Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis

Sara M. Nowinski, Ashley Solmonson, Joyce E. Rundhaug, Okkyung Rho, Jiyoon Cho, Cory U. Lago, Christopher L. Riley, Sunhee Lee, Shohei Kohno, Christine K. Dao, Takeshi Nikawa, Shawn B. Bratton, Casey W. Wright, Susan M. Fischer, John DiGiovanni and Edward M. Mills ()
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Sara M. Nowinski: College of Pharmacy, The University of Texas at Austin
Ashley Solmonson: Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin
Joyce E. Rundhaug: University of Texas MD Anderson Cancer Center
Okkyung Rho: College of Pharmacy, The University of Texas at Austin
Jiyoon Cho: College of Pharmacy, The University of Texas at Austin
Cory U. Lago: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health
Christopher L. Riley: Institute for Cellular and Molecular Biology, The University of Texas at Austin
Sunhee Lee: Institute for Cellular and Molecular Biology, The University of Texas at Austin
Shohei Kohno: College of Pharmacy, The University of Texas at Austin
Christine K. Dao: College of Pharmacy, The University of Texas at Austin
Takeshi Nikawa: Institute of Health Biosciences, Tokushima University Graduate School
Shawn B. Bratton: University of Texas MD Anderson Cancer Center
Casey W. Wright: College of Pharmacy, The University of Texas at Austin
Susan M. Fischer: University of Texas MD Anderson Cancer Center
John DiGiovanni: College of Pharmacy, The University of Texas at Austin
Edward M. Mills: College of Pharmacy, The University of Texas at Austin

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling.

Date: 2015
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DOI: 10.1038/ncomms9137

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