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

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.

E2 ubiquitin conjugase Bendless is essential for PINK1-Park activity to regulate Mitofusin under mitochondrial stress

“…Interestingly, we found that mitochondrial size is increased in these ppr A mutant clones (Figure S1E-E", 1F). Similar increase in mitochondrial size has been observed in LRPPRC knockdown in mouse liver (35) and in C.elegans (36). As many studies have shown that mitochondrial stress can result in increased mitochondrial size (3,4,36,38), we suspect a similar mechanism results in increased mitochondrial size in ppr mutant cells, while an independent mitochondrial quality control mechanism may suppress their fusion by inducing Marf turnover.…”

“…We propose that reduced ETC activity and mitochondrial stress in ppr (28,29,36), can induce SIMH (Figure 6D, S1E). Mitochondrial fusion has been observed upon loss of ppr homologs in C.elegans , mouse and human cell lines (35,64) as well as in other mutants where the ETC is compromised (52,65,66). Since SIMH increases ATP synthesis and inhibits mitophagy (3,4,67,68), increased mitochondrial size appears to be a compensatory adaptation in ppr mutants in response to a bioenergetic deficit or mitochondrial stress.…”

Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC

“…Interestingly, we found that mitochondrial size is increased in lrpprc2 A mutant clones (S1D-S1D" and S1E Fig). This is consistent with earlier findings that showed enlarged mitochondrial size in LRPPRC knockdown in mouse liver [42], C.elegans and mammalian cell culture [43]. As many studies have shown that mitochondrial stress can result in increased mitochondrial size [3,5,43,50], we suspect a similar mechanism results in increased mitochondrial size in lrpprc2 mutant cells, while an independent mitochondrial quality control mechanism may suppress their fusion by reducing Marf levels.…”

“…Loss of LRPPRC results in a neurometabolic disorder-French-Canadian Leigh Syndrome [40,41]. Studies in worms, mouse and human cells have also shown that loss of LRPPRC is associated with large mitochondrial size [42,43]. We found that loss of lrpprc2 results in proteasome-mediated Marf degradation in a PINK1-Park dependent mechanism.…”

Malonyl-CoA Accumulation as a Compensatory Cytoprotective Mechanism in Cardiac Cells in Response to 7-Ketocholesterol-Induced Growth Retardation

“…It is not unprecedented that the compensatory mitochondrial biogenesis occurs in response to mitochondrial dysfunction. Knockout of the leucine-rich pentatricopeptide repeat containing protein (LRPPRC)-encoding gene, whose mutations have been identified in Leigh syndrome, causes the defective assembly of the electron transport chain and triggers compensatory mitochondrial biogenesis [39]. Compensatory mitochondrial biogenesis occurs in cells with mitochondrial DNA mutations [40].…”