Misfolding of short-chain acyl-CoA dehydrogenase leads to mitochondrial fission and oxidative stress.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare inherited disorder of the mitochondrial beta-oxidation of fatty acids. Patients with SCADD present mainly with symptoms of neuromuscular character. In order to investigate factors involved in the pathogenesis, we studied a disease-associated variant of the SCAD protein (p.Arg83Cys, c.319C>T), which is known to compromise SCAD protein folding. We investigated the consequences of overexpressing the misfolded mitochondrial protein, and thus determined whether the misfolded p.Arg83Cys SCAD proteins can elicit a toxic reaction. Human astrocytes were transiently transfected with either wild-type or p.Arg83Cys encoding cDNA, and analyzed for insoluble proteins/aggregate-formation, alterations in mitochondrial morphology, and for the presence of reactive oxygen species (ROS) in the mitochondria. The majority of cells overexpressing the p.Arg83Cys SCAD variant protein presented with an altered mitochondrial morphology of a grain-like structure, whereas the majority of the cells overexpressing wild-type SCAD presented with a normal thread-like mitochondrial reticulum. We found this grain-like structure to be associated with an increased amount of ROS. The mitochondrial morphology change was partly alleviated by addition of the mitochondrial targeted antioxidant MitoQ, indicating a ROS-induced mitochondrial fission. We therefore propose that SCAD misfolding leads to production of ROS, which in turn leads to fission and a grain-like structure of the mitochondrial reticulum. This finding indicates a toxic response elicited by misfolded p.Arg83Cys SCAD proteins.