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ABCD 1 deletion‐induced mitochondrial dysfunction is corrected by SAHA : implication for adrenoleukodystrophy
Author(s) -
Baarine Mauhamad,
Beeson Craig,
Singh Avtar,
Singh Inderjit
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12992
Subject(s) - adrenoleukodystrophy , chemistry , biology , genetics , gene , peroxisome
X‐linked Adrenoleukodystrophy (X‐ ALD ), an inherited peroxisomal metabolic neurodegenerative disorder, is caused by mutations/deletions in the ATP‐binding cassette transporter ( ABCD 1) gene encoding peroxisomal ABC transporter adrenoleukodystrophy protein ( ALDP ). Metabolic dysfunction in X‐ ALD is characterized by the accumulation of very long chain fatty acids ≥ C22:0) in the tissues and plasma of patients. Here, we investigated the mitochondrial status following deletion of ABCD 1 in B12 oligodendrocytes and U87 astrocytes. This study provides evidence that silencing of peroxisomal protein ABCD 1 produces structural and functional perturbations in mitochondria. Activities of electron transport chain‐related enzymes and of citric acid cycle ( TCA cycle) were reduced; mitochondrial redox status was dysregulated and the mitochondrial membrane potential was disrupted following ABCD 1 silencing. A greater reduction in ATP levels and citrate synthase activities was observed in oligodendrocytes as compared to astrocytes. Furthermore, most of the mitochondrial perturbations induced by ABCD 1 silencing were corrected by treating cells with suberoylanilide hydroxamic acid, an Histone deacetylase inhibitor. These observations indicate a novel relationship between peroxisomes and mitochondria in cellular homeostasis and the importance of intact peroxisomes in relation to mitochondrial integrity and function in the cell types that participate in the pathobiology of X‐ ALD . These observations suggest suberoylanilide hydroxamic acid as a potential therapy for X‐ ALD .Schematic description of the effects of loss of peroxisomal ATP‐binding cassette transporter D1 (ABCD1) gene on cellular Redox and mitochondrial activities and their correction by suberoylanilide hydroxamic acid (SAHA) treatment. Pathogenomic accumulation of very long chain fatty acids (VLCFA) as a result of loss of ABCD1 leads to dysfunctions of mitochondrial biogenesis and its activities. Treatment with SAHA corrects mitochondrial dysfunctions. These studies describe unique cooperation between mitochondria and peroxisome for cellular activities.