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Koopman 2015 Abstract MiP2015

From Bioblast
Mitoenergetic dysfunction triggers a rapid compensatory increase in steady-state glucose flux.


Liemburg-Apers D, Schirris T, Russel F, Willems P, Koopman WJ (2015)

Event: MiP2015

ATP can be produced in the cytosol by glycolytic conversion of glucose (GLC) into pyruvate (PYR). The latter can be metabolized into lactate (LAC), which is released by the cell, or taken up by mitochondria to fuel ATP production by the tricarboxylic acid (TCA) 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 [1].

To gain insight into the kinetic properties of this adaptive mechanism we here determined how acute (30 min) inhibition of OXPHOS affected cytosolic GLC homeostasis. GLC dynamics were analyzed in single living C2C12 myoblasts expressing the fluorescent biosensor FLII12Pglu-700¡δ6 (FLII, [2]). 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 [3].

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 LAC production, cell volume and oxygen consumption revealed that glycolysis and mitochondria equally contribute to cellular ATP production in control myoblasts. Inhibition of OXPHOS induced a 2-fold 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 here demonstrate that OXPHOS inhibition increases steady-state GLC uptake and consumption in C2C12 myoblasts [3]. The latter activation fully compensates for the reduction in mitochondrial ATP production, thereby maintaining the balance between cellular ATP supply and demand. The underlying mechanistic aspects and further consequences of this phenomenon [e.g. 4,5] are currently investigated.

β€’ O2k-Network Lab: NL Nijmegen Koopman WJ


Tissue;cell: Skeletal muscle, Other cell lines 

Event: D1, Oral  MiP2015 


1-Dept Biochemistry; 2-Dept Pharmacology Toxicology; 3-Centre Systems Biol Bioenergetics; 4-Radboud Inst Molecular Life Sciences; Radboud Univ Medical Center, Nijmegen, The Netherlands. - [email protected]

References and acknowledgements

  1. Koopman WJH, Willems PHGM, Smeitink JAM (2012) Monogenic mitochondrial disorders. N Eng J Med 366:1132-41.
  2. Liemburg-Apers DC, Imamura H, Forkink M, Nooteboom M, Swarts HG, Brock R, Smeitink JAM, Willems PHGM, Koopman WJH (2011) Quantitative glucose and ATP sensing in living cells. Pharm Res 28:2745-57.
  3. Liemburg-Apers DC, Schirris TJJ, Russel FGM, Willems PHGM, Koopman WJH (2015) Mitoenergetic dysfunction triggers a rapid compensatory increase in steady-state glucose flux. Biophys J (in press).
  4. Liemburg-Apers DC, Willems PHGM, Koopman WJH, Grefte S (2015) Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. Arch Toxicol (in press).
  5. Willems PHGM, Rossignol R, Dieteren CEJ, Murphy MP, Koopman WJH (2015) Redox homeostasis and mitochondrial dynamics. Cell Metab (in press).