TOMM40 and TOMM22 of the Translocase Outer Mitochondrial Membrane Complex rescue statin-impaired mitochondrial dynamics, morphology, and mitophagy in skeletal myotubes

Abstract

ABSTRACTBackgroundStatins 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 as a cause of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates transcription ofTOMM40andTOMM22, genes that encode major subunits of the translocase of outer mitochondrial membrane (TOM) complex which is responsible for importing nuclear-encoded proteins and maintaining mitochondrial function. We therefore investigated the role ofTOMM40andTOMM22in mediating statin effects on mitochondrial function, dynamics, and mitophagy.MethodsCellular and biochemical assays and transmission electron microscopy were used to investigate effects of simvastatin andTOMM40andTOMM22expression on measures of mitochondrial function and dynamics in C2C12 and primary human skeletal cell myotubes.ResultsKnockdown ofTOMM40andTOMM22in skeletal cell myotubes impaired mitochondrial oxidative function, increased production of mitochondrial superoxide, reduced mitochondrial cholesterol and CoQ levels, disrupted mitochondrial dynamics and morphology, and increased mitophagy, with similar effects resulting from simvastatin treatment. Overexpression ofTOMM40andTOMM22in simvastatin-treated muscle cells rescued statin effects on mitochondrial dynamics, but not on mitochondrial function or cholesterol and CoQ levels. Moreover, overexpression of these genes resulted in an increase in number and density of cellular mitochondria.ConclusionThese results confirm that TOMM40 and TOMM22 are central in regulating mitochondrial homeostasis and demonstrate that downregulation of these genes by statin treatment mediates disruption of mitochondrial dynamics, morphology, and mitophagy, effects that may contribute to statin-induced myopathy.GRAPHICAL ABSTRACT