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Functional remodelling of perinuclear mitochondria alters nucleoplasmic Ca2+ signalling in heart failure
Voglhuber, Julia Holzer, Michael Radulović, Snježana Thai, Phung N. Djalinac, Natasa Matzer, Ingrid Bugger, Heiko Zirlik, Andreas Leitinger, Gerd
Voglhuber, Julia
Holzer, Michael
Radulović, Snježana
Thai, Phung N.
Djalinac, Natasa
Matzer, Ingrid
Bugger, Heiko
Zirlik, Andreas
Leitinger, Gerd
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2022-10-03
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http://dx.doi.org/10.1098/rstb.2021.0320
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 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’.
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Voglhuber Julia, Holzer Michael, Radulović Snježana, Thai Phung N., Djalinac Natasa, Matzer Ingrid, Wallner Markus, Bugger Heiko, Zirlik Andreas, Leitinger Gerd, Dedkova Elena N., Bers Donald M. and Ljubojevic-Holzer Senka 2022Functional remodelling of perinuclear mitochondria alters nucleoplasmic Ca2+ signalling in heart failurePhil. Trans. R. Soc. B37720210320
http://doi.org/10.1098/rstb.2021.0320
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Royal Society of London
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Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 337, Iss. 1864
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