Cargando…

ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca(2+) Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ

ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of...

Descripción completa

Detalles Bibliográficos
Autores principales: Pavez-Giani, Mario G., Sánchez-Aguilera, Pablo I., Bomer, Nils, Miyamoto, Shigeki, Booij, Harmen G., Giraldo, Paula, Oberdorf-Maass, Silke U., Nijholt, Kirsten T., Yurista, Salva R., Milting, Hendrik, van der Meer, Peter, de Boer, Rudolf A., Heller Brown, Joan, Sillje, Herman W. H., Westenbrink, B. Daan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122940/
https://www.ncbi.nlm.nih.gov/pubmed/33922643
http://dx.doi.org/10.3390/ijms22094427
_version_ 1783692761093898240
author Pavez-Giani, Mario G.
Sánchez-Aguilera, Pablo I.
Bomer, Nils
Miyamoto, Shigeki
Booij, Harmen G.
Giraldo, Paula
Oberdorf-Maass, Silke U.
Nijholt, Kirsten T.
Yurista, Salva R.
Milting, Hendrik
van der Meer, Peter
de Boer, Rudolf A.
Heller Brown, Joan
Sillje, Herman W. H.
Westenbrink, B. Daan
author_facet Pavez-Giani, Mario G.
Sánchez-Aguilera, Pablo I.
Bomer, Nils
Miyamoto, Shigeki
Booij, Harmen G.
Giraldo, Paula
Oberdorf-Maass, Silke U.
Nijholt, Kirsten T.
Yurista, Salva R.
Milting, Hendrik
van der Meer, Peter
de Boer, Rudolf A.
Heller Brown, Joan
Sillje, Herman W. H.
Westenbrink, B. Daan
author_sort Pavez-Giani, Mario G.
collection PubMed
description ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). Methods and results: Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild-type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evidenced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extramitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP synthase (E55A mutation), an indication that these effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca(2+) handling, which resulted in sarcoplasmic reticulum Ca(2+) overloading. The effects of IF1 on Ca(2+) handling were associated with the cytosolic activation of calcium–calmodulin kinase II (CaMKII) and inhibition of CaMKII or co-expression of catalytically dead CaMKIIδC was sufficient to prevent IF1 induced pathological hypertrophy. Conclusions: IF1 represents a novel member of the fetal-like gene program that contributes to mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca(2+) handling and mitochondrial-to-nuclear crosstalk involving CaMKII.
format Online
Article
Text
id pubmed-8122940
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-81229402021-05-16 ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca(2+) Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ Pavez-Giani, Mario G. Sánchez-Aguilera, Pablo I. Bomer, Nils Miyamoto, Shigeki Booij, Harmen G. Giraldo, Paula Oberdorf-Maass, Silke U. Nijholt, Kirsten T. Yurista, Salva R. Milting, Hendrik van der Meer, Peter de Boer, Rudolf A. Heller Brown, Joan Sillje, Herman W. H. Westenbrink, B. Daan Int J Mol Sci Article ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). Methods and results: Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild-type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evidenced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extramitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP synthase (E55A mutation), an indication that these effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca(2+) handling, which resulted in sarcoplasmic reticulum Ca(2+) overloading. The effects of IF1 on Ca(2+) handling were associated with the cytosolic activation of calcium–calmodulin kinase II (CaMKII) and inhibition of CaMKII or co-expression of catalytically dead CaMKIIδC was sufficient to prevent IF1 induced pathological hypertrophy. Conclusions: IF1 represents a novel member of the fetal-like gene program that contributes to mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca(2+) handling and mitochondrial-to-nuclear crosstalk involving CaMKII. MDPI 2021-04-23 /pmc/articles/PMC8122940/ /pubmed/33922643 http://dx.doi.org/10.3390/ijms22094427 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pavez-Giani, Mario G.
Sánchez-Aguilera, Pablo I.
Bomer, Nils
Miyamoto, Shigeki
Booij, Harmen G.
Giraldo, Paula
Oberdorf-Maass, Silke U.
Nijholt, Kirsten T.
Yurista, Salva R.
Milting, Hendrik
van der Meer, Peter
de Boer, Rudolf A.
Heller Brown, Joan
Sillje, Herman W. H.
Westenbrink, B. Daan
ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca(2+) Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ
title ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca(2+) Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ
title_full ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca(2+) Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ
title_fullStr ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca(2+) Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ
title_full_unstemmed ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca(2+) Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ
title_short ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca(2+) Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ
title_sort atpase inhibitory factor-1 disrupts mitochondrial ca(2+) handling and promotes pathological cardiac hypertrophy through camkiiδ
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122940/
https://www.ncbi.nlm.nih.gov/pubmed/33922643
http://dx.doi.org/10.3390/ijms22094427
work_keys_str_mv AT pavezgianimariog atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT sanchezaguilerapabloi atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT bomernils atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT miyamotoshigeki atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT booijharmeng atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT giraldopaula atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT oberdorfmaasssilkeu atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT nijholtkirstent atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT yuristasalvar atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT miltinghendrik atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT vandermeerpeter atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT deboerrudolfa atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT hellerbrownjoan atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT silljehermanwh atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid
AT westenbrinkbdaan atpaseinhibitoryfactor1disruptsmitochondrialca2handlingandpromotespathologicalcardiachypertrophythroughcamkiid