Fat Cadherins Regulate Mitochondrial Function

RESEARCH HIGHLIGHTS

Nature Reviews Molecular Cell Biology | AOP, published online 15 October 2014; doi:10.1038/nrm3892

METABOLISM Fat cadherins regulate

mitochondrial function NPG

Fat cadherins are large adhesion Ndufv2 and Fat and revealed that, in role in the electron transport chain, molecules that bind to the cadherin Drosophila melanogaster, Ndufv2 is the authors found that CV also Dachsous; the resulting cadherin required for PCP in the eye and wing, requires Ftmito for efficient assembly complex is known to regulate planar and that loss of Ndufv2 activates the and/or stability. This is in line with the cell polarity (PCP) and Hippo signalling. expression of Hippo and PCP signalling interaction of Fat with CG1746. Sing et al. now expand on the functions genes. So, Ndufv2 influences traditional In summary, Sing et al. have revealed a of Fat, revealing that a portion of its Fat functions, but does Fat influence the surprising role for Fat in promoting the cytoplasmic domain translocates to mitochondrial electron transport chain? Sing et al. assembly and function of the electron mitochondria, where it is required The authors found that cleavage of have revealed transport chain, and thus oxidative to maintain a functional electron Fat results in a ~68 kDa cytoplasmic phosphorylation. As tumour metabolism transport chain and thus oxidative fragment (in addition to known cleavage a surprising often switches from oxidative phosphorylation. products) and that this is imported role for Fat phosphorylation to glycolysis, this The mitochondrial electron transport into mitochondria; they call this Ftmito. in promoting suggests that the mutation of Fat (which chain is made up of five large protein Importantly, loss of Fat (and thus Ftmito) occurs in various tumours) may promote complexes, CI–CV. The authors caused a loss of CI activity and switched the assembly tumour progression by altering cellular found that Ndufv2 (nicotinamide the metabolism of mutant larvae from and function metabolism. adenine dinucleotide dehydrogenase oxidative phosphorylation to glycolysis; of the electron Katharine H. Wrighton ubiquinone flavoprotein 2), a core mutant larvae also showed reduced transport component of CI, and CG1746, a growth. Further analysis revealed that ORIGINAL RESEARCH PAPER Sing, A. et al. core component of CV, interact with CI does not assemble in Fat mutants and chain. The atypical cadherin fat directly regulates the cytoplasmic domain of Fat. They that Ftmito is likely to be a component mitochondrial function and metabolic state. Cell, 158, 1293–1308 (2014) characterized the relationship between of the CI holoenzyme. Extending its

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 15 | NOVEMBER 2014