The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
08 09 2021
08 09 2021
Historique:
received:
05
03
2021
accepted:
13
08
2021
entrez:
9
9
2021
pubmed:
10
9
2021
medline:
12
11
2021
Statut:
epublish
Résumé
Obesity and diabetes increase the risk of arrhythmia and sudden cardiac death. However, the molecular mechanisms of arrhythmia caused by metabolic abnormalities are not well understood. We hypothesized that mitochondrial dysfunction caused by high fat diet (HFD) promotes ventricular arrhythmia. Based on our previous work showing that saturated fat causes calcium handling abnormalities in cardiomyocytes, we hypothesized that mitochondrial calcium uptake contributes to HFD-induced mitochondrial dysfunction and arrhythmic events. For experiments, we used mice with conditional cardiac-specific deletion of the mitochondrial calcium uniporter (Mcu), which is required for mitochondrial calcium uptake, and littermate controls. Mice were used for in vivo heart rhythm monitoring, perfused heart experiments, and isolated cardiomyocyte experiments. MCU KO mice are protected from HFD-induced long QT, inducible ventricular tachycardia, and abnormal ventricular repolarization. Abnormal repolarization may be due, at least in part, to a reduction in protein levels of voltage gated potassium channels. Furthermore, isolated cardiomyocytes from MCU KO mice exposed to saturated fat are protected from increased reactive oxygen species (ROS), mitochondrial dysfunction, and abnormal calcium handling. Activation of calmodulin-dependent protein kinase (CaMKII) corresponds with the increase in arrhythmias in vivo. Additional experiments showed that CaMKII inhibition protects cardiomyocytes from the mitochondrial dysfunction caused by saturated fat. Hearts from transgenic CaMKII inhibitor mice were protected from inducible ventricular tachycardia after HFD. These studies identify mitochondrial dysfunction caused by calcium overload as a key mechanism of arrhythmia during HFD. This work indicates that MCU and CaMKII could be therapeutic targets for arrhythmia caused by metabolic abnormalities.
Identifiants
pubmed: 34497331
doi: 10.1038/s41598-021-97449-3
pii: 10.1038/s41598-021-97449-3
pmc: PMC8426388
doi:
Substances chimiques
Calcium Channels
0
Reactive Oxygen Species
0
mitochondrial calcium uniporter
0
Calcium-Calmodulin-Dependent Protein Kinase Type 2
EC 2.7.11.17
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
17808Subventions
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL136954
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01HL152236
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL123966
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142271
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007343
Pays : United States
Organisme : NHLBI NIH HHS
ID : NIH R01 HL136758
Pays : United States
Informations de copyright
© 2021. The Author(s).
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