Am J Physiol Cell Physiol 2019 Apr 17. Epub 2019 Apr 17.
Department of Nutrition, Université de Montréal, Montréal, QC H3C 3J7, Canada. Department of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
Leigh syndrome French Canadian type (LSFC) is a mitochondrial disease caused by mutations in the LRPRRC gene leading to a reduction of cytochrome c oxidase (COX) expression reaching 50% in skin fibroblasts. We have shown that, under basal conditions, LSFC and control cells display similar ATP levels. We hypothesized that this occurs through upregulation of mechanistic target of rapamycin (mTOR)-mediated metabolic reprogramming. Our results showed that, compared to controls, LSFC cells exhibited an upregulationof the mTORC1/p70S6K pathway, and higher levels of the hypoxia inducible factor (HIF)-1α and its downstream target, pyruvate dehydrogenase kinase 1 (PDHK1), a regulator of mitochondrial pyruvate dehydrogenase 1 (PDH1). Consistent with these signaling alterations, LSFC cells displayed a 40-61% increase in [U-C]glucose contribution to pyruvate, lactate and alanine formation, as well as higher levels of the phosphorylated and inactive form of PDH1-α. Interestingly, inhibition of mTOR with rapamycin did not alter HIF-1α or PDHK1 protein levels in LSFC fibroblasts. However, this treatment increased PDH1-α phosphorylation in control and LSFC cells and reduced ATP levels in control cells. Rapamycin also decreased LRPPRC expression by 41% and 11% in LSFC and control cells, respectively, and selectively reduced COXIV expression in LSFC fibroblasts. Taken together, our data demonstrate the importance of mTORC1, independently of the HIF-1α/PDHK1 axis, in maintaining LRPPRC and COX expression in LSFC cells.