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Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Shabana Din1, Matthew Mason, Mirko Völkers

  • 1San Diego State Heart Institute, San Diego State University, San Diego, CA 92182, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 27, 2013
PubMed

Insights

Pim-1 kinase activity prevents dynamin-related protein 1 (Drp1) mitochondrial localization, preserving mitochondrial morphology and inhibiting cell death during cardiac ischemic stress.

Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Biology
  • Cell Death Pathways

Background:

  • Mitochondrial dynamics are crucial in ischemic heart damage.
  • Dynamin-related protein 1 (Drp1) mediates mitochondrial fission and cell death during cardiac ischemia.
  • The role of Pim-1 in regulating Drp1 during ischemic stress is not well understood.

Purpose of the Study:

  • To investigate the relationship between Pim-1 activity and Drp1-mediated mitochondrial morphology in cardiomyocytes under ischemic conditions.
  • To elucidate the mechanism by which Pim-1 influences Drp1 localization and mitochondrial dynamics during simulated ischemia.

Main Methods:

  • Utilized transgenic hearts overexpressing cardiac Pim-1.
  • Employed adenoviral induction of Pim-1 and Pim-dominant negative constructs in neonatal rat cardiomyocytes (NRCMs).
  • Assessed mitochondrial morphology, Drp1 protein levels, Drp1 phosphorylation (S637), Drp1 mitochondrial localization, and expression of PUMA (p53 up-regulated modulator of apoptosis) following simulated ischemia (sI).

Main Results:

  • Overexpression of cardiac Pim-1 reduced total Drp1 levels, increased Drp1 phosphorylation at S637, and inhibited Drp1 mitochondrial localization.
  • Pim-1-expressing NRCMs maintained a reticular mitochondrial phenotype and showed decreased Drp1 sequestration after sI.
  • Pim-dominant negative NRCMs exhibited increased PUMA expression, enhanced Drp1 mitochondrial accumulation, and greater sensitivity to apoptosis.
  • Inhibition of PUMA attenuated Drp1 mitochondrial localization in Pim-dominant negative NRCMs, promoting reticular mitochondrial morphology and reducing cell death during sI.

Conclusions:

  • Pim-1 activity plays a protective role against ischemic heart damage by inhibiting Drp1 compartmentalization to mitochondria.
  • Pim-1 preserves mitochondrial integrity and prevents apoptosis during ischemic stress through Drp1-dependent mechanisms.
  • The findings highlight a novel regulatory axis involving Pim-1, Drp1, and PUMA in cardiomyocyte response to ischemia.

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