Dataset Information

IGF-1 boosts mitochondrial function by a Ca²⁺ uptake-dependent mechanism in cultured human and rat cardiomyocytes.

ABSTRACT: A physiological increase in cardiac workload results in adaptive cardiac remodeling, characterized by increased oxidative metabolism and improvements in cardiac performance. Insulin-like growth factor-1 (IGF-1) has been identified as a critical regulator of physiological cardiac growth, but its precise role in cardiometabolic adaptations to physiological stress remains unresolved. Mitochondrial calcium (Ca²⁺) handling has been proposed to be required for sustaining key mitochondrial dehydrogenase activity and energy production during increased workload conditions, thus ensuring the adaptive cardiac response. We hypothesized that IGF-1 enhances mitochondrial energy production through a Ca²⁺-dependent mechanism to ensure adaptive cardiomyocyte growth. We found that stimulation with IGF-1 resulted in increased mitochondrial Ca²⁺ uptake in neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes, estimated by fluorescence microscopy and indirectly by a reduction in the pyruvate dehydrogenase phosphorylation. We showed that IGF-1 modulated the expression of mitochondrial Ca²⁺ uniporter (MCU) complex subunits and increased the mitochondrial membrane potential; consistent with higher MCU-mediated Ca²⁺ transport. Finally, we showed that IGF-1 improved mitochondrial respiration through a mechanism dependent on MCU-mediated Ca²⁺ transport. In conclusion, IGF-1-induced mitochondrial Ca²⁺ uptake is required to boost oxidative metabolism during cardiomyocyte adaptive growth.

SUBMITTER: Sanchez-Aguilera P

PROVIDER: S-EPMC9944404 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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IGF-1 boosts mitochondrial function by a Ca<sup>2+</sup> uptake-dependent mechanism in cultured human and rat cardiomyocytes.

Sánchez-Aguilera Pablo P López-Crisosto Camila C Norambuena-Soto Ignacio I Penannen Christian C Zhu Jumo J Bomer Nils N Hoes Matijn F MF Van Der Meer Peter P Chiong Mario M Westenbrink B Daan BD Lavandero Sergio S

Frontiers in physiology 20230208

A physiological increase in cardiac workload results in adaptive cardiac remodeling, characterized by increased oxidative metabolism and improvements in cardiac performance. Insulin-like growth factor-1 (IGF-1) has been identified as a critical regulator of physiological cardiac growth, but its precise role in cardiometabolic adaptations to physiological stress remains unresolved. Mitochondrial calcium (Ca<sup>2+</sup>) handling has been proposed to be required for sustaining key mitochondrial d ...[more]

PMID: 36846332

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Project description:BackgroundRadiation therapy strongly increases the risk of atherosclerotic vascular disease, such as carotid stenosis. Radiation induces DNA damage, in particular in mitochondria, but the upstream and downstream signaling events are poorly understood. The objective of this study was to define such mechanisms.MethodsEndothelial-specific MCU (mitochondrial Ca2+ uniporter) knockout and C57Bl6/J mice with or without a preinfusion of a mitoTEMPO (mitochondrial reactive oxygen species [ROS] scavenger) were exposed to a single dose of cranial irradiation. 24, and 240 hours postirradiation, vascular reactivity, endothelial function, and mitochondrial integrity were assessed ex vivo and in vitro.ResultsIn cultured human endothelial cells, irradiation with 4 Gy increased cytosolic Ca2+ transients and the mitochondrial Ca2+ concentration ([Ca2+]mt) and activated MCU. These outcomes correlated with increases in mitochondrial ROS (mtROS), loss of NO production, and sustained damage to mitochondrial but not nuclear DNA. Moreover, irradiation impaired activity of the ETC (electron transport chain) and the transcription of ETC subunits encoded by mitochondrial DNA (mtDNA). Knockdown or pharmacological inhibition of MCU blocked irradiation-induced mtROS production, mtDNA damage, loss of NO production, and impairment of ETC activity. Similarly, the pretreatment with mitoTEMPO, a scavenger of mtROS, reduced irradiation-induced Ca2+ entry, and preserved both the integrity of the mtDNA and the production of NO, suggesting a feed-forward loop involving [Ca2+]m and mtROS. Enhancement of DNA repair in mitochondria, but not in the nucleus, was sufficient to block prolonged mtROS elevations and maintain NO production. Consistent with the findings from cultured cells, in C57BL/6J mice, head and neck irradiation decreased endothelium-dependent vasodilation, and mtDNA integrity in the carotid artery after irradiation. These effects were prevented by endothelial knockout of MCU or infusion with mitoTEMPO.ConclusionsIrradiation-induced damage to mtDNA is driven by MCU-dependent Ca2+ influx and the generation of mtROS. Such damage leads to reduced transcription of mitochondrial genes and activity of the ETC, promoting sustained mtROS production that induces endothelial dysfunction. Our findings suggest that targeting MCU and mtROS might be sufficient to mitigate irradiation-induced vascular disease.

Dataset Information

IGF-1 boosts mitochondrial function by a Ca²⁺ uptake-dependent mechanism in cultured human and rat cardiomyocytes.

Publications

IGF-1 boosts mitochondrial function by a Ca<sup>2+</sup> uptake-dependent mechanism in cultured human and rat cardiomyocytes.

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Dataset Information

IGF-1 boosts mitochondrial function by a Ca2+ uptake-dependent mechanism in cultured human and rat cardiomyocytes.

Publications

IGF-1 boosts mitochondrial function by a Ca<sup>2+</sup> uptake-dependent mechanism in cultured human and rat cardiomyocytes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

IGF-1 boosts mitochondrial function by a Ca²⁺ uptake-dependent mechanism in cultured human and rat cardiomyocytes.