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ID 115642
Nowinski, Sara M. The University of Texas at Austin|The University of Utah
Solmonson, Ashley The University of Texas at Austin
Rundhaug, Joyce E. University of Texas
Rho, Okkyung The University of Texas at Austin
Cho, Jiyoon The University of Texas at Austin
Lago, Cory U. National Institutes of Health
Riley, Christopher L. The University of Texas at Austin
Lee, Sunhee The University of Texas at Austin
Kohno, Shohei The University of Texas at Austin
Dao, Christine K. The University of Texas at Austin
Bratton, Shawn B. University of Texas
Wright, Casey W. The University of Texas at Austin
Fischer, Susan M. University of Texas
DiGiovanni, John The University of Texas at Austin
Mills, Edward M. The University of Texas at Austin
Content Type
Journal Article
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.
Journal Title
Nature Communications
Springer Nature
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Medical Sciences