Editors' ChoiceCell Biology

Mitochondria Are Getting Fat

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Science Signaling  30 Sep 2014:
Vol. 7, Issue 345, pp. ec266
DOI: 10.1126/scisignal.2005963

Fat is a large cadherin that regulates Hippo signaling and the planar cell polarity (PCP) pathway to control tissue growth and patterning. Sing et al. found that Fat also functions in the mitochondria to promote oxidative phosophorylation in Drosophila. Fat bound Ndufv2, a component of complex I of the mitochondrial electron transport chain. Flies in which Ndufv2 was knocked down had morphological defects in the eye and wing consistent with abnormal PCP signaling, and these defects were rescued by transgenic expression of Ndufv2, but not Ndufv2 lacking the iron-sulfur binding region, which has antioxidant properties. Knockdown of Ndufv2 inhibited activation of a PCP pathway transcriptional reporter in the eye and transcription of Hippo pathway target genes in wing imaginal discs. Flies with loss-of-function mutations in the gene encoding Fat (Ft) or in which Ndufv2 was knocked down had abnormal mitochondrial morphology and increased production of reactive oxygen species. In flies, Fat was posttranslationally processed into a fragment that localized to mitochondria and was required for the integrity of complex I. Ft mutant larvae had reduced growth and complex I activity, increased lactate production, and near normal amounts of ATP, indicative of increased glycolysis. Expression of a form of Fat that lacked the Ndufv2-binding region rescued Hippo and PCP signaling defects, but not larval growth reduction or increased lactate production, in Ft mutant flies. Thus, Fat promotes oxidative phosphorylation by directly interacting with complex I of the electron transport chain. Fat is a tumor suppressor in flies and is mutant in some cancers. Because Ft mutation induced glycolysis in the presence of oxygen in flies, similar mutations in human cancers could contribute to the altered metabolism called the Warburg effect.

A. Sing, Y. Tsatskis, L. Fabian, I. Hester, R. Rosenfeld, M. Serricchio, N. Yau, M. Bietenhader, R. Shanbhag, A. Jurisicova, J. A. Brill, G. A. McQuibban, H. McNeill, The atypical cadherin Fat directly regulates mitochondrial function and metabolic state. Cell 158, 1293–1308 (2014). [PubMed]

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