Mitochondrial dysfunction associated with TANGO2 deficiency

Sci Rep. 2022 Feb 23;12(1):3045. doi: 10.1038/s41598-022-07076-9.

Abstract

Transport and Golgi Organization protein 2 Homolog (TANGO2)-related disease is an autosomal recessive disorder caused by mutations in the TANGO2 gene. Symptoms typically manifest in early childhood and include developmental delay, stress-induced episodic rhabdomyolysis, and cardiac arrhythmias, along with severe metabolic crises including hypoglycemia, lactic acidosis, and hyperammonemia. Severity varies among and within families. Previous studies have reported contradictory evidence of mitochondrial dysfunction. Since the clinical symptoms and metabolic abnormalities are suggestive of a broad dysfunction of mitochondrial energy metabolism, we undertook a broad examination of mitochondrial bioenergetics in TANGO2 deficient patients utilizing skin fibroblasts derived from three patients exhibiting TANGO2-related disease. Functional studies revealed that TANGO2 protein was present in mitochondrial extracts of control cells but not patient cells. Superoxide production was increased in patient cells, while oxygen consumption rate, particularly under stress, along with relative ATP levels and β-oxidation of oleate were reduced. Our findings suggest that mitochondrial function should be assessed and monitored in all patients with TANGO2 mutation as targeted treatment of the energy dysfunction could improve outcome in this condition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aryl Hydrocarbon Receptor Nuclear Translocator* / deficiency
  • Aryl Hydrocarbon Receptor Nuclear Translocator* / genetics
  • Aryl Hydrocarbon Receptor Nuclear Translocator* / metabolism
  • Cells, Cultured
  • Child
  • Fatty Acids / metabolism
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Male
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Mitochondria* / ultrastructure
  • Mitochondrial Dynamics
  • Mitochondrial Proteins / metabolism

Substances

  • ARNT protein, human
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Fatty Acids
  • Mitochondrial Proteins
  • TANGO2 protein, human