# Atorvastatin Induces Bioenergetic Impairment and Oxidative Stress Through Reverse Electron Transport

## TL;DR

Atorvastatin, a cholesterol-lowering drug, causes mitochondrial dysfunction and oxidative stress, but these effects can be reduced with CoQ10 supplementation.

## Contribution

The study identifies a novel mechanism involving reverse electron transport and mitochondrial complex inhibition as a cause of Atorvastatin's side effects.

## Key findings

- Atorvastatin induces oxidative stress and mitochondrial impairment in human dermal fibroblasts.
- CoQ10 supplementation reduces ROS levels and restores mitochondrial function in statin-treated cells.
- High concentrations of Atorvastatin inhibit respiratory complexes I and III, leading to reverse electron transport and ROS production.

## Abstract

Statins are the first-line therapy for managing elevated cholesterol levels that represent a risk of acute cardiovascular events. However, the use of statins is associated with several side effects, likely due to the depletion of Coenzyme Q10 (CoQ10), a key component of the mitochondrial electron transport chain and a membrane antioxidant. In our study, we present evidence of the cytotoxic effects of Atorvastatin on human dermal fibroblasts in terms of oxidative stress and mitochondrial impairment. Interestingly, CoQ10 supplementation in statin-treated cells significantly reduced ROS levels and restored mitochondrial oxygen consumption rate and the intracellular ATP/ADP ratio. Moreover, our data suggest that the mechanism for Atorvastatin off-target effects at high concentrations involves the inhibition of respiratory complexes I and III, leading to reverse electron transport and ROS production by Complex I. These findings highlight the potential benefits of CoQ10 supplementation in mitigating statin-induced cytotoxicity and propose a mechanistic basis for the adverse effects associated with Atorvastatin therapy.