Article Text

PDF
21 HAX-1: a mitochondrial anti-apoptotic protein with emerging roles in cardiac muscle
  1. E Vafiadaki1,
  2. C K Lam2,
  3. W Zhao2,
  4. D A Arvanitis1,
  5. D Sanoudou1,3,
  6. A Kontrogianni-Konstantopoulos4,
  7. E G Kranias1,2
  1. 1Molecular Biology Division, Biomedical Research Foundation, Academy of Athens, Greece
  2. 2Department of Pharmacology and Cell Biophysics, University of Cincinnati, USA
  3. 3Department of Pharmacology, University of Athens, Greece
  4. 4Department of Biochemistry and Molecular Biology, University of Maryland, USA

Abstract

Cardiac contractility is controlled by key sarcoplasmic reticulum (SR) Ca2+ handling proteins that regulate intracellular Ca2+ homeostasis. Impaired Ca2+ handling has been associated with heart failure, thus emphasising its critical role in cardiac function. During cardiac relaxation, SR Ca2+ uptake is regulated by the activity of the sarco(endo)plasmic reticulum Ca2+ transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN). We have identified HS-1 associated protein X-1 (HAX-1), a ubiquitously expressed mitochondrial protein with anti-apoptotic function, as a novel binding partner of PLN. This association was found to cause a subcellular redistribution of HAX-1 from mitochondria to the ER and enhanced the protective effects of HAX-1 on cell survival. Deletion analysis determined that a C-terminal fragment encompassing amino acids 182–279 of HAX-1 were required for binding to PLN and ER localisation, while mitochondrial targeting required an N- terminal region of the protein. HAX-1 overexpression in HEK293 cells resulted in significant reduction of ER Ca2+ content, providing evidence for a role in promoting cell survival through modulation of ER Ca2+ stores. Moreover, HAX-1 overexpression in cardiomyocytes was associated with decreased SR Ca2+ content and depressed cardiomyocyte contractility. Our recent findings suggest a protective effect of HAX-1 on mitochondria as indicated by increased resistance to swelling induced by calcium and depressed cytochrome c release following oxidative stress in mitochondria isolated from HAX-1 overexpressing hearts. Collectively, our findings provide insights on the mechanisms through which HAX-1 may modulate cell survival, indicating its importance in cardiac muscle.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.