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

Area of Science:

• Cellular metabolism
• Mitochondrial function
• Biophysics

Background:

• Cellular ATP is generated via glycolysis and mitochondrial oxidative phosphorylation (OXPHOS).
• Dysregulation of this balance is implicated in diseases like cancer.
• Understanding adaptive responses to mitoenergetic dysfunction is critical.

Purpose of the Study:

• To investigate the kinetic properties of adaptive cytosolic glucose homeostasis.
• To determine how acute OXPHOS inhibition impacts glucose uptake and consumption.

Main Methods:

• Utilized a fluorescent biosensor (FLII) in C2C12 myoblasts to analyze glucose dynamics.
• Developed and validated a mathematical model for cytosolic glucose dynamics.
• Quantitatively predicted glucose uptake (V1) and consumption (V2) under varying conditions.

Main Results:

• OXPHOS inhibition doubled steady-state glucose uptake and consumption (Vsteady-state).
• Glycolytic ATP production flux increased twofold upon OXPHOS inhibition.
• Glucose consumption operates near maximal rates, indicating it's a rate-limiting step.

Conclusions:

• OXPHOS inhibition activates glucose uptake and consumption in C2C12 myoblasts.
• This glycolytic activation fully compensates for reduced mitochondrial ATP production.
• Cellular ATP supply and demand are maintained despite OXPHOS dysfunction.