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J Biol Chem. 2019 Jan 30. pii: jbc.RA118.006085. doi: 10.1074/jbc.RA118.006085. [Epub ahead of print]

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

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University of Wisconsin-Madison, United States.
University of Wisconsin, United States.
Morgridge Institute for Research.
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Department of Biomolecular Chemistry, William S. Middleton Memorial Veterans Hospital, University of Wisconsin-Madison, United States.


β-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 β-cells and hyperactive in β-cells from obese (ob/ob) mice. In wild-type 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 2-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 β-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 β-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 β-cells, and implicate CDK1 as a regulator of complex I that enhances β-cell glucose sensing.


Complex I; RO-3306; calcium; cyclin B1; cyclin-dependent kinase 1 (CDK1); insulin secretion; mitochondrial metabolism; ob/ob mice; obesity; pancreatic beta cell

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