The dysregulation of cellular energy metabolism is a key feature of many of the most prevalent diseases: in type 2 diabetes, mitochondrial function is diminished in muscle and thought to play a key role in insulin resistance;in cancer, tumor cells often exhibit attenuated mitochondrial respiration and increased rates of glycolysis (the Warburg effect);in neurodegenerative diseases such as Huntington's disease and Alzheimer's disease and likely others, mitochondrial respiration is impaired;and in cardiovascular diseases (and perhaps all of the preceding disease as well), dysregulated mitochondrial function can lead to incomplete oxidation and/or accumulation of reactive oxygen species that cause damage to cellular components and may influence apoptosis. Despite the fundamental importance of cellular mitochondrial and glycolytic processes, techniques to quantitate these processes have been cumbersome. Classic methods for measuring mitochondrial fatty acid oxidation involve radiolabeling or the use of the Clark Oxygen Electrode, both of which impose severe limitations on the throughput, versatility, and sample size requirements. The availability of the XF24-3 Extracellular Flux Analyzer (Seahorse Biosciences) overcomes these limitations and provides a mechanism for real time quantitation in a microplate format of several parameters of cellular metabolism, including rates of glycolysis, fatty acid oxidation, and mitochondrial oxidative capacity. The successful use by investigators at UCLA of an XF24 instrument that has been on loan to us has validated the utility of this technology and opened up new directions in research in the areas of nuclear receptors, thermogenesis, cancer, lipid metabolism, and stem cells. There are no other XF24 instruments of any type at UCLA, and to our knowledge, the only other instrument in the greater Los Angeles area is at the University of Southern California, 20 miles away. This application seeks to obtain an XF24-3 instrument to ensure continued access to this technology by investigators at UCLA.

Public Health Relevance

The most prevalent diseases in the United States today-cardiovascular diseases, cancer, type 2 diabetes, neurodegenerative diseases-are characterized by impaired regulation of cellular energy metabolism. The technology available with the Extracellular Flux Analyzer allows measurement of cellular energy pathways in small numbers of cells in real time, without the generation of radioactive or toxic waste products. Studies with this technology may lead to greater understanding of mechanisms underlying human diseases, and potentially to drug discovery and improved treatments.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biomedical Research Support Shared Instrumentation Grants (S10)
Project #
1S10RR026744-01
Application #
7793965
Study Section
Special Emphasis Panel (ZRG1-IMST-C (30))
Program Officer
Levy, Abraham
Project Start
2010-05-13
Project End
2011-05-12
Budget Start
2010-05-13
Budget End
2011-05-12
Support Year
1
Fiscal Year
2010
Total Cost
$167,823
Indirect Cost
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Horibata, Yasuhiro; Ando, Hiromi; Zhang, Peixiang et al. (2016) StarD7 Protein Deficiency Adversely Affects the Phosphatidylcholine Composition, Respiratory Activity, and Cristae Structure of Mitochondria. J Biol Chem 291:24880-24891
Ribas, Vicent; Drew, Brian G; Zhou, Zhenqi et al. (2016) Skeletal muscle action of estrogen receptor ? is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci Transl Med 8:334ra54
Singh, Rajan; Parveen, Meher; Basgen, John M et al. (2016) Increased Expression of Beige/Brown Adipose Markers from Host and Breast Cancer Cells Influence Xenograft Formation in Mice. Mol Cancer Res 14:78-92
Zhang, Jin; Khvorostov, Ivan; Hong, Jason S et al. (2016) UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J 35:899
Vergnes, Laurent; Davies, Graeme R; Lin, Jason Y et al. (2016) Adipocyte Browning and Higher Mitochondrial Function in Periadrenal But Not SC Fat in Pheochromocytoma. J Clin Endocrinol Metab 101:4440-4448
York, Autumn G; Williams, Kevin J; Argus, Joseph P et al. (2015) Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling. Cell 163:1716-29
Shih, Diana M; Yu, Janet M; Vergnes, Laurent et al. (2015) PON3 knockout mice are susceptible to obesity, gallstone formation, and atherosclerosis. FASEB J 29:1185-97
Agrawal, Rahul; Tyagi, Ethika; Vergnes, Laurent et al. (2014) Coupling energy homeostasis with a mechanism to support plasticity in brain trauma. Biochim Biophys Acta 1842:535-46
Aspuria, Paul-Joseph P; Lunt, Sophia Y; Väremo, Leif et al. (2014) Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism. Cancer Metab 2:21
Drew, Brian G; Ribas, Vicente; Le, Jamie A et al. (2014) HSP72 is a mitochondrial stress sensor critical for Parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle. Diabetes 63:1488-505

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