Format

Send to

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

The atypical cadherin fat directly regulates mitochondrial function and metabolic state.

Author information

1
Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
2
Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
3
Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G OA4, Canada.
4
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
5
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G OA4, Canada.
6
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: angus.mcquibban@utoronto.ca.
7
Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: mcneill@lunenfeld.ca.

Abstract

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.

PMID:
25215488
DOI:
10.1016/j.cell.2014.07.036
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center