The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila

Yuzuru Imai, Tomoko Kanao, Tomoyo Sawada, Yoshito Kobayashi, Yasuhiro Moriwaki, Yosuke Ishida, Kohsuke Takeda, Hidenori Ichijo, Bingwei Lu, Ryosuke Takahashi

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

PTEN-induced kinase 1 (PINK1), which is required for mitochondrial homeostasis, is a gene product responsible for earlyonset 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.

Original languageEnglish
Article numbere1001229
Pages (from-to)1-14
Number of pages14
JournalPLoS Genetics
Volume6
Issue number12
DOIs
Publication statusPublished - 2010 Dec

Fingerprint

Drosophila
inactivation
phosphotransferases (kinases)
Phosphotransferases
protein
phenotype
gene
homeostasis
mitochondrion
pathology
defect
muscle
Carrier Proteins
Parkinson disease
loss
Parkinson Disease
binding proteins
Genes
Phenotype
Ubiquitin-Protein Ligases

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila. / Imai, Yuzuru; Kanao, Tomoko; Sawada, Tomoyo; Kobayashi, Yoshito; Moriwaki, Yasuhiro; Ishida, Yosuke; Takeda, Kohsuke; Ichijo, Hidenori; Lu, Bingwei; Takahashi, Ryosuke.

In: PLoS Genetics, Vol. 6, No. 12, e1001229, 12.2010, p. 1-14.

Research output: Contribution to journalArticle

Imai, Y, Kanao, T, Sawada, T, Kobayashi, Y, Moriwaki, Y, Ishida, Y, Takeda, K, Ichijo, H, Lu, B & Takahashi, R 2010, 'The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila', PLoS Genetics, vol. 6, no. 12, e1001229, pp. 1-14. https://doi.org/10.1371/journal.pgen.1001229
Imai, Yuzuru ; Kanao, Tomoko ; Sawada, Tomoyo ; Kobayashi, Yoshito ; Moriwaki, Yasuhiro ; Ishida, Yosuke ; Takeda, Kohsuke ; Ichijo, Hidenori ; Lu, Bingwei ; Takahashi, Ryosuke. / The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila. In: PLoS Genetics. 2010 ; Vol. 6, No. 12. pp. 1-14.
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