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Mitochondria-associated ER Membranes MAMs and Glycosphingolipid Enriched Microdomains GEMs: Isolation from Mouse Brain
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Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death

Abhinav Diwan1, Scot J Matkovich, Qunying Yuan

  • 1Center for Pharmacogenomics, Washington University in St. Louis, St. Louis, MO 63110, USA.

The Journal of Clinical Investigation
|December 10, 2008
PubMed

Insights

The proapoptotic protein NIX causes heart failure by disrupting mitochondria and the endoplasmic reticulum/sarcoplasmic reticulum (ER/SR). Nix

Area of Science:

  • Molecular Biology
  • Cardiovascular Biology
  • Cell Death Pathways

Background:

  • The proapoptotic BCL2 family protein NIX is implicated in limiting red blood cell formation and causing heart failure.
  • The precise molecular mechanisms underlying NIX-induced cell death, particularly in the heart, remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which NIX induces cell death in cardiomyocytes.
  • To investigate the roles of mitochondria and the endoplasmic reticulum/sarcoplasmic reticulum (ER/SR) in NIX-mediated cardiac cell death.

Main Methods:

  • Utilized genetic mouse models with Nix ablation or specific Nix mutations.
  • Investigated NIX localization in cardiac cells using endogenous and recombinant NIX.
  • Assessed cardiomyocyte ER/SR calcium levels and mitochondrial membrane potential.
  • Analyzed caspase activation in response to NIX expression.

Main Results:

  • Endogenous and recombinant NIX were found to localize to both mitochondria and the ER/SR.
  • Cardiac NIX levels directly correlated with cardiomyocyte ER/SR calcium stores.
  • Nix ablation protected against apoptotic cardiomyopathy, while restoring SR calcium content re-sensitized Nix-null mice to cell death.
  • Mutants of NIX targeting either ER/SR or mitochondria were equally lethal, but only ER/SR-Nix induced loss of mitochondrial membrane potential.

Conclusions:

  • NIX mediates programmed cell death through complementary mechanisms involving direct mitochondrial disruption and ER/SR-mediated effects.
  • NIX integrates transcriptional and calcium-dependent signals to regulate cell death.
  • These findings reveal a novel function for NIX in integrating cellular stress pathways leading to cardiomyopathy.

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