Depressing mitochondria-reticulum interactions protects cardiomyocytes from lethal hypoxia-reoxygenation injury.

Abstract

BACKGROUND:

Under physiological conditions, Ca(2+) transfer from the endoplasmic reticulum (ER) to mitochondria might occur at least in part at contact points between the 2 organelles and involves the VDAC1/Grp75/IP3R1 complex. Accumulation of Ca(2+) into the mitochondrial matrix may activate the mitochondrial chaperone cyclophilin D (CypD) and trigger permeability transition pore opening, whose role in ischemia/reperfusion injury is well recognized. We questioned here whether the transfer of Ca(2+) from ER to mitochondria might play a role in cardiomyocyte death after hypoxia-reoxygenation.

METHODS AND RESULTS:

We report that CypD interacts with the VDAC1/Grp75/IP3R1 complex in cardiomyocytes. Genetic or pharmacological inhibition of CypD in both H9c2 cardiomyoblasts and adult cardiomyocytes decreased the Ca(2+) transfer from ER to mitochondria through IP3R under normoxic conditions. During hypoxia-reoxygenation, the interaction between CypD and the IP3R1 Ca(2+) channeling complex increased concomitantly with mitochondrial Ca(2+) content. Inhibition of either CypD, IP3R1, or Grp75 decreased protein interaction within the complex, attenuated mitochondrial Ca(2+) overload, and protected cells from hypoxia-reoxygenation. Genetic or pharmacological inhibition of CypD provided a similar effect in adult mice cardiomyocytes. Disruption of ER-mitochondria interaction via the downregulation of Mfn2 similarly reduced the interaction between CypD and the IP3R1 complex and protected against hypoxia-reoxygenation injury.

CONCLUSIONS:

Our data (1) point to a new role of CypD at the ER-mitochondria interface and (2) suggest that decreasing ER-mitochondria interaction at reperfusion can protect cardiomyocytes against lethal reperfusion injury through the reduction of mitochondrial Ca(2+) overload via the CypD/VDAC1/Grp75/IP3R1 complex.

• Authors: Melanie Paillard, Emily Tubbs, Pierre-Alain Thiebaut, Ludovic Gomez, Jeremy Fauconnier, Claire Crola Da Silva, Geoffrey Teixeira, Nathan Mewton, Elise Belaidi, Annie Durand, Maryline Abrial, Alain Lacampagne, Jennifer Rieusset, Michel Ovize
• Journal: Circulation (Circulation) Vol. 128 Issue 14 Pg. 1555-65 (Oct 01 2013) ISSN: 1524-4539 [Electronic] United States
• PMID: 23983249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclophilin D
• HSP70 Heat-Shock Proteins
• Inositol 1,4,5-Trisphosphate Receptors
• Membrane Proteins
• Multiprotein Complexes
• PPIF protein, mouse
• Vdac1 protein, rat
• glucose-regulated proteins
• Voltage-Dependent Anion Channel 1
• Cyclophilins
• Oxygen

Topics

• Animals
• Calcium Signaling (physiology)
• Cell Hypoxia (physiology)
• Cell Line
• Cells, Cultured (metabolism)
• Cyclophilin D
• Cyclophilins (deficiency, genetics, physiology)
• Endoplasmic Reticulum (physiology)
• HSP70 Heat-Shock Proteins (physiology)
• In Vitro Techniques
• Inositol 1,4,5-Trisphosphate Receptors (physiology)
• Intracellular Membranes (physiology)
• Male
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria, Heart (physiology)
• Multiprotein Complexes
• Myocardial Reperfusion Injury (prevention & control)
• Myocytes, Cardiac (drug effects, metabolism, pathology, ultrastructure)
• Oxygen (toxicity)
• Patch-Clamp Techniques
• Random Allocation
• Rats
• Voltage-Dependent Anion Channel 1 (physiology)