ArticleCardiovascular research2022
SR-Mitochondria Crosstalk Shapes Ca Signalling to Impact Pathophenotype in Disease Models Marked by Dysregulated Intracellular Ca Release.
Article in Cardiovascular research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Knowledge mapping of mitochondrial calcium uniporter from 2011 to 2022: A bibliometric analysis.Frontiers in physiology · 2023Pooled it
- Mitoquinone Prevents Cardiac Dysfunction by Normalizing Mitochondrial ROS and Calcium Handling in Acute Myocardial Infarction.Acta physiologica (Oxford, England) · 2026Article
- Biomarkers of Cardiac Metabolic Flexibility in Health, HFrEF and HFpEF.International journal of molecular sciences · 2026Review
- Calcium release deficiency syndrome: an emerging ryanodinopathy.Frontiers in molecular biosciences · 2026Review
- Ablation of mitochondrial calcium uniporter alleviates cardiac dysfunction in type 1 diabetes.Cell calcium · 2026Article
- PITX2 dosage-dependent changes in pacemaker cell state underlie sinus node dysfunction and atrial arrhythmias.Nature communications · 2025Article
- Increased Intermembrane Space [CaCirculation research · 2025Article
- Mitochondrial dysfunction as a central hub linking NaFrontiers in cardiovascular medicine · 2025Review
- PITX2 deficiency leads to atrial mitochondrial dysfunction.Cardiovascular research · 2024Article
- Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT.Journal of molecular and cellular cardiology plus · 2024Article
- Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease.Physiology (Bethesda, Md.) · 2024Review
- Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction.Cardiovascular diabetology · 2024Review
- Top Stories: Mitochondrial origin of inherited cardiac arrhythmias.Heart rhythm · 2024Article
- Distinct Effects of Mitochondrial NaJournal of the American Heart Association · 2023Article
- Article
- Mitochondrial dysfunction in heart diseases: Potential therapeutic effects ofFrontiers in pharmacology · 2023Review
- Therapeutic Approaches of Ryanodine Receptor-Associated Heart Diseases.International journal of molecular sciences · 2022Review
- CaPflugers Archiv : European journal of physiology · 2022Review
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10 authors at 4 institutions in 1 country.
Funding
Abstract
aimsDiastolic Ca release (DCR) from sarcoplasmic reticulum (SR) Ca release channel ryanodine receptor (RyR2) has been linked to multiple cardiac pathologies, but its exact role in shaping divergent cardiac pathologies remains unclear. We hypothesize that the SR-mitochondria interplay contributes to disease phenotypes by shaping Ca signalling. METHODS AND
resultsA genetic model of catecholaminergic polymorphic ventricular tachycardia (CPVT2 model of CASQ2 knockout) and a pre-diabetic cardiomyopathy model of fructose-fed mice (FFD), both marked by DCR, are employed in this study. Mitochondria Ca (mCa) is modulated by pharmacologically targeting mitochondria Ca uniporter (MCU) or permeability transition pore (mPTP), mCa uptake, and extrusion mechanisms, respectively. An MCU activator abolished Ca waves in CPVT2 but exacerbated waves in FFD cells. Mechanistically this is ascribed to mitochondria's function as a Ca buffer or source of reactive oxygen species (mtROS) to exacerbate RyR2 functionality, respectively. Enhancing mCa uptake reduced and elevated mtROS production in CPVT2 and FFD, respectively. In CPVT2, mitochondria took up more Ca in permeabilized cells, and had higher level of mCa content in intact cells vs. FFD. Conditional ablation of MCU in the CPVT2 model caused lethality and cardiac remodelling, but reduced arrhythmias in the FFD model. In parallel, CPVT2 mitochondria also employ up-regulated mPTP-mediated Ca efflux to avoid mCa overload, as seen by elevated incidence of MitoWinks (an indicator of mPTP-mediated Ca efflux) vs. FFD. Both pharmacological and genetic inhibition of mPTP promoted mtROS production and exacerbation of myocyte Ca handling in CPVT2. Further, genetic inhibition of mPTP exacerbated arrhythmias in CPVT2.
conclusionIn contrast to FFD, which is more susceptible to mtROS-dependent RyR2 leak, in CPVT2 mitochondria buffer SR-derived DCR to mitigate Ca-dependent pathological remodelling and rely on mPTP-mediated Ca efflux to avoid mCa overload. SR-mitochondria interplay contributes to the divergent pathologies by disparately shaping intracellular Ca signalling.
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