Mitochondrial Function in Gilles de la Tourette Syndrome Patients With and Without Intragenic IMMP2L Deletions

Abstract

Background: Gilles de la Tourette syndrome (GTS) is a neurodevelopmental condition characterized by motor and vocal tics. The underlying etiology remains largely unknown, and GTS is considered as a complex multifactorial disorder associated with effects of several genes in combination with environmental factors. The inner mitochondrial membrane peptidase, subunit 2 (IMMP2L) has been suggested as one of the susceptibility genes for GTS, and IMMP2L-deficient mouse and human cells show increased levels of mitochondrial oxidative stress and altered cell fate programming. Hence, a potential involvement of IMMP2L-induced mitochondrial dysfunction in GTS pathology is yet to be elucidated. To address this, we investigated mitochondrial function in a group of GTS patients with intragenic IMMP2L deletions and compared with GTS without IMMP2L deletions and healthy controls.Methods: Mitochondrial function in fibroblasts from GTS patients and non-GTS parents (with and without IMMP2L deletions) compared to healthy controls were evaluated by measuring mitochondrial superoxide production, mitochondrial membrane potential, mitochondrial mass, and mitochondrial respiration. In addition, we evaluated apoptosis and senescence.Results: None of the mitochondrial parameters assessed in this study were significantly distinctive when comparing GTS patients with and without IMMP2L deletions against healthy controls or parents with or without IMMP2L deletions, and we did not observe altered cell programming. Conclusion:This study suggests that IMMP2L deletions do not lead to a substantial general mitochondrial dysfunction in GTS fibroblasts. Assessing a large cohort of controls and patients of similar age and gender would possibly reveal small differences in mitochondrial function. However, it is possible that IMMP2L variants affect mitochondrial function during specific instances of stress stimuli or in brain regions suggested to be affected in GTS.

Mitochondrial proteases in human diseases

“…Based on these results, it was suggested that defective cerebellar IMMP2L might play a role in GTS pathogenesis. However, analysis of various mitochondrial parameters (superoxide levels, membrane potential, mitochondrial respiratory chain) in fibroblasts from GTS patients with and without IMMP2L deletions did not detect significant changes within the analyzed groups [71]. Involvement of IMMP2L in the pathogenesis of Tourette syndrome is therefore unclear and needs further analyses, as IMMP2L deletions might have a specific effect on cells with high-energy demand, for example, neurons.…”

Tourette syndrome research highlights from 2020

“…These association studies were performed on case-control populations limited in size and need further replication. Furthermore, a study showed that deletions altering IMMP2L (encoding the mitochondrial inner membrane protease subunit 2) do not lead to a substantial mitochondrial dysfunction in fibroblasts of TS subjects, thus questioning the biological relevance of variants in this gene (Bjerregaard et al 2020). Finally, a recent study showed that socioeconomic status and education have to be taken into account when studying genetic factors involved in TS as these constitute potential confounders limiting the power of current genetic studies studies (Wendt et al 2021).…”

A Comprehensive Review of Tic Disorders in Children

“…In an animal study, the Immp2l mutation caused excessive mitochondrial superoxide generation and an increase in cellular oxidative stress [ 100 ]. However, a recent study using skin fibroblasts from patients with TS with the IMMP2L deletions revealed no evidence of substantial mitochondrial dysfunction in GTS fibroblasts [ 101 ].…”