The atypical cadherin fat directly regulates mitochondrial function and metabolic state

Cell. 2014 Sep 11;158(6):1293-1308. doi: 10.1016/j.cell.2014.07.036.


Fat (Ft) cadherins are enormous cell adhesion molecules that function at the cell surface to regulate the tumor-suppressive Hippo signaling pathway and planar cell polarity (PCP) tissue organization. Mutations in Ft cadherins are found in a variety of tumors, and it is presumed that this is due to defects in either Hippo signaling or PCP. Here, we show Drosophila Ft functions in mitochondria to directly regulate mitochondrial electron transport chain integrity and promote oxidative phosphorylation. Proteolytic cleavage releases a soluble 68 kDa fragment (Ft(mito)) that is imported into mitochondria. Ft(mito) binds directly to NADH dehydrogenase ubiquinone flavoprotein 2 (Ndufv2), a core component of complex I, stabilizing the holoenzyme. Loss of Ft leads to loss of complex I activity, increases in reactive oxygen species, and a switch to aerobic glycolysis. Defects in mitochondrial activity in ft mutants are independent of Hippo and PCP signaling and are reminiscent of the Warburg effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cadherins / metabolism*
  • Cell Adhesion Molecules / chemistry
  • Cell Adhesion Molecules / metabolism*
  • Cell Polarity
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / metabolism*
  • Electron Transport Chain Complex Proteins / metabolism
  • Electron Transport Complex I / metabolism
  • Eye / growth & development
  • Genes, Tumor Suppressor
  • Humans
  • MAP Kinase Kinase 4 / metabolism
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • Protein Transport
  • Reactive Oxygen Species / metabolism
  • Wings, Animal / growth & development


  • Cadherins
  • Cell Adhesion Molecules
  • Drosophila Proteins
  • Electron Transport Chain Complex Proteins
  • Reactive Oxygen Species
  • ft protein, Drosophila
  • MAP Kinase Kinase 4
  • Electron Transport Complex I