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Nat Commun. 2015 Aug 27;6:8137. doi: 10.1038/ncomms9137.

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

Author information

1
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.
2
Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.
3
Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
4
Science Park Research Division, University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA.
5
Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
6
Department of Nutritional Physiology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.

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.

PMID:
26310111
PMCID:
PMC4552083
DOI:
10.1038/ncomms9137
[Indexed for MEDLINE]
Free PMC Article

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