ArticleProceedings of the National Academy of Sciences of the United States of America2015
Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 116 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
116 citing papers in PubMed, 1 synthesis or guideline pooled it, 159 citations in OpenAlex.
- Knowledge mapping of mitochondrial calcium uniporter from 2011 to 2022: A bibliometric analysis.Frontiers in physiology · 2023Pooled it
- Mitochondrial oxidative stress, calcium and dynamics in cardiac ischaemia-reperfusion injury.The Journal of physiology · 2026Review
- Restoration of mitochondrial CaJournal of molecular and cellular cardiology · 2026Article
- MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.Nature metabolism · 2026Article
- Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses.bioRxiv : the preprint server for biology · 2026Article
- Article
- Mitochondrial Calcium Uniporter Regulates Metabolic Remodeling and Smooth Muscle Cell Proliferation in Type 2 Diabetes.Journal of the American Heart Association · 2025Article
- MICU proteins facilitate CaResearch square · 2025Article
- Mitochondrial CaCell reports · 2025Article
- Enhancement of mitochondrial calcium uptake is cardioprotective against maladaptive hypertrophy by retrograde signaling uptuning Akt.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Mitochondrial calcium uniporter complex: An emerging therapeutic target for cardiovascular diseases (Review).International journal of molecular medicine · 2025Review
- How does mitochondrial Ca2+ change during ischemia and reperfusion? Implications for activation of the permeability transition pore.The Journal of general physiology · 2025Review
- The mitochondrial calcium uniporter inhibitor Ru265 increases neuronal excitability and reduces neurotransmission via off-target effects.British journal of pharmacology · 2024Article
- MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Mitochondrial Structure and Function in Human Heart Failure.Circulation research · 2024Review
- Calcium signaling from sarcoplasmic reticulum and mitochondria contact sites in acute myocardial infarction.Journal of translational medicine · 2024Review
- Mitochondrial CaJACC. Basic to translational science · 2024Article
- MCU-independent CaScientific reports · 2024Article
- The mitochondria as a potential therapeutic target in cerebral I/R injury.Frontiers in neuroscience · 2024Review
- Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.Biomolecules · 2023Review
56 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
24 authors at 4 institutions in 1 country.
Funding
Abstract
Myocardial mitochondrial Ca(2+) entry enables physiological stress responses but in excess promotes injury and death. However, tissue-specific in vivo systems for testing the role of mitochondrial Ca(2+) are lacking. We developed a mouse model with myocardial delimited transgenic expression of a dominant negative (DN) form of the mitochondrial Ca(2+) uniporter (MCU). DN-MCU mice lack MCU-mediated mitochondrial Ca(2+) entry in myocardium, but, surprisingly, isolated perfused hearts exhibited higher O2 consumption rates (OCR) and impaired pacing induced mechanical performance compared with wild-type (WT) littermate controls. In contrast, OCR in DN-MCU-permeabilized myocardial fibers or isolated mitochondria in low Ca(2+) were not increased compared with WT, suggesting that DN-MCU expression increased OCR by enhanced energetic demands related to extramitochondrial Ca(2+) homeostasis. Consistent with this, we found that DN-MCU ventricular cardiomyocytes exhibited elevated cytoplasmic [Ca(2+)] that was partially reversed by ATP dialysis, suggesting that metabolic defects arising from loss of MCU function impaired physiological intracellular Ca(2+) homeostasis. Mitochondrial Ca(2+) overload is thought to dissipate the inner mitochondrial membrane potential (ΔΨm) and enhance formation of reactive oxygen species (ROS) as a consequence of ischemia-reperfusion injury. Our data show that DN-MCU hearts had preserved ΔΨm and reduced ROS during ischemia reperfusion but were not protected from myocardial death compared with WT. Taken together, our findings show that chronic myocardial MCU inhibition leads to previously unanticipated compensatory changes that affect cytoplasmic Ca(2+) homeostasis, reprogram transcription, increase OCR, reduce performance, and prevent anticipated therapeutic responses to ischemia-reperfusion injury.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.