Atorvastatin Induces Bioenergetic Impairment and Oxidative Stress Through Reverse Electron Transport

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Statins are primary treatments for high cholesterol, crucial for preventing cardiovascular events.
• Statin use is linked to side effects potentially caused by Coenzyme Q10 (CoQ10) depletion.
• CoQ10 is vital for mitochondrial energy production and acts as an antioxidant.

Purpose of the Study:

• To investigate the cytotoxic effects of Atorvastatin on human dermal fibroblasts.
• To explore the role of CoQ10 supplementation in mitigating Atorvastatin-induced toxicity.
• To elucidate the mechanism behind Atorvastatin's off-target effects.

Main Methods:

• Assessed cytotoxicity, oxidative stress (ROS levels), and mitochondrial function (oxygen consumption, ATP/ADP ratio) in human dermal fibroblasts.
• Compared effects of Atorvastatin alone versus Atorvastatin with CoQ10 supplementation.
• Investigated the impact of Atorvastatin on mitochondrial respiratory complexes I and III.

Main Results:

• Atorvastatin induced significant oxidative stress and mitochondrial impairment in fibroblasts.
• CoQ10 supplementation reversed ROS elevation and restored mitochondrial function and ATP levels.
• High concentrations of Atorvastatin inhibited respiratory complexes I and III, causing reverse electron transport and ROS generation.

Conclusions:

• Atorvastatin exhibits cytotoxicity through oxidative stress and mitochondrial dysfunction.
• CoQ10 supplementation shows promise in mitigating statin-induced side effects.
• Inhibition of mitochondrial respiratory complexes I and III is a potential mechanism for Atorvastatin toxicity.