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Related Concept Videos

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The inner mitochondrial membrane is the primary site of ATP synthesis. The inner membrane domain that forms a smooth layer adjacent to the outer membrane is called the inner boundary membrane. This domain contains membrane transporters that drive metabolites in and out of the mitochondria.  In contrast, the inner membrane network that invaginates into the matrix space is called the cristae membrane. This domain accounts for principle mitochondrial function as it accommodates the protein...
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Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
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A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
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In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
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Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.
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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
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Mitochondrial Ca2+ Retention Capacity Assay and Ca2+-triggered Mitochondrial Swelling Assay
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Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT.

Shanna Hamilton1,2,3, Radmila Terentyeva1,2, Roland Veress1,2

  • 1Department of Physiology and Cell Biology (S.H., R.T., R.V., F.P., S.G., A.E.B., D.T.), The Ohio State University, Columbus.

Circulation Research
|October 23, 2025
PubMed
Summary
This summary is machine-generated.

Ryanodine receptor 2 (RyR2) hyperactivity in cardiac disease damages mitochondria by increasing calcium in the mitochondrial intermembrane space, activating calpain. This protease cleaves OPA1, disrupting mitochondrial structure and promoting arrhythmias.

Keywords:
calciumcardiovascular diseasesheart failuremitochondrial proteinsryanodine receptor calcium release channelsarcoplasmic reticulum

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Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Medicine
  • Molecular Cardiology

Background:

  • Mitochondrial dysfunction is linked to cardiovascular diseases, often involving abnormal ryanodine receptor 2 (RyR2) activity.
  • Mechanisms connecting RyR2 gain-of-function to mitochondrial remodeling are not fully understood.

Purpose of the Study:

  • To investigate if RyR2 hyperactivity increases mitochondrial intermembrane space calcium ([Ca2+]), activating calpain and leading to OPA1 cleavage and mitochondrial cristae remodeling.
  • To explore the role of calpain in the mitochondrial structural changes associated with catecholaminergic polymorphic ventricular tachycardia (CPVT).

Main Methods:

  • Generated a rat model of CPVT with RyR2 gain-of-function mutation.
  • Developed a novel biosensor to measure mitochondrial intermembrane space calcium ([Ca2+]) in cardiomyocytes.
  • Utilized optical mapping, electron microscopy, and gene editing to assess calpain's role in the mitochondrial intermembrane space.

Main Results:

  • CPVT myocytes exhibited altered mitochondrial cristae, increased mitochondrial intermembrane space calcium, reduced OPA1, and elevated mitochondrial reactive oxygen species (ROS).
  • Calpain-mediated OPA1 cleavage disrupted cristae, impairing electron transport chain supercomplex assembly and increasing ROS production.
  • Genetic inhibition of calpain in the mitochondrial intermembrane space reversed mitochondrial defects and reduced arrhythmias in CPVT hearts.

Conclusions:

  • RyR2 hyperactivity drives mitochondrial damage via increased mitochondrial intermembrane space calcium, activating calpain.
  • Calpain activation cleaves OPA1, widening cristae, reducing electron transport chain supercomplexes, and increasing ROS, which exacerbates RyR2 hyperactivity and ventricular tachyarrhythmia.
  • Targeting mitochondrial intermembrane space calpain may offer a therapeutic strategy for patients at risk of sudden cardiac death.