Proteomics profiling of Lrpprc knockout mice liver mitochondria following resolution by hybrid CN/BN PAGE

ABSTRACT: Mouse models of genetic mitochondrial diseases are generally used to understand specific molecular defects and their biochemical consequences, but rarely to map compensatory changes allowing survival. Here we took advantage of the extraordinary mitochondrial resilience of hepatic Lrpprc knockout mice to explore this question using native proteomics profiling and lipidomics. In these mice, lack of the mtRNA binding protein LRPPRC induces a global mitochondrial translation defect and a severe reduction (>80%) in the assembly and activity of the electron transport chain (ETC) complex IV (CIV). Yet, animals show no signs of liver failure and capacity of the ETC is completely preserved. Beyond stimulation of mitochondrial biogenesis, results show that the abundance of mitoribosomes per unit of mitochondria is increased and proteostatic mechanisms are induced in absence of LRPPRC to preserve a balance in the availability of mitochondrial- vs nuclear-encoded ETC subunits. At the level of individual organelles, a strong preferential integration of residual CIV in supercomplexes (SCs) is observed, pointing to a role of these supramolecular arrangements in preserving ETC function. This can be mechanistically explained by the upregulation of the assembly factor COX7A2L and its stabilization into SCs. Furthermore, lipidomics and proteomics evidences indicate a shift in the phospholipids composition of mitochondrial membrane including an upregulation of SC stabilizing cardiolipin (CL) species, and several CL-binding protein complexes playing key roles in CL metabolism. Together these data reveal a complex in vivo network of molecular adjustments involved in preserving mitochondrial integrity in energy consuming organs facing OXPHOS defects, which could be therapeutically exploited.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Goutham Vasam  

LAB HEAD: Yan Burelle

PROVIDER: PXD021867 | Pride | 2021-09-09

REPOSITORIES: Pride