Mitochondrial Targeting of AKAP350C

Abstract

Mitochondria are crucial organelles in cell function and survival. Fission and fusion are very important for maintenance of mitochondrial structure and function, and the dynamics of this remain poorly understood. AKAPs (A‐Kinase Anchoring Proteins) were discovered as anchors that provide localized cAMP/PKA signaling, but they play many other roles as well. Rab32, an AKAP, localizes to mitochondria‐associated membranes of the ER (MAM) and plays a role in mitochondrial dynamics by associating with Drp1, a fission protein. AKAP149 localizes to both the ER and mitochondria and plays a role in stress response in some cell types. We are specifically interested in AKAP350 (also AKAP450/AKAP9/CG‐NAP). We have completed cloning of a new splice variant, AKAP350C, which is ubiquitously expressed and contains a unique 55 amino acid carboxyl terminal sequence. Endogenous AKAP350C associates with the mitochondria. Overexpression of AKAP350C causes the collapse of mitochondria towards the nucleus and localizes near the ER and the collapsed mitochondria. The unique 55 amino acid region contains an amphipathic alpha helix that is required for AKAP350C targeting. Mutations disrupting or deleting this alpha helix abolish targeting to the mitochondria. We hypothesize that AKAP350C anchors PKA and other proteins to mitochondria for regulation of mitochondrial dynamics. Research support is provided by NIH grant RO1DK43405.