Induction of mitochondrial destabilization and necrotic cell death by apolar mitochondria-directed SOD mimetics

Szabó, Alíz and Balog, Mária and Márk, László and Montskó, Gergely and Turi, Zsuzsanna and Gallyas Jr., Ferenc and Sümegi, Balázs and Kálai, Tamás and Hideg, Kálmán and Kovács, Krisztina (2011) Induction of mitochondrial destabilization and necrotic cell death by apolar mitochondria-directed SOD mimetics. Mitochondrion, 11. pp. 476-487. ISSN 1567-7249, ESSN: 1872-8278

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Abstract

In this paper, we present evidence, for the first time, that increasing the lipophilicity of mitochondria targeting SOD mimetics reverses their cytoprotective properties, destabilizing the mitochondrial membrane system and promoting cell death. A new mitochondria-directed apolar SOD mimetic, HO-3814, was found to provoke mitochondrial swelling and loss of mitochondrial membrane potential, and these effects were not inhibited by cyclosporine A. HO-3814-induced cell death was predominantly necrotic, caspase-independent, and not affected by mitochondrial permeability transition inhibitors or cyclophilin D-suppression, inhibitors of mitogen-activated protein kinases or Akt, or various antioxidants. In contrast, Bcl-2 overexpression diminished the effects of HO-3814.

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