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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.

Author information

1
University of Wisconsin-Madison, United States.
2
University of Wisconsin, United States.
3
Morgridge Institute for Research.
4
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.

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 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.

KEYWORDS:

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

PMID:
30700550
DOI:
10.1074/jbc.RA118.006085
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