Loss of hepatic LRPPRC alters mitochondrial bioenergetics, regulation of permeability transition and trans-membrane ROS diffusion

Abstract

The French-Canadian variant of Leigh Syndrome (LSFC) is an autosomal recessive oxidative phosphorylation (OXPHOS) disorder caused by a mutation in LRPPRC, coding for a protein involved in the stability of mitochondrially-encoded mRNAs. Low levels of LRPPRC are present in all patient tissues, but result in a disproportionately severe OXPHOS defect in the brain and liver, leading to unpredictable subacute metabolic crises. To investigate the impact of the OXPHOS defect in the liver, we analyzed the mitochondrial phenotype in mice harboring an hepatocyte-specific inactivation of Lrpprc. Loss of LRPPRC in the liver caused a generalized growth delay, and typical histological features of mitochondrial hepatopathy. At the molecular level, LRPPRC deficiency caused destabilization of polyadenylated mitochondrial mRNAs, altered mitochondrial ultrastructure, and a severe complex IV (CIV) and ATP synthase (CV) assembly defect. The impact of LRPPRC deficiency was not limited to OXPHOS, but also included impairment of long-chain fatty acid oxidation, a striking dysregulation of the mitochondrial permeability transition pore, and an unsuspected alteration of trans-membrane H2O2 diffusion, which was traced to the ATP synthase assembly defect, and to changes in the lipid composition of mitochondrial membranes. This study underscores the value of mitochondria phenotyping to uncover complex and unexpected mechanisms contributing to the pathophysiology of mitochondrial disorders.

OSCP subunit of mitochondrial ATP synthase: role in regulation of enzyme function and of its transition to a pore

“…In mice with a heart conditional knockout of Lrpprc, impairment of ATP production was matched by lack of assembly of F‐ATP synthase and presence of F‐ATP synthase subcomplexes, which lacked subunits OSCP and A6L and catalysed oligomycin‐insensitive ATP hydrolysis (Mourier et al, ). Mice with hepatocyte‐specific conditional inactivation of Lrpprc showed assembly defects of F‐ATP synthase (whose activity was largely insensitive to oligomycin) with decreased formation of dimers and a remarkable inactivation of the PTP (Cuillerier et al, ). Interestingly, in spite of increased CyPD expression, the PTP was insensitive to CsA, suggesting that alterations in the peripheral stalk could have prevented CyPD binding (Cuillerier et al, ).…”

“…Mice with hepatocyte‐specific conditional inactivation of Lrpprc showed assembly defects of F‐ATP synthase (whose activity was largely insensitive to oligomycin) with decreased formation of dimers and a remarkable inactivation of the PTP (Cuillerier et al, ). Interestingly, in spite of increased CyPD expression, the PTP was insensitive to CsA, suggesting that alterations in the peripheral stalk could have prevented CyPD binding (Cuillerier et al, ).…”

Lipidomics unveils lipid dyshomeostasis and low circulating plasmalogens as biomarkers in a monogenic mitochondrial disorder

“…LSFC patients display some lipid-handling abnormalities as evidenced from high circulating levels of long-chain acylcarnitines (LCACs), which are proxies of mitochondrial fatty acid (FA) β-oxidation perturbations (12). These patients are also affected by hepatic microvesicular steatosis (8,(13)(14)(15). Hepatic steatosis has also been reported in mice harboring liver-specific inactivation of Lrpprc (H-Lrpprc -/-) (15) and is rescued by overexpression of Lrpprc in mouse liver (13,14,16).…”

Negative Regulation of Mitochondrial Antiviral Signaling Protein–Mediated Antiviral Signaling by the Mitochondrial Protein LRPPRC During Hepatitis C Virus Infection

“…The main role of LRPPRC in the regulation of mitochondrial physiology appears to be related to its ability to bind RNA, in concert with the protein SLIRP, and to regulate its stability . Effects of LRPPRC mutations are not limited to mitochondrial oxidative phosphorylation; alterations in fatty acid β‐oxidation, permeability transition pore, ROS dynamics, and mitophagy have also been detected . Although no evidence of an abnormal inflammatory state in the French Canadian Leigh syndrome has yet been reported, the enhanced sensitivity to cell death observed in this disorder could have a functional link with a dysregulated activity of MAVS.…”