Alterations in mitochondrial function in fibroblasts from patients with Leigh Syndrome French Canadian type (LSFC)

Abstract

LSFC is a monogenic metabolic disease characterized by 1) cytochrome c oxidase deficiency, resulting from a mutation in the leucine‐rich pentatricopeptide repeat motif containing gene LRPPRC, and 2) episodes of lactic acidosis “crisis” leading to death early in life. The mechanisms responsible for these crises remain to be elucidated. In this study, we used fibroblasts from LSFC patients as a working model to test the hypothesis that impaired mitochondrial function and network dynamics in these cells may predispose them to premature death. Calcium retention capacity (CRC), oxygen (O2) consumption, reactive oxygen species production, mitochondrial membrane potential (ΔΨ) and network morphology were assessed in intact or permeabilized control and LSFC fibroblasts. Compared to controls, LSFC fibroblasts showed multiple abnormalities under basal condition, including decreased CRC (36%), O2 consumption (30–59%), ΔΨ (67%) and increased mitochondrial fission. In addition, nutrient overload, which induces premature death of LSFC fibroblasts (FASEB J 2011 25:722.15), exacerbated mitochondrial fission in these cells. Together, these results suggest that mitochondria from LSFC fibroblasts are dysfunctional and this may limit the capacity of these cells to maintain homeostasis, particularly under conditions of nutrient overload. (Supported by: Association de l'acidose lactique and CIHR Emerging Team Grants)