Mitochondrial HTRA2 Plays a Positive, Protective Role in Dictyostelium discoideum but Is Cytotoxic When Overexpressed

Genes
Suwei ChenPaul R Fisher

Abstract

HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson's disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis in the mitochondrial intermembrane space. Its loss has been reported to result in accumulation of unfolded and misfolded proteins. However, in at least one case, PD-associated HTRA2 mutation can cause its hyperphosphorylation, possibly resulting in protease hyperactivity. The consequences of overactive mitochondrial HTRA2 are not clear. Dictyostelium discoideum provides a well-established model for studying mitochondrial dysfunction, such as has been implicated in the pathology of PD. We identified a single homologue of human HTRA2 encoded in the Dictyostelium discoideum genome and showed that it is localized to the mitochondria where it plays a cytoprotective role. Knockdown of HTRA2 expression caused defective morphogenesis in the multicellular phases of the Dictyostelium life cycle. In vegetative cells, it did not impair mitochondrial respiration but nonetheless caused slow growth (particularly when the cells were utilizing a bacterial f...Continue Reading

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Citations

Oct 31, 2020·Microbial Biotechnology·Javier Martín-GonzálezJesus Lacal
Nov 27, 2020·Neurobiology of Aging·Prabhjyot SainiZiv Gan-Or
Mar 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Yuki ToyamaLewis E Kay

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Methods Mentioned

BETA
PCR
Electrophoresis
dissecting microscopy

Software Mentioned

Helical Wheel
BLAST
MitoProt
Predotar
InterProScan

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