Nek4 and mitofusins interaction and its impact in mitochondria/ER communication and cancer cell fate

Abstract

Nek4 is a serine/threonine kinase that has already been implicated in primary cilia stabilization, DNA damage response, autophagy, and epithelia-mesenchymal transition. The role of Nek4 in cancer cell survival and chemotherapy resistance has also been shown. However, the precise mechanisms by which Nek4 operates remain to be elucidated. Our previous results have shown that Nek4 interacts with both fusion mitochondrial proteins, Mitofusin 1 (Mfn1) and Mitofusin 2 (Mfn2), and that it is located in mitochondria-endoplasmic reticulum contact sites. In addition, Nek4 deficiency causes mitochondrial elongation, reduced cristae morphogenesis, and impaired mitochondrial respiration, which suggests a role in mitochondrial homeostasis. Preliminary results indicate the Nek4 expression changes affect endoplasmic reticulum-mitochondria contacts and phospholipid transference, lipid droplets size, and the phosphorylation state of Mfn1 and Mfn2 proteins. Since Nek4 overexpression is associated with chemotherapy resistance and cancer cells survival, we propose to robustly document the role of Nek4 in the movement of phospholipids and calcium between endoplasmic reticulum and mitochondria, and to demonstrate the operation of Mfn proteins. In addition, we want to demonstrate whether these roles of Nek4 permit to explain why this protein is involved in chemotherapy resistance and cancer cells survival. (AU)