Characterisation of a novel CRLS1 variant in multi-system mitochondrial disease pathogenesis identifies mitochondrial and endoplasmic reticular stress responses to cardiolipin dysfunction

ABSTRACT: Mitochondrial diseases (MD) are a group of inherited diseases with highly varied and complex clinical presentations and their molecular diagnosis has been improved through next generation sequencing. Here, we report four individuals, two of whom are siblings, affected by a progressive mitochondrial encephalopathy who carry biallelic variants in the cardiolipin biosynthesis gene CRLS1. Using patient fibroblasts, we characterised defects in mitochondrial function that were reflective of CRLS1 dysfunctions, providing functional evidence that the CRLS1 I109N variant causes the MD phenotype observed in this patient. Lipid profiling highlighted that the CRLS1 variants reduced cardiolipin levels, altered its acyl-chain composition and caused a significant increase in phosphatidylglycerol, the substrate of cardiolipin synthase. Proteomic profiling of patient cells and Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. Our findings support that deleterious variants in CRLS1 cause a novel autosomal recessive MD, presenting as a severe encephalopathy with multisystemic involvement. Furthermore, we have identified key changes in cardiolipin and proteome profiles across various degrees of cardiolipin dysfunction, facilitating future advances in diagnostic technologies based on curated signatures in high-throughput datasets.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

DISEASE(S): Mitochondrial Metabolism Disease

SUBMITTER: Timothy McCubbin  

LAB HEAD: Aleksandra Filipovska

PROVIDER: PXD029861 | Pride | 2023-03-06

REPOSITORIES: Pride