# Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes

## TL;DR

This study explores how statins impair mitochondrial function in muscle cells and suggests that targeting TOMM40 and TOMM22 could help prevent statin-induced muscle damage.

## Contribution

The study identifies TOMM40 and TOMM22 as key regulators of mitochondrial function affected by statins and shows that their overexpression can rescue mitochondrial dynamics.

## Key findings

- Simvastatin downregulates TOMM40 and TOMM22, leading to mitochondrial dysfunction and increased mitophagy.
- Overexpression of TOMM40 and TOMM22 rescues mitochondrial dynamics and morphology in statin-treated cells.
- TOMM40 and TOMM22 play essential roles in maintaining mitochondrial function and dynamics.

## Abstract

Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of TOMM40 and TOMM22, genes that encode major subunits of the translocase of the outer mitochondrial membrane (TOM) complex. Mitochondrial effects of knockdown of TOMM40 and TOMM22 in mouse C2C12 and primary human skeletal cell myotubes include impaired oxidative function, increased superoxide production, reduced cholesterol and CoQ levels, and disrupted markers of mitochondrial dynamics and morphology as well as increased mitophagy, with similar effects resulting from simvastatin exposure. Overexpression of TOMM40 and TOMM22 in simvastatin-treated mouse and human skeletal muscle cells rescued effects on markers of mitochondrial dynamics and morphology, but not oxidative function or cholesterol and CoQ levels. These results show that TOMM40 and TOMM22 have key roles in maintaining both mitochondrial dynamics and function and indicate that their downregulation by statin treatment results in mitochondrial effects that may contribute to statin-induced myopathy.