Aurora kinase A localises to mitochondria to control organelle dynamics and energy production

Abstract

Many epithelial cancers show cell cycle dysfunction tightly correlated with the overexpression of the serine/threonine kinase Aurora A (AURKA). Its role in mitotic progression has been extensively characterised, and evidence for new AURKA functions emerges. Here, we reveal that AURKA is located and imported in mitochondria in several human cancer cell lines. Mitochondrial AURKA impacts on two organelle functions: mitochondrial dynamics and energy production. When AURKA is expressed at endogenous levels during interphase, it induces mitochondrial fragmentation independently from RALA. Conversely, AURKA enhances mitochondrial fusion and ATP production when it is over-expressed. We demonstrate that AURKA directly regulates mitochondrial functions and that AURKA over-expression promotes metabolic reprogramming by increasing mitochondrial interconnectivity. Our work paves the way to anti-cancer therapeutics based on the simultaneous targeting of mitochondrial functions and AURKA inhibition.

AURKA destruction is decoupled from its activity at mitotic exit but suppresses interphase activity

“…Horn and co-authors had identified the fission factor dynamin-related protein-1 (DRP1) as the target of FZR1 required for its effect on mitochondrial morphology [43]. Here we found that inhibition of AURKA activity completely rescued mitochondrial length and morphology in FZR1 KO cells ( Figure 5E,F), consistent with data showing AURKA to be an upstream regulator of DRP1 [11,13]. Treatment of FZR1 KO cells with an AURKB-specific inhibitor had no effect on mitochondrial length (Supplementary Figure S4).…”

“…Next, we explored how FZR1 affects known AURKA functions in interphase. We and others have previously described a role for AURKA, at physiologically relevant levels of expression, in promoting mitochondrial fission during interphase [11,12], an observation thought to be significant to cellular metabolism given the intimate link between mitochondrial morphology and function [42]. We hypothesized therefore that one consequence of increased interphase AURKA activity should be increased mitochondrial fragmentation in FZR1 KO cells, and indeed mitochondrial fragmentation following FZR1 siRNA treatment of HeLa cells has previously been described [43].…”

“…So, what are the FZR1-sensitive AURKA-dependent events of interphase? Previous studies have shown that AURKA activity acts as an upstream regulator of mitochondrial morphology through RALA-dependent and -independent pathways [11,13]. Mitochondria are highly dynamic organelles that undergo constant fission and fusion to modulate connectivity of the mitochondrial network, allowing the cell to respond to metabolic demands and maintain a healthy mitochondrial network.…”

“…AURKA also has a number of non-mitotic roles that include disassembly of the primary cilium, regulation of myc family transcription factors and response to replication stress [6][7][8][9][10]. We and others recently reported that AURKA constitutively regulates mitochondrial morphology and function [11,12] in addition to a previously reported role in promoting mitochondrial fission in mitosis [13].…”

Optimised FRET pairs and quantification approaches to detect the activation of Aurora kinase A at mitosis

“…AURKA was first described to be a mitotic protein with multiple partners and playing key roles in centrosome maturation, in the regulation of mitotic timing, and in building and stabilising the mitotic spindle (Nikonova et al, 2013). Nonetheless, it is now becoming increasingly clear that AURKA has several roles outside of mitosis, such as favouring neurite outgrowth (Mori et al, 2009), transcriptional activity through the MYC promoter (Zheng et al, 2016), and mitochondrial homeostasis (Bertolin et al, 2018;Grant et al, 2018). In this light, it is still unknown whether mitotic and non-mitotic functions of AURKA are made possible by a single, recycling pool of the kinase or by different pools at specific subcellular locations.…”