Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease

Chung Han Hsieh, Atossa Shaltouki, Ashley E. Gonzalez, Alexandre Bettencourt da Cruz, Lena F. Burbulla, Erica St. Lawrence, Birgitt Schüle, Dimitri Krainc, Theo D. Palmer, Xinnan Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

193 Scopus citations

Abstract

Mitochondrial movements are tightly controlled to maintain energy homeostasis and prevent oxidative stress. Miro is an outer mitochondrial membrane protein that anchors mitochondria to microtubule motors and is removed to stop mitochondrial motility as an early step in the clearance of dysfunctional mitochondria. Here, using human induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we build on a previous connection of Parkinson's disease (PD)-linked PINK1 and Parkin to Miro by showing that a third PD-related protein, LRRK2, promotes Miro removal by forming a complex with Miro. Pathogenic LRRK2G2019S disrupts this function, delaying the arrest of damaged mitochondria and consequently slowing the initiation of mitophagy. Remarkably, partial reduction of Miro levels in LRRK2G2019S human neuron and Drosophila PD models rescues neurodegeneration. Miro degradation and mitochondrial motility are also impaired in sporadic PD patients. We reveal that prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis.

Original languageEnglish (US)
Pages (from-to)709-724
Number of pages16
JournalCell stem cell
Volume19
Issue number6
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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