Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Mutations in the putative mitochondrial AAA+ chaperone CLPB have recently been associated with a pleiotropic syndrome characterized by progressive brain atrophy, intellectual disability, cataracts, neutropenia, and 3-methlyglutaconic aciduria. We have identified CLPB as a substrate of the rhomboid protease PARL and localized CLPB to the intermembrane space (IMS) of mitochondria. Our observations lead to the central hypothesis of the project that impaired mitochondrial proteostasis and possibly impaired retrograde stress signaling is of pathogenic relevance in CLPB-associated disease.
To model the loss of CLPB in disease, we will generate Clpb-/- mice using CRISPR/Cas9-mediated genome editing and use human Clpb-/- cells expressing catalytic inactive CLPB or variants harboring pathogenic missense mutations. We will identify specific substrates of CLPB by label-free, quantitative mass spectroscopy and employ proteome-wide approaches and gene expression profiling to determine how CLPB affects mitochondrial proteostasis under various stress conditions. Together, these experiments will define how mutations in CLPB affect the functional integrity of mitochondria and cause disease.
The current project aims at elucidating the pathogenic mechanism of a mitochondrial disorder caused by mutations in the AAA+ chaperone CLPB. Patients accumulate 3-methlyglutaconic acid in the urine, a characteristic of an emerging class of mitochondrial diseases apparently associated with the loss of mitochondrial membrane integrity. A detailed understanding of the pathogenic mechanism will thus contribute to validate the suitability of 3-methlyglutaconic acid a diagnostic biomarker.
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Prof. Dr. med. Thomas Benzing
Chair of the CMMC
