Gregg 2019 J Biol Chem
|Gregg T, Sdao SM, Dhillon RS, Rensvold JW, Lewandowski SL, Pagliarini DJ, Denu JM, Merrins MJ (2019) Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at Complex I in pancreatic β-cells. J Biol Chem 294:4656-66.|
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.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
• Keywords: Complex I, RO-3306, Calcium, Cyclin B1, Cyclin-dependent kinase 1 (CDK1), Insulin secretion, Mitochondrial metabolism, ob/ob mice, Obesity, Pancreatic beta cell • Bioblast editor: Plangger M • O2k-Network Lab: US WI Madison Denu JM
Labels: MiParea: Respiration Pathology: Diabetes, Obesity
Organism: Mouse Tissue;cell: Islet cell;pancreas;thymus Preparation: Permeabilized tissue Enzyme: Complex I
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, NS, ROX HRR: Oxygraph-2k