Altered mitochondrial function in fibroblast cell lines derived from disease carriers of spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive childhood-onset neuromuscular disease with a carrier frequency of ~1:50. Mitochondrial abnormalities are widespread in patients with SMA. Disease carriers for SMA (i.e., the parents of patients with SMA) are viewed as asymptomatic for SMA disease. As far as we are aware, mitochondria have not been previously examined in SMA carriers, yet as they are maternally inherited, mitochondrial function in SMA carriers has putative implications for disease pathogenesis.

Fibroblast cell lines derived from SMA carriers and controls were obtained from two different sources and cultured under standard conditions. The mitochondrial membrane potential, reactive oxygen species (ROS) production, citrate synthase activity, and bioenergetic analysis were examined as measures of mitochondrial function. The mitochondrial genome was also sequenced in a subset of the fibroblast cell lines to identify any mitochondrial DNA variants.

Here, we show a depolarized mitochondrial membrane potential, increased levels of reactive oxygen species, and reduced citrate synthase activity in SMA carriers compared with controls. A likely pathogenic variant in the MT-CO3 gene (which encodes subunit III of cytochrome c oxidase) was also identified in a paternal carrier.

This study was conducted as a preliminary investigation of mitochondrial function in SMA carriers. Our findings suggest that disease carriers of SMA show differences in mitochondrial function, indicative of a subclinical mitochondrial phenotype. Further investigation in a larger sample set is warranted.