Erin L. Seifert, PhD
Jefferson Alumni Hall, Suite 263A
Philadelphia, PA 19107
Most Recent Peer-reviewed Publications
- Reliance of ER-mitochondrial calcium signaling on mitochondrial EF-hand Ca2+ binding proteins: Miros, MICUs, LETM1 and solute carriers
- Erratum: Muscle uncoupling protein 3 overexpression mimics endurance training and reduces circulating biomarkers of incomplete β-oxidation (FASEB Journal (2013) 27 (4213- 4225) DOI: 10.1096/fj.13-234302)
- The SIRT1 deacetylase protects mice against the symptoms of metabolic syndrome
- Muscle uncoupling protein 3 overexpression mimics endurance training and reduces circulating biomarkers of incomplete β-oxidation
- MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter
PhD, Physiology, McGill University - 2002
Topics in the regulation of energy metabolism in muscle, liver, white and brown adipose tissue, and the CNS
Basic gastrointestinal physiology
Basic cardiopulmonary physiology
The long term goal of research my laboratory is to understand mechanisms that regulate mitochondrial metabolism, and how the resulting changes in mitochondrial metabolism modulate cell function.
Project 1: Elucidating the biological role of mitochondrial Acot2 in highly oxidative tissues.
Mitochondrial beta-oxidation is required for survival in mammals when glucose is limiting. It also strongly influences cellular utilization of other substrates to the extent that the process of beta-oxidation strongly impacts key metabolic parameters. How beta-oxidation exerts this influence is poorly understood. Mitochondria harbor enzymes that use beta-oxidation intermediates as substrates. It is becoming increasingly clear that these enzymes can modulate beta-oxidation, with an impact on overall cellular substrate metabolism. Acyl-CoA thioesterase-2 is a mitochondrial thioesterase, expressed in highly oxidative cells and with a low Km for substrate, that hydrolyzes long-chain fatty-acyl CoA into fatty acid anion and free CoASH; its biological role is unknown, yet it is well positioned to exert important modulation of beta-oxidation. This proposal tests the hypothesis that modulation of beta-oxidation by Acot2 decreases the mitochondrial fatty acyl-CoA-to-CoA ratio without lowering ATP output. We further hypothesize that the changed complement of beta-oxidation intermediates resulting from Acot2 activity facilitates substrate switching and cellular glucose disposal. Acot2 can be deleted either by crossing mice expressing cre recombinase driven by a tissue-specific promoter, or by injecting mice with two floxed Acot2 alleles with an isotype specific adeno-associated virus harboring the cre recombinase gene. Gain-of-function models can be generated using adenovirus or AAV expressing Acot2 cDNA. Experiments are done in whole animals, isolated mitochondria and tissues, and in cultures of primary cells (hepatocytes, cardiomyocytes and skeletal myotubes). Our general approach is to use state-of-the-art and classic tools for functional studies of mitochondrial bioenergetics and substrate metabolism. These studies are complemented by mRNA (qPCR) and protein expression analyses.
Project 2 (in collaboration with Drs. György Hajnóczky and György Csordás): Uncovering the mechanism and biological role of MICU1.
Calcium uptake by mitochondria is fundamental for energy metabolism and cell signaling. There is a long and rich literature on the biophysics and physiology of mitochondrial calcium uptake. However, the molecular entities that govern mitochondrial calcium uptake have only recently begun to be revealed. MICU1 was the first such molecular that was discovered (in 2010). We have shown to it plays a crucial regulatory role for calcium uptake via the calcium uniporter, now known to be formed by MCU. Together with the laboratories of Drs. Hajnóczky and Csordás, we study the mechanisms and biological role of MICU1. My lab is focused on the role of MICU1 in mitochondrial bioenergetics and cellular substrate metabolism.