Ceramides increase mitochondrial ROS generation via altered mitochondrial dynamics in skeletal muscle

Abstract

The role of reactive oxygen species (ROS) as mediators of chronic diseases is increasingly well established. Ceramides are known to induce mitochondrial ROS production, which likely explains some of the deleterious effects of ceramide accumulation. We propose that ceramide accrual in skeletal muscle induces mitochondrial fission, which is requisite for ceramide‐induced ROS generation. We found that exogenous ceramide treatment and endogenous ceramide biosynthesis both increased mitochondrial fission and increased expression of dynamin‐related protein 1 (Drp1), which is a prime mediator of mitochondrial fission. Moreover, ceramide accrual increased H2O2 production in muscle cells. Inhibition of serine palmitoyltransferase (SPT) via pharmacological (myriocin) and genetic (SPT2 siRNA) inhibition prevented increased ROS production in palmitate‐treated cells. Also, lack of Drp1 (siRNA) prevented mitochondrial fission with ceramide treatment and completely prevented ROS generation. Altogether, these findings suggest ceramide‐induced mitochondrial fission is an important mediator of the observed ROS generation in the presence of ceramide‐rich cells. Given the multiple chronic diseases that are affected by ceramide metabolism, such as insulin resistance, these findings may lead to improved and novel therapies. This work was supported by a BYU Undergraduate Research Award (BJT) and a BYU Mentoring Environment Grant (BTB).