MilliporeSigma
  • Home
  • Search Results
  • HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart.

HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart.

Proceedings of the National Academy of Sciences of the United States of America (2015-11-11)
Chi Keung Lam, Wen Zhao, Guan-Sheng Liu, Wen-Feng Cai, George Gardner, George Adly, Evangelia G Kranias
ABSTRACT

The major underpinning of massive cell death associated with myocardial infarction involves opening of the mitochondrial permeability transition pore (mPTP), resulting in disruption of mitochondria membrane integrity and programmed necrosis. Studies in human lymphocytes suggested that the hematopoietic-substrate-1 associated protein X-1 (HAX-1) is linked to regulation of mitochondrial membrane function, but its role in controlling mPTP activity remains obscure. Herein we used models with altered HAX-1 expression levels in the heart and uncovered an unexpected role of HAX-1 in regulation of mPTP and cardiomyocyte survival. Cardiac-specific HAX-1 overexpression was associated with resistance against loss of mitochondrial membrane potential, induced by oxidative stress, whereas HAX-1 heterozygous deficiency exacerbated vulnerability. The protective effects of HAX-1 were attributed to specific down-regulation of cyclophilin-D levels leading to reduction in mPTP activation. Accordingly, cyclophilin-D and mPTP were increased in heterozygous hearts, but genetic ablation of cyclophilin-D in these hearts significantly alleviated their susceptibility to ischemia/reperfusion injury. Mechanistically, alterations in cyclophilin-D levels by HAX-1 were contributed by the ubiquitin-proteosomal degradation pathway. HAX-1 overexpression enhanced cyclophilin-D ubiquitination, whereas proteosomal inhibition restored cyclophilin-D levels. The regulatory effects of HAX-1 were mediated through interference of cyclophilin-D binding to heat shock protein-90 (Hsp90) in mitochondria, rendering it susceptible to degradation. Accordingly, enhanced Hsp90 expression in HAX-1 overexpressing cardiomyocytes increased cyclophilin-D levels, as well as mPTP activation upon oxidative stress. Taken together, our findings reveal the role of HAX-1 in regulating cyclophilin-D levels via an Hsp90-dependent mechanism, resulting in protection against activation of mPTP and subsequent cell death responses.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Potassium phosphate dibasic, 99.95% trace metals basis
Sigma-Aldrich
Sodium bicarbonate-12C, 99.9 atom % 12C
Sigma-Aldrich
Nitrogen, ≥99.998%
Sigma-Aldrich
Taurine, suitable for cell culture, meets USP testing specifications
Sigma-Aldrich
Taurine, ≥99%
Sigma-Aldrich
Potassium phosphate dibasic, reagent grade, ≥98.0%
Sigma-Aldrich
Potassium phosphate monobasic, BioUltra, for molecular biology, anhydrous, ≥99.5% (T)
Sigma-Aldrich
Tetramethylrhodamine ethyl ester perchlorate, suitable for fluorescence, ≥90% (HPCE)
SAFC
Taurine
Sigma-Aldrich
Taurine, BioUltra, ≥99.5% (T)
Sigma-Aldrich
Propidium iodide solution, solution (1.0 mg/ml in water)
Sigma-Aldrich
L-Glutamine, BioUltra, ≥99.5% (NT)
Sigma-Aldrich
Potassium phosphate dibasic, anhydrous, for luminescence, for molecular biology, BioUltra, ≥99.0% (T)
SAFC
L-Glutamine
Sigma-Aldrich
Potassium phosphate monobasic, for molecular biology, ≥98.0%
Sigma-Aldrich
L-Glutamine, meets USP testing specifications, suitable for cell culture, 99.0-101.0%, from non-animal source
Sigma-Aldrich
L-Glutamine, ReagentPlus®, ≥99% (HPLC)
Sigma-Aldrich
L-Glutamine, γ-irradiated, BioXtra, suitable for cell culture
Sigma-Aldrich
Potassium phosphate dibasic solution, 1.0 M
Sigma-Aldrich
Potassium phosphate monobasic, powder, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥99.0%
Sigma-Aldrich
Potassium phosphate dibasic, meets USP testing specifications
Sigma-Aldrich
Creatine, anhydrous
Sigma-Aldrich
L-Carnitine inner salt, synthetic, ≥98%
Sigma-Aldrich
Potassium phosphate monobasic, ReagentPlus®
Sigma-Aldrich
L-Glutamine
Sigma-Aldrich
Sodium carbonate-12C, 99.9 atom % 12C
Sigma-Aldrich
Potassium phosphate monobasic, 99.99% trace metals basis
Sigma-Aldrich
Taurine, ≥98%, FG
Sigma-Aldrich
Potassium phosphate monobasic, ACS reagent, ≥99.0%
Sigma-Aldrich
Potassium phosphate dibasic, ACS reagent, ≥98%