Adrenoleukodystrophy and the mitochondrial connection: clues for supplementing Lorenzo’s oil

The 1992 American film ‘Lorenzo’s Oil’ became a euphemism for finding cures for devastating neurological diseases. Lorenzo’s disease was adrenoleukodystrophy, which is caused by defects in peroxisomal fatty acid beta-oxidation. The defect results in the accumulation of very-long chain fatty acids in several organs, particularly the adrenal cortex, testis and the nervous system. Myelinated tissues are most severely affected, underlying the chief clinical symptoms, which can vary from vegetative state in early childhood to paraparesis in adulthood (Kemp et al. , 2012). The genetic cause of adrenoleukodystrophy was identified as recessive mutations in the X-linked ABCD1 gene (Mosser et al. , 1993), which codes for a peroxisomal membrane transporter responsible for shuttling very long chain fatty acids into peroxisomes. Although mitochondria are major sites of lipid catabolism, these very long chain fatty acids (>22 carbons) cannot be metabolized in mitochondria, and need to gain access to peroxisomes to be degraded. Interestingly, not all males with adrenoleukodystrophy develop CNS demyelination and consequent neuroinflammation, suggesting that modifying factors (genetic, epigenetic and environmental) play a role in the CNS symptoms of adrenoleukodystrophy.Although the pathophysiology of adrenoleukodystrophy is not fully understood, individuals with adrenoleukodystrophy show high levels of saturated very long chain fatty acids—mostly cerotic acid (C26:0)—in affected tissues. Free saturated fatty acids are known inducers of apoptosis and this effect increases with chain length (Artwohl et al. , 2009). Accordingly, exposure of oligodendrocytes and astrocytes to C22:0, C24:0 and C26:0 (but not C16:0) fatty acids caused cell …