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J Biol Chem. 2019 Mar 22;294(12):4656-4666. doi: 10.1074/jbc.RA118.006085. Epub 2019 Jan 30.

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

Author information

1
From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism and.
2
Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705.
3
Morgridge Institute for Research and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53715, and.
4
From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism and merrins@wisc.edu.
5
William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.

Abstract

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 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 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.

KEYWORDS:

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

PMID:
30700550
PMCID:
PMC6433064
[Available on 2020-03-22]
DOI:
10.1074/jbc.RA118.006085

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