Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic -cells

Trillian Gregg, Sophia M. Sdao, Rashpal S. Dhillon, Jarred W. Rensvold, Sophie L. Lewandowski, David J. Pagliarini, John M. Denu, Matthew J. Merrins

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4 Scopus citations

Abstract

-Cell mitochondria play a central role in coupling glucose metabolism with insulin secretion. Here, we identified a metabolic function of cyclin-dependent kinase 1 (CDK1)/cyclin B1—the activation of mitochondrial respiratory complex I—that is active in quiescent adult -cells and hyperactive in -cells from obese (ob/ob) mice. In WT islets, respirometry revealed that 65% of complex I flux and 49% of state 3 respiration is sensitive to CDK1 inhibition. Islets from ob/ob mice expressed more cyclin B1 and exhibited a higher sensitivity to CDK1 blockade, which reduced complex I flux by 76% and state 3 respiration by 79%. The ensuing reduction in mitochondrial NADH utilization, measured with two-photon NAD(P)H fluorescence lifetime imaging (FLIM), was matched in the cytosol by a lag in citrate cycling, as shown with a FRET reporter targeted to -cells. Moreover, time-resolved measurements revealed that in ob/ob islets, where complex I flux dominates respiration, CDK1 inhibition is sufficient to restrict the duty cycle of ATP/ADP and calcium oscillations, the parameter that dynamically encodes -cell glucose sensing. Direct complex I inhibition with rotenone mimicked the restrictive effects of CDK1 inhibition on mitochondrial respiration, NADH turnover, ATP/ADP, and calcium influx. These findings identify complex I as a critical mediator of obesity-associated metabolic remodeling in -cells and implicate CDK1 as a regulator of complex I that enhances -cell glucose sensing.

Original languageEnglish
Pages (from-to)4656-4666
Number of pages11
JournalJournal of Biological Chemistry
Volume294
Issue number12
DOIs
StatePublished - Mar 22 2019
Externally publishedYes

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    Gregg, T., Sdao, S. M., Dhillon, R. S., Rensvold, J. W., Lewandowski, S. L., Pagliarini, D. J., Denu, J. M., & Merrins, M. J. (2019). Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic -cells. Journal of Biological Chemistry, 294(12), 4656-4666. https://doi.org/10.1074/jbc.RA118.006085