal Investigator: Amit Joshi
Organization: UNIVERSITY OF TENNESSEE KNOXVILLE
Fiscal Year: 2024
Award: $377,002
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
Intracellular membrane-bound organelles are a hallmark of all eukaryotic cells. Understanding how cells
generate different organelles remains one of the central problems in cell biology. Some organelles, like the
endoplasmic reticulum (ER) and mitochondria, are self-generating whereas other organelles can be
generated de novo. The ER plays a central role in organelle biogenesis. Even though the ER is a single
continuous membrane that extends from the outer nuclear envelope into the periphery of the cell, there are
discrete regions in the ER membrane called ER subdomains. Nascent peroxisomes and lipid droplets (LDs)
form at specialized ER subdomains. Remarkably, little is known about these ER subdomains and their role
in regulating organelle biogenesis. The goal of our research is to determine the mechanisms of peroxisome
and LD biogenesis by detailed characterization of the discrete ER subdomains using S. cerevisiae and
mammalian cell culture. Previously, we identified a family of reticulon-like ER membrane tubulating proteins,
Pex30 in yeasts and multiple C2 domains containing transmembrane proteins, MCTP1 and MCTP2, in
higher eukaryotes. We demonstrated that both Pex30 and MCTPs are localized at discrete ER subdomains
where nascent pre-peroxisomal vesicles and LDs are formed. Based on these findings, we proposed to
identify the proteins and lipids enriched at the specialized ER subdomains using unbiased as well as
candidate-based approaches. We will then test the effects of modulating the functions of candidate proteins
and lipids on the formation, abundance, morphology, and distribution of peroxisomes and LDs. Investigating
the mechanistic details of peroxisomes and LDs biogenesis from these ER subdomains is not only
important for understanding basic principles of cell biology but also has critical medical implications. Several
life-threatening neurological disorders including Zellweger syndrome associated with peroxisomal defects
and metabolic disorders such as type 2 diabetes and fatty liver disease caused due to LD defects have no
cure. Determining the mechanisms of organelle biogenesis will have implications in understanding the
pathophysiology of these disorders and provide us hints for potential therapeutic targets.
Terms: <Adult-Onset Diabetes Mellitus><Baker's Yeast><Binding><Biogenesis><Brewer's Yeast><C2 Domain><Cell Body><Cell Culture Techniques><Cells><Cellular biology><Cerebro-Hepato-Renal Syndrome><Cerebrohepatorenal Syndrome><Defect><Disease><Disorder><Dysfunction><Endoplasmic Reticulum><Ergastoplasm><Eukaryota><Eukaryote><Eukaryotic Cell><Family><Fatty Liver><Functional disorder><Goals><Integral Membrane Protein><Intracellular Membranes><Intrinsic Membrane Protein><Ketosis-Resistant Diabetes Mellitus><Life><Lipids><Lipodystrophy><Liver Steatosis><Mammalian Cell><Maturity-Onset Diabetes Mellitus><Medical><Membrane><Metabolic Diseases><Metabolic Disorder><Mitochondria><Molecular Interaction><Morphology><NIDDM><Nervous System Diseases><Nervous System Disorder><Neurologic Disorders><Neurological Disorders><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear Envelope><Nuclear Membrane><Organelles><Origin of Life><Physiopathology><Play><Proteins><Research><Role><S cerevisiae><S. cerevisiae><Saccharomyces cerevisiae><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><T2 DM><T2D><T2DM><Testing><Thesaurismosis><Transmembrane Protein><Transmembrane Protein Gene><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vesicle><Work><Yeasts><Zellweger Disease><Zellweger Syndrome><adult onset diabetes><cell biology><cell culture><cell cultures><congenital iron overload><fatty liver disease><hepatic steatosis><hepatosteatosis><ketosis resistant diabetes><maturity onset diabetes><membrane structure><metabolism disorder><mitochondrial><neurological disease><pathophysiology><peroxisome><social role><therapeutic target><type 2 DM><type II DM><type two diabetes>