The atypical cadherin Fat directly regulates mitochondrial function to control planar cell polarity and Hippo signaling. Anson D Sing^1,2, Yonit Tzatzkis², Maïlis Bietenhader³, Lacramioara Fabian⁴, Tasha Stoltz³, Robyn Rosenfeld^1,2, Julie A Brill^1,4, G Angus McQuibban³, Helen McNeill^1,2. 1) Molecular Genetics, University of Toronto, Toronto, ON, Canada; 2) Samual Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; 3) Department of Biochemistry, University of Toronto, Toronto, ON, Canada; 4) Collaborative Program in Developmental Biology, Hospital for Sick Children, Toronto, ON Canada.

   The cell adhesion molecule Fat (Ft) is a large cadherin that regulates both the growth restricting Hippo signaling pathway and a form of tissue organization known as planar cell polarity (PCP). How Ft coordinates these is unclear. We have found an unexpected role for Ft in directly regulating mitochondrial function, and demonstrate a critical role for mitochondria in the regulation of PCP and Hippo signaling activity during Drosophila development. We show that the intracellular domain of Ft is cleaved to release a soluble fragment which contains multiple mitochondrial targeting sequences. This domain is imported into mitochondria, where it binds Ndufv2, a core component of mitochondrial Complex I that plays an important role in the regulation of reactive oxygen species (ROS). Loss of Ndufv2 leads to PCP defects in the eye and wing and increased expression of the PCP gene four-jointed as well as the downstream Hippo pathway targets, Crumbs and Expanded. Loss of Ft leads to increased ROS levels, and increased activity of the ROS target JNK. Importantly, expression of a mitochondrially targeted fragment of the Ft cytoplasmic domain reduces ROS and ATP levels. We propose that Ft import into mitochondria impacts Ndufv2-dependent mitochondrial function, which in turn signals further to coordinate Hippo pathway activity and PCP regulation.