Cornelissen 2020 Hum Mol Genet
|Cornelissen T, Spinazzi M, Martin S, Imberechts D, Vangheluwe P, Bird M, De Strooper B, Vandenberghe W (2020) CHCHD2 harboring the Parkinson's disease-linked T61I mutation precipitates inside mitochondria and induces precipitation of wild-type CHCHD2. Hum Mol Genet 29:1096-106.|
Abstract: The T61I mutation in CHCHD2, a protein residing in the mitochondrial intermembrane space, causes an autosomal dominant form of Parkinson's disease (PD), but the underlying pathogenic mechanisms are not well understood. Here, we compared the subcellular localization and solubility of wild-type and T61I mutant CHCHD2 in human cells. We found that mitochondrial targeting of both wild-type and T61I CHCHD2 depended on the four cysteine residues in the C-terminal coiled-coil-helix-coiled-coil-helix (CHCH) domain but not on the N-terminal predicted mitochondrial targeting sequence. The T61I mutation did not interfere with mitochondrial targeting of the mutant protein, but induced its precipitation in the IMS. Moreover, T61I CHCHD2 induced increased mitochondrial production of reactive oxygen species (ROS) and apoptosis, which was prevented by treatment with anti-oxidants. Retention of T61I CHCHD2 in the cytosol through mutation of the cysteine residues in the CHCH domain prevented its precipitation as well as its apoptosis-inducing effect. Importantly, T61I CHCHD2 potently impaired the solubility of wild-type CHCHD2. In conclusion, our data show that the T61I mutation renders mutant CHCHD2 insoluble inside mitochondria, suggesting loss of function of the mutant protein. In addition, T61I CHCHD2 exerts a dominant-negative effect on the solubility of wild-type CHCHD2, explaining the dominant inheritance of this form of PD.
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Labels: MiParea: Respiration, nDNA;cell genetics Pathology: Parkinson's Stress:Cell death, Oxidative stress;RONS Organism: Human Tissue;cell: Fibroblast Preparation: Permeabilized cells
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, CIV, NS, ROX HRR: Oxygraph-2k
Labels, 2020-02, Alert2020