TY - JOUR
T1 - Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic -cells
AU - Gregg, Trillian
AU - Sdao, Sophia M.
AU - Dhillon, Rashpal S.
AU - Rensvold, Jarred W.
AU - Lewandowski, Sophie L.
AU - Pagliarini, David J.
AU - Denu, John M.
AU - Merrins, Matthew J.
N1 - Publisher Copyright:
© 2019 American Society for Biochemistry and Molecular Biology Inc. All Rights Reserved.
PY - 2019/3/22
Y1 - 2019/3/22
N2 - -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.
AB - -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.
UR - http://www.scopus.com/inward/record.url?scp=85063660172&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.006085
DO - 10.1074/jbc.RA118.006085
M3 - Article
C2 - 30700550
AN - SCOPUS:85063660172
SN - 0021-9258
VL - 294
SP - 4656
EP - 4666
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 12
ER -