Pro‐oxidants and mitochondrial Ca2+: their relationship to apoptosis and oncogenesis

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-oncogen bcl-2 have an increased mitochondrial membrane potential (δψ), 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 δψ stabilizes mitochondria, thereby prevents apoptosis, and may confer increased growth potential to cells.