Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Voglhuber, J; Holzer, M; Radulović, S; Thai, PN; Djalinac, N; Matzer, I; Wallner, M; Bugger, H; Zirlik, A; Leitinger, G; Dedkova, EN; Bers, DM; Ljubojevic-Holzer, S.
Functional remodelling of perinuclear mitochondria alters nucleoplasmic Ca2+ signalling in heart failure.
Philos Trans R Soc Lond B Biol Sci. 2022; 377(1864): 20210320 Doi: 10.1098/rstb.2021.0320 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Holzer Michael
Holzer Senka
Voglhuber Julia
Co-Autor*innen der Med Uni Graz
Bugger Heiko Matthias
Leitinger Gerd
Matzer Ingrid
Radulovic Snjezana
Wallner Markus
Zirlik Andreas

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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 Ca2+ 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 Ca2+ uptake shapes nucleoplasmic Ca2+ transients (CaTs) and limits nucleoplasmic Ca2+ loading. The loss of PN mitochondrial Ca2+ buffering capacity translates into increased nucleoplasmic CaTs and may explain disproportionate rise in nucleoplasmic [Ca2+] in failing cardiomyocytes at increased stimulation frequencies. Therefore, a previously unidentified benefit of restoring the mitochondrial Ca2+ uptake may be normalization of nuclear Ca2+ 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'.
Find related publications in this database (using NLM MeSH Indexing)
Animals - administration & dosage
Calcium - metabolism
Heart Failure - administration & dosage
Humans - administration & dosage
Mice - administration & dosage
Mitochondria - physiology
Myocytes, Cardiac - metabolism
Reactive Oxygen Species - metabolism
Ventricular Remodeling - physiology

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