Adaptive optimization of the OXPHOS assembly line partially compensates lrpprc-dependent mitochondrial translation defects in mice

Alexanne Cuillerier ,Christine Des Rosiers ,Caroline Daneault ,Goutham Vasam ,Anik Forest ,Matthieu Ruiz ,Jenna A Rossi ,George Cairns ,Virgilio J J Cadete ,Yan Burelle

doi:10.1038/s42003-021-02492-5

Abstract

Mouse models of genetic mitochondrial disorders 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, low levels of the mtRNA binding protein LRPPRC induce 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 overt liver failure and capacity of the ETC is 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 presence of low LRPPRC levels to preserve a balance in the availability of mitochondrial- vs nuclear-encoded ETC subunits. At the level of individual organelles, a stabilization of residual CIV in supercomplexes (SCs) is observed, pointing to a role of these supramolecular arrangements in preserving ETC function. While the SC assembly factor COX7A2L could not contribute to the stabilization of CIV, important changes in membrane glycerophospholipid (GPL), most notably an increase in SC-stabilizing cardiolipins species (CLs), were observed along with an increased abundance of other supramolecular assemblies known to be stabilized by, and/or participate 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.

Highlights

Mouse models of genetic mitochondrial disorders are generally used to understand specific molecular defects and their biochemical consequences, but rarely to map compensatory changes allowing survival
Because equal amounts of mitochondrial protein extracts were loaded in the gels, these results suggest that the number of mitoribosomes per mitochondrial unit was substantially increased (Fig. 1d, e)
Our results provide novel evidence for stabilization of residual complex IV (CIV) in supercomplexes through a mechanism that may involve changes in the GPL composition of mitochondrial membranes, most notably cardiolipins species (CLs), which are reported to play a role in stabilizing protein-protein interactions in the inner membrane

Summary

Introduction

Mouse models of genetic mitochondrial disorders are generally used to understand specific molecular defects and their biochemical consequences, but rarely to map compensatory changes allowing survival. While the SC assembly factor COX7A2L could not contribute to the stabilization of CIV, important changes in membrane glycerophospholipid (GPL), most notably an increase in SC-stabilizing cardiolipins species (CLs), were observed along with an increased abundance of other supramolecular assemblies known to be stabilized by, and/or participate 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. Mice behave normally and present striking preservation of respiratory chain capacity[14] Their ability to tolerate fasting through the energetically costly process of gluconeogenesis is preserved, and they show no evidence of overt liver failure[14], suggesting efficient adaptive changes are present to compensate for the translation defect resulting from LRPPRC deficiency. Our results point to several adaptive countermeasures which collectively allow for relative preservation of mitochondrial and liver function despite the severity of the LRPPRC-dependent translation defect

Methods

Results

Conclusion