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Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells: Mitotane-induced cytochrome c oxidase defect

Abstract : Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p'-DDD) is the most effective medical therapy for adrenocortical carcinoma but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mitochondrial dysfunction has never been established. We examined the functional consequences on proliferation, steroidogenesis, and mitochondrial respiratory chain, biogenesis and morphology, of mitotane exposure in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration 50μM (14 mg/L), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mitochondrial proteins involved in steroidogenesis (STAR, CYP11B1, CYP11B2). In both H295R and SW13 cells, 50μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase, COX). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by Blue Native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 and nuclear DNA-encoded COX4 subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mitochondrial biogenesis (increase in mtDNA content and PGC1α expression) and triggered fragmentation of the mitochondrial network. Altogether, our results provide first evidence that mitotane induced a mitochondrial respiratory chain defect in human adrenocortical cells.
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https://www.hal.inserm.fr/inserm-00817795
Contributor : Marc Lombes <>
Submitted on : Tuesday, April 1, 2014 - 7:00:13 AM
Last modification on : Wednesday, September 16, 2020 - 5:04:17 PM
Long-term archiving on: : Tuesday, July 1, 2014 - 10:36:27 AM

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Ségolène Hescot, Abdelhamid Slama, Anne Lombes, Angelo Paci, Hervé Remy, et al.. Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells: Mitotane-induced cytochrome c oxidase defect. 2014. ⟨inserm-00817795⟩

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