The French-Canadian variant of Leigh syndrome (LSFC) is a distinct and particularly severe presentation of Leigh syndrome characterized by the onset of unpredictable acidotic crises leading to death of 80% of them before the age of five. This autosomal recessive disorder is caused by mutations in LRPPRC, encoding an mRNA binding protein of the same name with a high affinity for mitochondrial transcripts. As a result of the mutations, levels of LRPPRC are decreased in all tissues and cause a severe deficiency of complex IV of the respiratory chain, with a deeper involvement of brain and liver. To gain better knowledge on the pathophysiology of this disease, and of the impact of the OXPHOS defect on the liver, our research consortium developed a mouse model of the disease harboring a liver specific inactivation of Lrpprc (H-Lrpprc). The goal of this thesis is to investigate the in vivo consequences of hepatic Lrpprc inactivation and to test potential therapy for mitochondrial diseases. The characterization of this model and the analysis of the mitochondrial phenotype are presented in Chapter 2 (Cuillerier et al, Human Molecular Genetics, 2017). Despite this severe phenotype, H-Lrpprc mice show no signs of overt liver failure and maintain energy levels, suggesting mechanisms are in place to sustain residual complex IV function. The underlying compensatory mechanisms granting these mice a remarkable resilience were explored and are presented in Chapter 4 (Cuillerier et al, Communications Biology, 2021). Along this project, we developed a protocol, and the optimized conditions of this method are described in Chapter 3 (Cuillerier and Burelle, JoVE, 2019). Although great progress has been made, there are currently no effective or curative treatments for LSFC and mitochondrial diseases. Recently, extensive pre-clinical and clinical studies supported the emergence and safety of mesenchymal stem cells therapy in the treatment of various diseases. Following transplantation, MSCs promote repair through various mechanisms including secretion of cytokines/exosomes, and transfer of mitochondria directly to target cells with impaired mitochondria offering a possibility to replace mutant dysfunctional organelles, which is relevant in the context of genetic mitochondrial diseases. Based on this, the objective of the last chapter of this thesis is to test the therapeutic potential of MSCs for genetic mitochondrial disorders using MSC-based approaches and LSFC as a disease model. Unfortunately, we encountered several obstacles along the way, including the departure of our main collaborator and stem cell expert, and delays in experimental procedures due to the COVID-19 pandemic. Consequently, this study was not completed at the moment of submission of this thesis, and is therefore presented as a pilot study in the form of a manuscript in Chapter 5. Overall, these projects unveiled alterations of mitochondrial functions that go beyond OXPHOS, a complex network of compensatory mechanisms in place to palliate these defects, and finally, encouraging preliminary results suggest MSC therapy could be beneficial for the treatment of mitochondrial diseases.