Cardiac ischemia/reperfusion stress reduces inner mitochondrial membrane protein (mitofilin) levels during early reperfusion
| Autor: | Yansheng Feng, Nathalie Tombo, Abdulhafiz Imam Aliagan, Jean C. Bopassa, Harpreet Singh |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Programmed cell death Ischemia Myocardial Reperfusion Injury Mitochondrial Membrane Transport Proteins Biochemistry Mitochondria Heart Article Mice 03 medical and health sciences 0302 clinical medicine Physiology (medical) medicine Animals Myocyte Myocytes Cardiac Inner mitochondrial membrane Cyclophilin chemistry.chemical_classification Reactive oxygen species Membrane Proteins medicine.disease Mitochondria Cell biology 030104 developmental biology Mitochondrial permeability transition pore chemistry Apoptosis Mitochondrial Membranes Reperfusion 030217 neurology & neurosurgery |
| Zdroj: | Free Radic Biol Med |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2020.06.039 |
| Popis: | Mitochondrial inner membrane protein (Mitofilin or Mic60) is a mitochondria-shaping protein that plays a key role in maintaining mitochondrial cristae structure and remodeling. We recently showed that Mitofilin knockdown in H9c2 myoblasts induces mitochondrial structural damage resulting in mitochondrial dysfunction that is responsible for cell death via apoptosis. Here, we investigated the role of Mitofilin regulation in ischemia/reperfusion (I/R) injury and studied the relationship between Mitofilin and Cyclophilin (CypD), a key regulator of mitochondrial permeability transition pore (mPTP) opening. C57Bl6 male mice hearts were subjected to different ischemia times (15, 30, or 45 min) followed by a 2 h reperfusion period, or 45 min ischemia followed by 0, 15, 30, 60, or 120 min reperfusion to determine the impact of ischemia or reperfusion times on Mitofilin levels and its interaction with CypD. We found that the increase in myocardial infarct size and the reduction of mitochondrial calcium retention capacity were concomitant with Mitofilin reduction as a function of ischemic duration. We also found that 15 min reperfusion after 45 min ischemia was sufficient to cause a reduction of Mitofilin levels compared to sham, while 45 min ischemia alone was not enough to cause a significant decrease of Mitofilin. We revealed that the c-terminus coiled-coiled domain of Mitofilin is important for its interaction with CypD and the deletion of this identified sequence resulted in a loss of Mitofilin-CypD link, dissipation of mitochondrial membrane potential and increase in cell death. A decrease of the levels of Mitofilin was also associated with mitochondrial structural integrity damage, increased reactive oxygen species (ROS) production, and calpain activity. Our results indicate that Mitofilin physically binds to CypD in the inner mitochondrial membrane and the disruption of this interaction may play a critical role in the increase of mitochondrial dysfunction and initiation of myocytes’ death after I/R injury. |
| Databáze: | OpenAIRE |
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