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

Carlos T. Moraes
DOI: http://dx.doi.org/10.1093/brain/awt189 2339-2341 First published online: 10 July 2013

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 death within 24 h. Likewise, treatment of neural cells with C26:0 was toxic to mitochondria leading to deregulation of intracellular calcium (Hein et al., 2008).

Abcd1 knockout mice have a phenotype that resembles adrenoleukodystrophy and show oxidative damage in the spinal cord months before neuropathological signs appear. More recently, mitochondrial degeneration was found to be a prominent feature in the pathology of this mouse model and this mitochondrial dysfunction was associated with increased oxidative stress (Lopez-Erauskin et al., 2012).

Despite the movie’s relatively happy ending, subsequent studies showed that Lorenzo’s oil, a mixture of unsaturated fatty acids that inhibit elongation of saturated fatty acids, was beneficial mostly to presymptomatic patients with only minor effects if administered after disease onset (Berger and Gartner, 2006). Therefore, adrenoleukodystrophy continues to be a devastating disease without a cure or even effective treatment if not detected early on. Consequently, the search for novel treatments is still active.

Because of the observed mitochondrial and oxidative abnormalities, Morató et al. (2013) reason in the present issue that activating pathways associated with the preservation of mitochondrial biogenesis and antioxidant defences could be beneficial to mouse models of the disease. Activators of this pathway have been shown to improve health in models of mitochondrial diseases (Wenz et al., 2008) as well as of neurodegenerative conditions such as Huntington’s disease (Johri et al., 2012). Among the various candidates to activate this pathway, pioglitazone stands out as an approved treatment as well as a drug capable of crossing the blood–brain barrier. Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and—to a lesser extent—PPARα, modulating expression of genes involved in the control of glucose and lipid metabolism. Although PPARγ is not a specific activator of mitochondrial biogenesis, it increases transcription of some genes coding for mitochondrial proteins together with the PPAR co-activator PGC-1α. Morató et al. (2013) treated Abcd1 mice at 12 months of age with pioglitazone corresponding to a dose of 9 mg/kg/day per mouse. They also employed a similar regimen to a more severe model of the disease (Abcd1/Abcd2−/− mice).

The reduction in transcript levels for PGC-1α, the transcription factors NRF1, TFAM and PPARγ as well as downstream mitochondrial protein-coding genes observed in Abcd1 spinal cords were markedly improved with the pioglitazone treatment (Fig. 1). Moreover, biochemical and metabolic profiles, including oxidative damage, also improved (Morató et al., 2013). Mitochondrial levels were increased and the locomotor defects found in the double Abcd1/2 mutants normalized by pioglitazone. These are remarkable improvements, considering that the treatment does not have a major impact on the levels of very-long chain fatty acids in affected tissues. However, the levels of C26:0 were reduced by ∼15%, possibly because pioglitazone reduces the activity of a key enzyme responsible for the synthesis of very-long chain fatty acids (ELOVL3, Fig. 1). Pioglitazone’s target, PPARγ is involved in lipid uptake and metabolism, and some of its effects may minimize the consequences of accumulated very-long chain fatty acids. Although it is difficult to assess whether the relatively small decreases in C26:0 fatty acids observed would have disproportionate beneficial effects, the more robust improvements in mitochondrial biogenesis and antioxidant markers suggest that these latter pathways have a major impact on the pathophysiology of the disease.

Figure 1

Potential mechanisms by which pioglitazone protects adrenoleukodystrophy cells. Morató et al. (2013) observed that pioglitazone-treated mice had a reduction in ELOVL3, which is involved in the synthesis of very-long chain fatty acids. However, because the levels of very-long fatty acids were not markedly decreased, they suggest that the beneficial effect of the treatment was related to an increase in mitochondrial biogenesis and anti-oxidant defences. This effect would be mediated by PGC-1α, which is increased with the treatment. ADL = adrenoleukodystrophy.

Increases in mitochondrial biogenesis are beneficial to many degenerative conditions that may not primarily be caused by a bioenergetics defect, but have mitochondrial involvement as part of their pathophysiology. Increased mitochondrial biogenesis is believed to mediate many of the beneficial effects of exercise, caloric restriction and resveratrol (Lopez-Lluch et al., 2008). It also improves outcomes in models of Parkinson’s and Huntington’s diseases, among others (Tsunemi and La Spada, 2012). Is there a common element between these conditions that can shed light on the mechanism responsible for the beneficial role of increased mitochondrial biogenesis? Although one is tempted to speculate that oxidative damage may be the common target, and increased mitochondrial biogenesis correlates with increased antioxidant defences, other equally plausible possibilities exist. These include: increased mitochondrial dynamics, increased mitochondrial unfolded protein response, which is often associated with an increase in endoplasmic reticulum unfolded protein response (Haynes and Ron, 2010), increased metabolism of free fatty acids, and improved bioenergetics status of progenitor cells, which could help repair damaged tissues. In addition, glitazones have been found to bind with high affinity to CDGSH iron sulphur domain 1 protein (also known as mitoNEET), an outer mitochondrial membrane protein (Paddock et al., 2007). mitoNEET has been suggested to function in the transport of iron into the mitochondria and its binding of pioglitazone may influence oxidative stress by, for example, limiting the levels of iron inside high peroxide-producing defective mitochondria (Fig. 1).

These findings suggest that pioglitazone, already approved for human use, could be administered to patients with adrenoleukodystrophy. However, history has taught us that it is easier to treat mouse models than people with disease and rigorous double-blind studies are now required to determine the effectiveness of this approach. Although the mechanism remains elusive, the positive outcomes in animal models make it clear that the development of better drugs to stimulate the biogenesis of some or all mitochondrial components in the CNS will continue to advance in the coming years.


Dr Moraes receives funding from the National Institutes of Health Grants NS079965, AG036871, EY010804 and the Muscular Dystrophy Association.


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