NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

Abstract

Little is known about Nima‐related kinase (NEKs), a widely conserved family of kinases that have key roles in cell‐cycle progression. Nevertheless, it is now clear that multiple NEK family members act in networks, not only to regulate specific events of mitosis, but also to regulate metabolic events independently of the cell cycle. NEK5 was shown to act in centrosome disjunction, caspase‐3 regulation, myogenesis, and mitochondrial respiration. Here, we demonstrate that NEK5 interacts with LonP1, an AAA+ mitochondrial protease implicated in protein quality control and mtDNA remodeling, within the mitochondria and it might be involved in the LonP1‐TFAM signaling module. Moreover, we demonstrate that NEK5 kinase activity is required for maintaining mitochondrial mass and functionality and mtDNA integrity after oxidative damage. Taken together, these results show a new role of NEK5 in the regulation of mitochondrial homeostasis and mtDNA maintenance, possibly due to its interaction with key mitochondrial proteins, such as LonP1.

NEK5 activity regulates the mesenchymal and migratory phenotype in breast cancer cells

“…Speci cally, groups have demonstrated NEK5 activity in centrosome disjunction, myogenesis, cell cycle progression, caspase-3 activity, and regulation of mitochondrial functions. Most recently Ferezin et al revealed NEK5 regulates mitochondrial homeostasis and mtDNA maintenance due to potential interactions with mitochondrial proteins [31]. The emergence of more publications with respect to characterizing NEK5 activity demonstrate that the scienti c community recognizes potentially important roles of NEK5 in regulating key biologic processes [21].…”

Nek4 regulates mitochondrial respiration and morphology

“…Nek4 has been previously detected in mitochondrial fractions, and it has been proposed that it may interact with several mitochondrial proteins [10]. Based on this observation, and that other members of the Nek family show effects on mitochondria [13][14][15][16][17][18][19], we decided to investigate the effects of Nek4 on mitochondrial respiration. Nek4.1 Flag expressing cells showed an increase in basal or in ATP-coupled respiration (Fig.…”

The Multifaceted Regulation of Mitochondrial Dynamics During Mitosis

“…(C) MPS1 is recruited to mitochondria through binding to VDAC1 and inhibits the VDAC1-dependent cytochrome c release and subsequent apoptosis ( Zhang et al, 2016 ). (D) NEK5 binds to the AAA+ mitochondrial protease LONP1 and this interaction is correlated with increased mtDNA integrity and ROS resistance, but the exact mechanisms are not yet defined ( Ferezin et al, 2021 ). (E) APC/C CDH 1 ubiquitylates the NADPH-producing enzyme IDH2, leading to elevated ROS production, although no direct mechanism has been described ( Lambhate et al, 2021 ).…”

“…Recently, the Nima-related kinase 5 (NEK5) was added to the list of mitotic kinases that can localize and exert new functions at mitochondria. NEK5 was found to interact and co-localize with the AAA+ mitochondrial Lon protease (LONP1) in proximity ligations assays (PLA) and the authors suggest that a fraction of NEK5 can be localized at the mitochondrial nucleoids through a signaling axis that involves the transcription factor A mitochondrial (TFAM) ( Ferezin et al, 2021 ). The binding between NEK5 and LONP1 was correlated with increased mitochondrial DNA (mtDNA) integrity, resistance to oxidative damage and positive regulation of mtDNA repair genes, however, the exact molecular mechanisms are not yet defined ( Figure 2D ).…”