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Published on: September 7, 2012
Pivotal role of mitochondrial Ca(2+) in microcystin-induced mitochondrial permeability transition in rat hepatocytes
1Department of Community, Occupational, and Family Medicine, Faculty of Medicine (MD3), National University of Singapore, 16 Medical Drive, Singapore, 117597, Singapore.
Abstract:
We have shown earlier that microcystin-LR (MLR), a specific hepatotoxin, induced onset of mitochondrial permeability transition (MPT) and apoptosis in rat hepatocytes. Here we attempted to investigate the role of mitochondrial Ca(2+) in MLR-induced onset of MPT and cell death. Using confocal microscopy, we found that MLR caused an early surge of mitochondrial Ca(2+) prior to the onset of MPT and cell death. Pretreatment with 1,2-bis(O-aminophenoxyl)ethane-N,N,N',N'-tetracetic acid tetra(acetoxymethyl)ester (an intracellular Ca(2+) chelator) or ruthenium red (an inhibitor of mitochondrial Ca(2+) uniporter) prevented the early mitochondrial Ca(2+) surge and attenuated the subsequent onset of MPT and cell death. On the other hand, a mitochondrial uncoupler, CCCP, rapidly disrupted the mitochondrial membrane potential and also prevented the mitochondrial Ca(2+) surge, onset of MPT, and cell death. We thus conclude that mitochondrial Ca(2+) plays an important role in the onset of MPT and cell death in MLR-treated rat hepatocytes.
Insights
Microcystin-LR (MLR) hepatotoxin triggers mitochondrial permeability transition (MPT) and cell death. This study reveals that mitochondrial calcium (Ca2+) surge is crucial for MLR-induced MPT and hepatocyte death.
Area of Science:
- Hepatology
- Toxicology
- Mitochondrial Biology
Background:
- Microcystin-LR (MLR) is a potent hepatotoxin known to induce apoptosis.
- Mitochondrial permeability transition (MPT) is a key event in programmed cell death.
Purpose of the Study:
- To investigate the role of mitochondrial calcium (Ca2+) in MLR-induced MPT and hepatocyte death.
- To elucidate the mechanism by which MLR triggers MPT and apoptosis.
Main Methods:
- Confocal microscopy to visualize mitochondrial Ca2+ dynamics.
- Use of Ca2+ chelators and mitochondrial uniporter inhibitors.
- Employing mitochondrial uncouplers to assess membrane potential disruption.
Main Results:
- MLR induced an early surge in mitochondrial Ca2+ preceding MPT and cell death.
- Inhibiting mitochondrial Ca2+ uptake prevented MLR-induced MPT and attenuated cell death.
- Mitochondrial uncouplers disrupted membrane potential, preventing Ca2+ surge and cell death.
Conclusions:
- Mitochondrial Ca2+ plays a critical role in the initiation of MPT and cell death induced by MLR.
- Targeting mitochondrial Ca2+ may offer a therapeutic strategy against MLR toxicity.
