2. Academic Validation
  3. Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1

Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1

  • Mol Cell. 2019 Mar 7;73(5):1028-1043.e5. doi: 10.1016/j.molcel.2019.01.002.
Shiori Sekine 1,  Chunxin Wang 1,  Dionisia P Sideris 1,  Eric Bunker 1,  Zhe Zhang 1,  Richard J Youle 2
Affiliations

Affiliations

  • 1 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
  • 2 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
PMID: 30733118 DOI: 10.1016/j.molcel.2019.01.002
Abstract

Mutations in PTEN-induced kinase 1 (PINK1) can cause recessive early-onset Parkinson's disease (PD). Import arrest results in PINK1 kinase activation specifically on damaged mitochondria, triggering Parkin-mediated Mitophagy. Here, we show that PINK1 import is less dependent on Tim23 than on mitochondrial membrane potential (ΔΨm). We identified a negatively charged amino acid cluster motif that is evolutionarily conserved just C-terminal to the PINK1 transmembrane. PINK1 that fails to accumulate at the outer mitochondrial membrane, either by mutagenesis of this negatively charged motif or by deletion of Tom7, is imported into depolarized mitochondria and cleaved by the OMA1 protease. Some PD patient mutations also are defective in import arrest and are rescued by the suppression of OMA1, providing a new potential druggable target for PD. These results suggest that ΔΨm loss-dependent PINK1 import arrest does not result solely from Tim23 inactivation but also through an actively regulated "tug of war" between Tom7 and OMA1.

Keywords

OMA1; TIM23 complex; TOM complex; mitochondrial protease; mitophagy.

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