title: The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila.
abstract: PTEN-induced kinase 1 (PINK1), which is required for mitochondrial homeostasis, is a gene product responsible for early-onset Parkinson's disease (PD). Another early onset PD gene product, Parkin, has been suggested to function downstream of the PINK1 signalling pathway based on genetic studies in Drosophila. PINK1 is a serine/threonine kinase with a predicted mitochondrial target sequence and a probable transmembrane domain at the N-terminus, while Parkin is a RING-finger protein with ubiquitin-ligase (E3) activity. However, how PINK1 and Parkin regulate mitochondrial activity is largely unknown. To explore the molecular mechanism underlying the interaction between PINK1 and Parkin, we biochemically purified PINK1-binding proteins from human cultured cells and screened the genes encoding these binding proteins using Drosophila PINK1 (dPINK1) models to isolate a molecule(s) involved in the PINK1 pathology. Here we report that a PINK1-binding mitochondrial protein, PGAM5, modulates the PINK1 pathway. Loss of Drosophila PGAM5 (dPGAM5) can suppress the muscle degeneration, motor defects, and shorter lifespan that result from dPINK1 inactivation and that can be attributed to mitochondrial degeneration. However, dPGAM5 inactivation fails to modulate the phenotypes of parkin mutant flies. Conversely, ectopic expression of dPGAM5 exacerbated the dPINK1 and Drosophila parkin (dParkin) phenotypes. These results suggest that PGAM5 negatively regulates the PINK1 pathway related to maintenance of the mitochondria and, furthermore, that PGAM5 acts between PINK1 and Parkin, or functions independently of Parkin downstream of PINK1.
authors.affiliation: Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan. yimai@idac.tohoku.ac.jp
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Imai
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kanao
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Sawada
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Moriwaki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ishida
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Bingwei
authors.initials: B
authors.lastname: Lu
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D004330:Drosophila / Q000201:enzymology* / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D010735:Phosphoglycerate Kinase; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C534484:PINK1 protein, Drosophila; C487430:park protein, Drosophila