論文

査読有り 国際誌
2012年

Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria.

PLoS genetics
  • Song Liu
  • Tomoyo Sawada
  • Seongsoo Lee
  • Wendou Yu
  • George Silverio
  • Philomena Alapatt
  • Ivan Millan
  • Alice Shen
  • William Saxton
  • Tomoko Kanao
  • Ryosuke Takahashi
  • Nobutaka Hattori
  • Yuzuru Imai
  • Bingwei Lu
  • 全て表示

8
3
開始ページ
e1002537
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1371/journal.pgen.1002537

Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.

リンク情報
DOI
https://doi.org/10.1371/journal.pgen.1002537
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/22396657
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291531
ID情報
  • DOI : 10.1371/journal.pgen.1002537
  • ISSN : 1553-7390
  • PubMed ID : 22396657
  • PubMed Central 記事ID : PMC3291531

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