The Hippo pathway regulates cell proliferation and organ size. Banerjee and colleagues reveal that this pathway also regulates mitochondrial fusion and function in Drosophila melanogaster and in human cells (Gene Dev.http://doi.org/jcq; 2012).

In Drosophila, Hippo negatively regulates transcription by promoting Warts (Wts)-mediated phosphorylation and inhibition of the transcription factor Yorkie (Yki; known as YAP in mammals). The authors found that overexpression of Yki (YAP2), or mutations in Hippo or Wts, increased mitochondrial size. Electron microscopy revealed that expression of YAP2 or Yki elongated mitochondria in human or fly cells, indicating that the Hippo pathway might regulate mitochondrial size. Indeed, microarray analyses followed by chromatin immunoprecipitation (ChIP)-chip arrays showed that Yki bound to enhancer regions and promoted transcription of two key mitochondrial fusion genes, Opa1 and Marf. Antioxidant and electron transport chain complex I genes were also bound by Yki and upregulated on Yki overexpression.

Intriguingly, RNA interference (RNAi)-mediated depletion of Opa1 and Marf blocked tissue growth induced by Yki overexpression, suggesting that these proteins are key effectors of Hippo-mediated regulation of organ size. Yki activity is known to promote cell survival and proliferation; these phenotypes are also linked to mitochondrial fusion. The authors suggest that the Hippo–Yki pathway might stimulate tissue growth, promote cell proliferation and inhibit apoptosis through regulation of mitochondrial fusion.