Adrenoleukodystrophy (ALD)
X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder involving the ABCD1 gene. The resulting dysfunctional ABCD1 protein leads to the accumulation of Very Long Chain Fatty Acids (VLCFAs), followed by cellular alterations and the disruption of the message transmission system of the brain formed by the axons. When the damage occurs in the spinal cord, it is called Adrenomyeloneuropathy (AMN). To better understand disease mechanisms, the present study investigated the role of mitochondria, the cell’s energy provider, in the pathological process. Using an ABCD1-deficient mouse model of AMN and various microscopy techniques, researchers showed that mitochondria from the spinal cord were small and doughnut-shaped instead of tubular, indicating mitochondrial stress. These morphological alterations were accompanied by increased phosphorylated (activated) DRP1 protein levels compared to controls, suggesting the involvement of DRP1 in these mitochondrial changes. Further evaluations on human skin cells (fibroblasts) derived from AMN and control individuals suggested that, in AMN, high levels of VLCFAs first trigger the formation of pro-oxidant molecules (oxidative stress), then increase phosphorylated DRP1 levels and ultimately lead to the appearance of doughnut-shaped mitochondria. Indeed, the treatment of AMN cells exposed to VLCFAs with either antioxidants or DRP1 inhibitors reduced the number of abnormal mitochondria. Antioxidant treatment also decreased mitochondrial alterations in the mouse model of AMN. Similarly, the C. elegans worm model of AMN showed reduced mitochondrial and axonal abnormalities upon treatment with a small interfering RNA (siRNA) directed towards the DRP1 gene to block its expression in the cells. To corroborate their findings, researchers show that symptomatic AMN individuals’ cerebrospinal fluid (CSF) contains higher levels of mitochondrial DNA than controls, demonstrating a trackable marker for mitochondrial damage. Data from these different disease models and human AMN individuals highlight the contribution of mitochondria in axonal degeneration in X-ALD and open the path to novel, mitochondria-focused strategies.