Toward understanding the tissue specificity of mitochondrial disease caused by pathogenic mutations in the LRPPRC gene

The leucine-rich pentatricopeptide repeat containing (LRPPRC) protein, in complex with SRA Stem-Loop interacting RNA binding (SLIRP) protein, has an important role in mitochondrial gene expression. Mutations in the LRPPRC gene are associated with early-onset multisystem mitochondrial disease characterized by complex IV deficiency, involving the nervous system with liver or heart. The most frequent LRPPRC mutation (A354V) causes French Canadian type of Leigh Syndrome (LSFC) where LS is associated with hepatopathy. As all mitochondrial diseases, LRPPRC-related disease is a tissue specific disorder that can not be explained given the ubiquitous expression of LRPPRC. A deeper understanding of the tissue-specificity is necessary to advance our knowledge of the disease nature and for the development of efficient treatments. The aim of this study was to determine how LRPPRC mutations influence the stability of the LRPPRC protein and SLIRP, consequently impairing OXPHOS system in human and mouse models. Here I demonstrated that LRPPRC compound heterozygous mutations found in a French child result in low steady-state levels of LRPPRC and SLIRP proteins, leading to decreased levels of OXPHOS complex I and IV. Moreover, I systematically investigated the consequences of these mutations in replicating cell lines and differentiated tissues from transgenic mouse. I highlighted potential differences between human cells and mouse cells where human cells exhibit more drastic OXPHOS deficiency in comparison to mouse cells, even if showing the same residual level of mutant LRPPRC protein. Moreover, I demonstrated that, even though all tissues from transgenic mice show a drastic decrease in LRPPRC protein, only brain, liver and skeletal muscle present a mild complex IV defect, while kidney displays a weak complex I deficiency and heart is unaffected. These results point out that mice may have compensatory mechanisms that mitigate mitochondrial deficiencies.