The active form of the metabolic sensor: AMP-activated protein kinase (AMPK) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis.
The metabolic rheostat AMP-activated protein kinase (AMPK) is unexpectedly required for proper cell division and faithful chromosomal segregation during mitosis. Although it is conceptually attractive to assume that AMPK-interpreted microenvironmental bioenergetics may strictly engage cell's energy status, cell grow, and cell division to avoid that energy stresses trigger cell death, the ultimate framework of AMPK activity towards chromosomal and cytoskeletal mitotic regulation is a question that remains unanswered. We herein reveal that the active form of the alpha-catalytic AMPK subunit (P-AMPKalpha(Thr172))-but not its total form (AMPKalpha)-transiently associates with several mitotic structures including centrosomes, spindle poles, the central spindle midzone and the midbody throughout all of the mitotic stages and cytokinesis in human cancer-derived epithelial cells. At prophase, P-AMPKalpha(Thr172) associates with the two asters of microtubules that begin to nucleate from mature centrosomes. The overlapping localization of P-AMPKalpha(Thr172) with the mitotic centrosomal Aurora-A kinase is also apparent on the microtubules near the spindle poles in metaphase and in early anaphase. This Aurora A-like centrosomal localization of P-AMPKalpha(Thr172) cannot be detected following chromatid separation following anaphase-telophase transition. Rather, toward the end of anaphase and in telophase P-AMPKalpha(Thr172) reactivity exhibited a similar but not identical localization to that occupied by the bona fide chromosomal passenger proteins INCENCP and Aurora-B. This localization of P-AMPKalpha(Thr172) at the central spindle and midbody persisted during the furrowing process and, at the completion of telophase, staining of P-AMPKalpha(Thr172) as doublet was apparent on either side of the midbody within the intercellular cytokinetic bridge. An identical mitotic geography of P-AMPKalpha(Thr172) was observed in cancer cells lacking the AMPK kinase LKB1, in non-cancerous human epithelial cells, and in mouse fibroblasts. The active form of AMPKalpha bound to the mitotic apparatus may physically tether the bioenergetic state of a cell to the four-dimensional regulation of the chromosomal and cytoskeletal mitotic events, thus suggesting a putative cytokinetic suppressor function. In this newly discovered scenario, we suggest a primordial mitotic role for the alpha catalytic AMPK subunit in the eukaryotic evolutionary process as it may ensure, at the cell level, an exquisite coordination between sensing of energy resources and the fundamental biological process of genome division.
Vazquez-Martin
Alejandro
A
Catalan Institute of Oncology (ICO) and Girona Biomedical Research Institute (IdIBGi), Dr. Josep Trueta University Hospital, E-17007 Girona, Catalonia, Spain.
Oliveras-Ferraros
Cristina
C
Menendez
Javier A
JA
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000705:Anaphase / Q000502:physiology; D000818:Animals; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D018385:Centrosome / Q000201:enzymology*; D020090:Chromosome Segregation; D048749:Cytokinesis; D006801:Humans; D051379:Mice; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D008941:Spindle Apparatus / Q000201:enzymology* / Q000648:ultrastructure; D013692:Telophase / Q000502:physiology; D014404:Tubulin / Q000378:metabolism
D014404:Tubulin; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human