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, Edward M. Mills

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Article number8137
JournalNature communications
Volume6
DOIs
StatePublished - Aug 27 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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