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Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in

J Tabitha Hees1,2, Simone Wanderoy1,2, Jana Lindner2

  • 1TUM Medical Graduate Center, Technical University of Munich, Munich, Germany.

Nature Metabolism
|March 20, 2024
PubMed

Insights

Insulin signaling prevents Pink1 mRNA from binding to mitochondria, which is crucial for PINK1 activation and mitophagy. This metabolic control is disrupted in Alzheimer

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Mitochondrial quality control is vital for neuronal health and often fails in neurodegenerative diseases.
  • PTEN-induced kinase 1 (PINK1) detects damaged mitochondria, a process dependent on Pink1 mRNA localization to mitochondria.
  • AMP-activated protein kinase (AMPK) is a key energy sensor in cells.

Purpose of the Study:

  • To investigate the role of insulin and AMPK signaling in regulating Pink1 mRNA localization and PINK1 activity.
  • To elucidate the molecular mechanism by which insulin signaling affects Pink1 mRNA binding to mitochondria.
  • To explore the link between insulin resistance, apolipoprotein E4, and mitochondrial dysfunction in the context of neurodegeneration.

Main Methods:

  • Investigated the effect of insulin signaling activation on Pink1 mRNA binding to mitochondria.
  • Utilized biochemical assays to identify the phosphorylation site on SYNJ2BP targeted by AMPK.
  • Examined the impact of insulin resistance induced by apolipoprotein E4 on Pink1 mRNA localization and PINK1 activity in neuronal models.

Main Results:

  • Insulin signaling activation inhibits Pink1 mRNA binding to mitochondria by preventing AMPK-mediated phosphorylation of SYNJ2BP.
  • Loss of mitochondrial Pink1 mRNA association is essential for PINK1 protein activation and mitophagy.
  • Insulin resistance, particularly with apolipoprotein E4, causes aberrant Pink1 mRNA retention at mitochondria, impairing PINK1 activity, especially in neuronal processes.

Conclusions:

  • Insulin and AMPK signaling act as a metabolic switch controlling Pink1 mRNA localization and subsequent PINK1 activity in neurons.
  • This pathway provides a mechanistic link between metabolic disturbances like insulin resistance and mitochondrial dysfunction observed in neurodegenerative diseases such as Alzheimer's disease.

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