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Cellular needs and conditions vary from cell to cell and change within individual cells over time. For example, the required enzymes and energetic demands of stomach cells are different from those of fat storage cells, skin cells, blood cells, and nerve cells. Furthermore, a digestive cell works much harder to process and break down nutrients during the time that closely follows a meal compared with many hours after a meal. As these cellular demands and conditions vary, so do the amounts and...
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The atypical cadherin fat directly regulates mitochondrial function and metabolic state.

Anson Sing1, Yonit Tsatskis2, Lacramioara Fabian3

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Fat cadherins are crucial for mitochondrial function, directly regulating the electron transport chain. Loss of Fat cadherins impairs oxidative phosphorylation and promotes aerobic glycolysis, independent of Hippo and PCP pathways.

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Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Fat (Ft) cadherins are large cell adhesion molecules involved in Hippo signaling and planar cell polarity.
  • Mutations in Ft cadherins are linked to various tumors, presumed to be due to Hippo or PCP pathway defects.

Purpose of the Study:

  • To investigate the novel role of Drosophila Fat cadherins in cellular metabolism.
  • To determine if Fat cadherins directly impact mitochondrial function.

Main Methods:

  • Investigated the subcellular localization of Fat cadherins.
  • Analyzed the impact of Fat cadherin loss on mitochondrial electron transport chain (ETC) activity.
  • Assessed reactive oxygen species (ROS) production and metabolic shifts in ft mutants.

Main Results:

  • Fat cadherins are proteolytically cleaved, releasing a mitochondrial-imported fragment (Ft(mito)).
  • Ft(mito) directly binds to Ndufv2, stabilizing Complex I of the ETC.
  • Loss of Ft leads to impaired Complex I activity, increased ROS, and a metabolic switch to aerobic glycolysis (Warburg effect).

Conclusions:

  • Drosophila Fat cadherins play a direct, non-canonical role in regulating mitochondrial integrity and function.
  • Mitochondrial defects in ft mutants are independent of Hippo and PCP signaling.
  • Fat cadherins represent a potential new target for understanding and treating metabolic dysregulation in cancer.