Functional remodelling of perinuclear mitochondria alters nucleoplasmic Ca 2+ signalling in heart failure

Author:

Voglhuber Julia12ORCID,Holzer Michael23ORCID,Radulović Snježana4ORCID,Thai Phung N.5ORCID,Djalinac Natasa1ORCID,Matzer Ingrid1ORCID,Wallner Markus16ORCID,Bugger Heiko1ORCID,Zirlik Andreas1ORCID,Leitinger Gerd4ORCID,Dedkova Elena N.78ORCID,Bers Donald M.7ORCID,Ljubojevic-Holzer Senka129ORCID

Affiliation:

1. Department of Cardiology, Medical University of Graz, Graz, Austria

2. BioTechMed-Graz, Graz, Austria

3. Division of Pharmacology, Otto-Loewi Research Centre, Medical University of Graz, Graz, Austria

4. Research Unit Electron Microscopic Techniques, Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria

5. Department of Internal Medicine, Cardiovascular Medicine, University of California Davis, Davis, CA, USA

6. Lewis Katz School of Medicine, Temple University, Cardiovascular Research Center, Philadelphia, PA, USA

7. Department of Pharmacology, University of California Davis, Davis, CA, USA

8. Department of Molecular Biosciences, University of California Davis, Davis, CA, USA

9. Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria

Abstract

Mitochondrial dysfunction in cardiomyocytes is a hallmark of heart failure development. Although initial studies recognized the importance of different mitochondrial subpopulations, there is a striking lack of direct comparison of intrafibrillar (IF) versus perinuclear (PN) mitochondria during the development of HF. Here, we use multiple approaches to examine the morphology and functional properties of IF versus PN mitochondria in pressure overload-induced cardiac remodelling in mice, and in non-failing and failing human cardiomyocytes. We demonstrate that PN mitochondria from failing cardiomyocytes are more susceptible to depolarization of mitochondrial membrane potential, reactive oxygen species generation and impairment in Ca 2+ uptake compared with IF mitochondria at baseline and under physiological stress protocol. We also demonstrate, for the first time to our knowledge, that under normal conditions PN mitochondrial Ca 2+ uptake shapes nucleoplasmic Ca 2+ transients (CaTs) and limits nucleoplasmic Ca 2+ loading. The loss of PN mitochondrial Ca 2+ buffering capacity translates into increased nucleoplasmic CaTs and may explain disproportionate rise in nucleoplasmic [Ca 2+ ] in failing cardiomyocytes at increased stimulation frequencies. Therefore, a previously unidentified benefit of restoring the mitochondrial Ca 2+ uptake may be normalization of nuclear Ca 2+ signalling and alleviation of altered excitation–transcription, which could be an important therapeutic approach to prevent adverse cardiac remodelling. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

Funder

University of California Davis

Austrian Science Fund

BioTechMed-Graz

University of California

National Institute of Health

Friedreich's Ataxia Research Alliance

Publisher

The Royal Society

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology

Cited by 7 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3