Mutant SPART causes defects in mitochondrial protein import and bioenergetics reversed by Coenzyme Q

Pathogenic variants in SPART cause Troyer syndrome, characterized by lower extremity spasticity and weakness, short stature and cognitive impairment, and a severe mitochondrial impairment. Herein, we report the identification of a role of Spartin in nuclear-encoded mitochondrial proteins. SPART biallelic missense variants were detected in a 5-year-old boy with short stature, developmental delay and muscle weakness with impaired walking distance. Patient-derived fibroblasts showed an altered mitochondrial network, decreased mitochondrial respiration, increased mitochondrial reactive oxygen species and altered Ca2+ versus control cells. We investigated the mitochondrial import of nuclear-encoded proteins in these fibroblasts and in another cell model carrying a SPART loss-of-function mutation. In both cell models the mitochondrial import was impaired, leading to a significant decrease in different proteins, including two key enzymes involved in CoQ10 (CoQ) synthesis, COQ7 and COQ9, with a severe reduction in CoQ content, versus control cells. CoQ supplementation restored cellular ATP levels to the same extent shown by the re-expression of wild-type SPART, suggesting CoQ treatment as a promising therapeutic approach for patients carrying mutations in SPART.

Automated summary

Pathogenic variants in SPART cause Troyer syndrome characterized by spasticity, weakness, short stature, cognitive impairment, and severe mitochondrial dysfunction. This study identified a role of Spartin in nuclear-encoded mitochondrial proteins. Fibroblasts derived from a patient with SPART missense variants showed mitochondrial abnormalities, reduced respiration, increased reactive oxygen species, and altered calcium levels. Impaired mitochondrial import was observed in these fibroblasts and in a cell model with a SPART loss-of-function mutation, resulting in decreased levels of different proteins, including key enzymes involved in CoQ synthesis. CoQ supplementation restored ATP levels, suggesting it as a potential therapeutic approach for patients with SPART mutations.