Dataset Information

Mitoenergetic Dysfunction Triggers a Rapid Compensatory Increase in Steady-State Glucose Flux.

ABSTRACT: ATP can be produced in the cytosol by glycolytic conversion of glucose (GLC) into pyruvate. The latter can be metabolized into lactate, which is released by the cell, or taken up by mitochondria to fuel ATP production by the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) system. Altering the balance between glycolytic and mitochondrial ATP generation is crucial for cell survival during mitoenergetic dysfunction, which is observed in a large variety of human disorders including cancer. To gain insight into the kinetic properties of this adaptive mechanism we determined here how acute (30 min) inhibition of OXPHOS affected cytosolic GLC homeostasis. GLC dynamics were analyzed in single living C2C12 myoblasts expressing the fluorescent biosensor FLII(12)Pglu-700??6 (FLII). Following in situ FLII calibration, the kinetic properties of GLC uptake (V1) and GLC consumption (V2) were determined independently and used to construct a minimal mathematical model of cytosolic GLC dynamics. After validating the model, it was applied to quantitatively predict V1 and V2 at steady-state (i.e., when V1 = V2 = Vsteady-state) in the absence and presence of OXPHOS inhibitors. Integrating model predictions with experimental data on lactate production, cell volume, and O2 consumption revealed that glycolysis and mitochondria equally contribute to cellular ATP production in control myoblasts. Inhibition of OXPHOS induced a twofold increase in Vsteady-state and glycolytic ATP production flux. Both in the absence and presence of OXPHOS inhibitors, GLC was consumed at near maximal rates, meaning that GLC consumption is rate-limiting under steady-state conditions. Taken together, we demonstrate here that OXPHOS inhibition increases steady-state GLC uptake and consumption in C2C12 myoblasts. This activation fully compensates for the reduction in mitochondrial ATP production, thereby maintaining the balance between cellular ATP supply and demand.

SUBMITTER: Liemburg-Apers DC

PROVIDER: S-EPMC4601044 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Mitoenergetic Dysfunction Triggers a Rapid Compensatory Increase in Steady-State Glucose Flux.

Liemburg-Apers Dania C DC Schirris Tom J J TJ Russel Frans G M FG Willems Peter H G M PH Koopman Werner J H WJ

Biophysical journal 20151001 7

ATP can be produced in the cytosol by glycolytic conversion of glucose (GLC) into pyruvate. The latter can be metabolized into lactate, which is released by the cell, or taken up by mitochondria to fuel ATP production by the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) system. Altering the balance between glycolytic and mitochondrial ATP generation is crucial for cell survival during mitoenergetic dysfunction, which is observed in a large variety of human disorders including c ...[more]

PMID: 26445438

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Project description:OBJECTIVE: To evaluate the capacity of a rapid T2 weighted three-dimensional (3D) sequence to diagnose foetal brain abnormalities by comparing the results with current two-dimensional (2D) methods. We have also made assessments of the estimates of energy deposition using those methods. METHODS: 50 pregnant females were included in this study under the guidance of the institutional review board. All their foetuses had suspected brain abnormalities on antenatal ultrasonography or were at increased risk of a brain malformation based on the results of an earlier pregnancy. All the foetuses had a routine MR protocol that includes three orthogonal plane single-shot fast-spin echoes and 2D steady-state sequences. In addition, a 3D rapid steady-state sequence of the foetal brain was performed (acquisition time approximately 40 s), and the standard and 3D sequences were reported independently and the results were compared. The specific absorption rate (SAR) predicted by the scanner was recorded in 12 cases in order to estimate the energy deposited by the three sequences. RESULTS: The 3D rapid steady-state sequences produced diagnostic-quality images in 41/50 (82%) cases. All the failures were in second trimester foetuses (9/26-35% failure rate). There was a discrepancy between the standard report and findings using the 3D sequence in 2/41 of the foetuses with good-quality 3D imaging. The predicted SAR deposition of the 3D steady-state sequences was comparable with the single-shot fast-spin echo sequence. CONCLUSION: Our initial assessments of a 3D rapid steady-state sequence to image the foetus are encouraging in terms of diagnostic information and acceptable energy deposition values. The high failure rate in second trimester foetuses probably relates to the greater mobility of the smaller foetuses, and improvements in the 3D sequence are required in terms of reduced acquisition time and higher resolution. ADVANCES IN KNOWLEDGE: We have shown that 3D T2 weighted images of the foetal brain can be acquired in a clinical setting and produce diagnostic-quality imaging in a high proportion of cases. The success rate in acquiring diagnostic-quality images is related to gestational age. Good-quality images were obtained in all third trimester foetuses but only in approximately two-thirds of second trimester foetuses. This probably reflects the problem of the greater mobility of second trimester foetuses. 3D T2 weighted acquisitions have great potential for improving the antenatal diagnosis of foetal brain abnormalities and may reduce the time that a pregnant female needs to spend on the MR scanner.

Dataset Information

Mitoenergetic Dysfunction Triggers a Rapid Compensatory Increase in Steady-State Glucose Flux.

Publications

Mitoenergetic Dysfunction Triggers a Rapid Compensatory Increase in Steady-State Glucose Flux.

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