Ataxia telangiectasia mutated influences cytochrome c oxidase activity

Area of Science:

• Mitochondrial biology
• Cellular metabolism
• Enzyme kinetics

Background:

• Ataxia telangiectasia mutated (ATM) deficient cells exhibit impaired mitochondrial function, increased reactive oxygen species (ROS), and mitochondrial DNA (mtDNA) deletions.
• Specific impact of ATM on skeletal muscle mitochondrial enzymes, particularly cytochrome c oxidase (COX), remains unclear.

Purpose of the Study:

• To investigate the role of ATM in regulating COX activity within skeletal muscle.
• To determine if ATM deficiency affects other mitochondrial enzyme activities in skeletal muscle.

Main Methods:

• Comparison of COX activity in tibialis anterior muscles from ATM-deficient and wild-type mice.
• Assay of multiple mitochondrial enzyme activities (SDH, IDH, α-KGDH, mGPD, Complex III) in skeletal muscle.
• In vitro inhibition of ATM using KU55933 in wild-type extensor digitorum longus muscles and subsequent COX activity measurement.
• Correlation analysis between COX activity and glucose 6-phosphate dehydrogenase (G6PD) activity.

Main Results:

• COX activity was significantly reduced by approximately 40% in ATM-deficient mice skeletal muscle.
• No significant differences in the activity of other tested mitochondrial enzymes (SDH, IDH, α-KGDH, mGPD, Complex III) were observed between groups.
• Pharmacological inhibition of ATM in wild-type muscle led to a ~50% decrease in COX activity.
• COX activity positively correlated with glucose 6-phosphate dehydrogenase (G6PD) activity, a marker of NADPH production for antioxidant defense.

Conclusions:

• ATM plays a crucial protective role in maintaining cytochrome c oxidase (COX) activity in skeletal muscle.
• ATM deficiency leads to specific impairment of COX function, suggesting a targeted mechanism rather than global mitochondrial dysfunction.
• The findings highlight a link between ATM, COX activity, and antioxidant defense pathways involving NADPH.