Nervonic acid, a long chain monounsaturated fatty acid, improves mitochondrial function in adrenomyeloneuropathy fibroblasts

BACKGROUND AND PURPOSE: Nervonic acid plays a vital role in maintaining normal brain and neuronal function. Nervonic acid has gained increasing attention because of its potential neuroprotective and anti-inflammatory properties. Nonetheless, the beneficial effects of nervonic acid are yet to be fully investigated. Adrenomyeloneuropathy (AMN), a type of X-linked adrenoleukodystrophy (ALD), is a progressive inherited metabolic disease characterised by accumulation of saturated very long-chain fatty acids (VLCFAs) in plasma and tissues, leading to increasing oxidative stress, mitochondrial dysfunction, neuroinflammation, cognitive dysfunction and disability. We previously found that nervonic acid can biochemically reverse the accumulation of saturated VLCFAs and increase cellular ATP production in ALD. Here, we investigated nervonic acid as a potential therapy for ALD by assessing its impact on mitochondrial function. EXPERIMENTAL APPROACH: We assessed the effect of nervonic acid on cellular bioenergetics and oxidative stress in AMN patient-derived fibroblasts. We employed Seahorse real-time cell metabolic analysis and imaging of cells treated with increasing concentrations of nervonic acid. Normal dermal fibroblasts served as the healthy control. KEY RESULTS: AMN cells demonstrate significantly impaired basal respiration, ATP production, maximal respiration and spare respiratory capacity compared to healthy fibroblasts. These mitochondrial respiration parameters significantly improved on treatment with nervonic acid in a concentration-dependent manner. Nervonic acid treatment also significantly reduced mitochondria-derived and total cellular reactive oxygen species, indicating mitigation of total oxidative stress. CONCLUSION AND IMPLICATIONS: Our findings indicate a new mechanism of action for nervonic acid in ALD and other mitochondrial dysfunction-associated diseases. This can also indirectly prevent downstream inflammation, thus altering disease progression.