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Pro-oxidants and mitochondrial Ca2+: their relationship to apoptosis and oncogenesis
1Laboratory of Biochemistry I, Swiss Federal Institute of Technology (ETH), Zürich.
Abstract:
Apoptosis is a physiological process for active cell removal. One of its hallmarks is an increased cytosolic Ca2+ content. Several genes involved in apoptosis control have been identified, but their mode of action is not understood in detail. Apoptosis may relate to oncogenesis, in that some malignant tumors may grow because genes engaged in apoptosis control are altered. L929 cells overexpressing the proto-oncogene bcl-2 have an increased mitochondrial membrane potential (delta psi), as have many carcinoma cells. bcl-2 protects L929 cells against apoptosis caused by pro-oxidant-induced mitochondrial Ca2+ 'cycling' and increased cytosolic Ca2+ levels. Nerve growth factor, which induces catalase, and inhibitors of mitochondrial Ca2+ release also prevent apoptosis. It is suggested that a pro-oxidant-induced Ca2+ release from mitochondria, followed by Ca2+ cycling and ATP depletion, is a common basic event during apoptosis. Accordingly, maintenance of delta psi stabilizes mitochondria, thereby prevents apoptosis, and may confer increased growth potential to cells.
Insights
Apoptosis, or programmed cell death, involves calcium (Ca2+) and can be linked to cancer. Maintaining mitochondrial membrane potential (delta psi) prevents apoptosis and may promote cell growth.
Area of Science:
- Cell Biology
- Biochemistry
- Oncology
Background:
- Apoptosis is a crucial physiological process for active cell removal.
- Altered apoptosis control genes are implicated in oncogenesis and tumor growth.
- Increased cytosolic Ca2+ is a hallmark of apoptosis.
Purpose of the Study:
- To investigate the role of mitochondrial membrane potential (delta psi) in apoptosis.
- To explore the relationship between bcl-2 proto-oncogene, Ca2+ cycling, and apoptosis.
- To understand the mechanisms underlying apoptosis in relation to cell growth.
Main Methods:
- Utilized L929 cells overexpressing the bcl-2 proto-oncogene.
- Monitored mitochondrial membrane potential (delta psi) and cytosolic Ca2+ levels.
- Investigated the effects of pro-oxidants, nerve growth factor, and mitochondrial Ca2+ release inhibitors.
Main Results:
- Overexpression of bcl-2 increased mitochondrial membrane potential (delta psi) and protected cells from apoptosis.
- Pro-oxidant-induced mitochondrial Ca2+ cycling and subsequent ATP depletion were identified as key events in apoptosis.
- Maintenance of delta psi stabilized mitochondria, preventing apoptosis.
Conclusions:
- A common pathway for apoptosis involves pro-oxidant-induced Ca2+ release from mitochondria, leading to Ca2+ cycling and ATP depletion.
- Stabilizing mitochondrial membrane potential (delta psi) is a key mechanism to prevent apoptosis.
- Preventing apoptosis by maintaining delta psi may contribute to increased cellular growth potential, potentially linking to cancer progression.