ArticleAntioxidants & redox signaling2014
Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter.
Article in Antioxidants & redox signaling, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 87 citations in OpenAlex.
- Small-conductance CaThe Journal of physiology · 2026Review
- Mitochondrial CaCommunications biology · 2026Article
- Inhibition of Pyk2 prevents Cx43 remodeling and cardiomyocyte injury during hypoxic and adrenergic stress.Journal of molecular and cellular cardiology · 2026Article
- Artificial intelligence-driven design and optimization of mitochondria-targeted nanocarriers for chronic heart failure.Frontiers in bioengineering and biotechnology · 2026Review
- Mitochondrial CaJournal of cellular physiology · 2025Review
- Mitochondrial Calcium Uniporter (MCU)-Mediated Calcium Overload in Psychoactive Drug Neurotoxicity: From Pathogenesis to Therapeutic Targets.International journal of molecular sciences · 2025Review
- Disrupting the network of co-evolving amino terminal domain residues relieves mitochondrial calcium uptake inhibition by MCUb.Computational and structural biotechnology journal · 2025Article
- c-Src Is Responsible for Mitochondria-Mediated Arrhythmic Risk in Ischemic Cardiomyopathy.Circulation. Arrhythmia and electrophysiology · 2024Article
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- Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection.Antioxidants (Basel, Switzerland) · 2024Review
- Kinase signalling adaptation supports dysfunctional mitochondria in disease.Frontiers in molecular biosciences · 2024Review
- SARS-CoV-2-ORF3a variant Q57H reduces its pro-apoptotic activity in host cells.F1000Research · 2024Article
- Multifaceted functions of Drp1 in hypoxia/ischemia-induced mitochondrial quality imbalance: from regulatory mechanism to targeted therapeutic strategy.Military Medical Research · 2023Review
- TRPM7 kinase mediates hypomagnesemia-induced seizure-related death.Scientific reports · 2023Article
- Calcium and Reactive Oxygen Species Signaling Interplays in Cardiac Physiology and Pathologies.Antioxidants (Basel, Switzerland) · 2023Review
- CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection.Science advances · 2022Article
- The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1.Scientific reports · 2022Article
- Mitochondrial calcium exchange in physiology and disease.Physiological reviews · 2022Review
- Mitochondrial CaInternational journal of molecular sciences · 2022Review
- Article
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Authors and funding
17 authors at 5 institutions in 3 countries.
Funding
Abstract
aimsMitochondrial Ca2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca2+ entry through posttranslational modifications of MCU are completely unknown. Therefore, we investigated α1-adrenergic-mediated signal transduction of MCU posttranslational modification and function in cardiac cells.
resultsα1-adrenoceptor (α1-AR) signaling translocated activated proline-rich tyrosine kinase 2 (Pyk2) from the cytosol to mitochondrial matrix and accelerates mitochondrial Ca2+ uptake via Pyk2-dependent MCU phosphorylation and tetrametric MCU channel pore formation. Moreover, we found that α1-AR stimulation increases reactive oxygen species production at mitochondria, mitochondrial permeability transition pore activity, and initiates apoptotic signaling via Pyk2-dependent MCU activation and mitochondrial Ca2+ overload. INNOVATION: Our data indicate that inhibition of α1-AR-Pyk2-MCU signaling represents a potential novel therapeutic target to limit or prevent mitochondrial Ca2+ overload, oxidative stress, mitochondrial injury, and myocardial death during pathophysiological conditions, where chronic adrenergic stimulation is present.
conclusionThe α1-AR-Pyk2-dependent tyrosine phosphorylation of the MCU regulates mitochondrial Ca2+ entry and apoptosis in cardiac cells.
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