Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo.
Recently, a mutation in the mitochondrial protease Omi/HtrA2, G399S, was found in sporadic Parkinson's disease (PD) patients, leading to the designation of Omi/HtrA2 as PD locus 13 (PARK13). G399S reportedly results in reduced Omi protease activity. In vitro studies have suggested that Omi/HtrA2 acts downstream of PINK1, mutations in which mediate recessive forms of PD. We, as well as other, have previously shown that the Drosophila homologs of the familial PD genes, PINK1 (PARK6) and PARKIN (PARK2), function in a common genetic pathway to regulate mitochondrial integrity and dynamics. Whether Omi/HtrA2 regulates mitochondrial integrity and whether it acts downstream of PINK1 in vivo remain to be explored. Here, we show that Omi/HtrA2 null mutants in Drosophila, in contrast to pink1 or parkin null mutants, do not show mitochondrial morphological defects. Extensive genetic interaction studies do not provide support for models in which Omi/HtrA2 functions in the same genetic pathway as pink1, or carries out partially redundant functions with pink1, at least with respect to regulation of mitochondrial integrity and dynamics. Furthermore, Omi/HtrA2 G399S retains significant, if not full, function of Omi/HtrA2, compared with expression of protease-compromised versions of the protein. In light of recent findings showing that G399S can be found at comparable frequencies in PD patients and healthy controls, we do not favor a hypothesis in which Omi/HtrA2 plays an essential role in PD pathogenesis, at least with respect to regulation of mitochondrial integrity in the pink1/parkin pathway.
Yun
Jina
J
Department of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
Cao
Joseph H
JH
Dodson
Mark W
MW
Clark
Ira E
IE
Kapahi
Pankaj
P
Chowdhury
Ruhena B
RB
Guo
Ming
M
D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D000074923:High-Temperature Requirement A Serine Peptidase 2; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D029721:Drosophila Proteins; D012333:RNA, Messenger; C523996:p protein, Drosophila; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C530280:HtrA2 protein, Drosophila; C487430:park protein, Drosophila