Open Biology (Jul 2023)

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

  • Chiara Diquigiovanni,
  • Nicola Rizzardi,
  • Antje Kampmeier,
  • Irene Liparulo,
  • Francesca Bianco,
  • Bianca De Nicolo,
  • Erica Cataldi-Stagetti,
  • Elisabetta Cuna,
  • Giulia Severi,
  • Marco Seri,
  • Miriam Bertrand,
  • Tobias B. Haack,
  • Adela Della Marina,
  • Frederik Braun,
  • Romana Fato,
  • Alma Kuechler,
  • Christian Bergamini,
  • Elena Bonora

DOI
https://doi.org/10.1098/rsob.230040
Journal volume & issue
Vol. 13, no. 7

Abstract

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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.

Keywords