Metformin‐induced mitochondrial function and ABCD2 up‐regulation in X‐linked adrenoleukodystrophy involves AMP‐activated protein kinase

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurometabolic disease caused by mutations/deletions in the Abcd1 gene. Similar mutations/deletions in the Abcd1 gene often result in diagonally opposing phenotypes of mild adrenomyeloneuropathy and severe neuroinflammatory cerebral adrenoleukodystrophy (ALD), which suggests involvement of downstream modifier genes. We recently documented the first evidence of loss of AMP-activated protein kinase a1 (AMPKa1) in ALD patient-derived cells. Here, we report the novel loss of AMPKa1 in postmortem brain white matter of patients with ALD phenotype. Pharmacological activation of AMPK can rescue the mitochondrial dysfunction and inhibit the pro-inflammatory response. The FDA approved anti-diabetic drug Metformin, a well-known AMPK activator, induces mitochondrial biogenesis and is documented for its anti-inflammatory role. We observed a dose-dependent activation of AMPKa1 in metformin-treated X-ALD patient-derived fibroblasts. Metformin also induced mitochondrial oxidative phosphorylation and ATP levels in X-ALD patient-derived fibroblasts. Metformin treatment decreased very long chain fatty acid levels and pro-inflammatory cytokine gene expressions in X-ALD patient-derived cells. Abcd2 [adrenoleukodystrophy protein-related protein] levels were increased in metformin-treated X-ALD patient-derived fibroblasts and Abcd1-KO mice primary mixed glial cells. Abcd2 induction was AMPKa1-dependent since metformin failed to induce Abcd2 levels in AMPKa1-KO mice-derived primary mixed glial cells. In vivo metformin (100 mg/Kg) in drinking water for 60 days induced Abcd2 levels and mitochondrial oxidative phosphorylation protein levels in the brain and spinal cord of Abcd1-KO mice. Taken together, these results provide proofof-principle for therapeutic potential of metformin as a useful strategy for correcting the metabolic and inflammatory derangements in X-ALD by targeting AMPK. Keywords: Abcd1-KO mice, ABCD2, AMPKa1, metformin, mitochondria, X-ALD. J. Neurochem. (2016) 138, 86-100.Read the Editorial Highlight for this article on page 10.X-linked Adrenoleukodystrophy (X-ALD) is a progressive inherited demyelinating disorder for which there is currently no satisfactory therapy available (Berger et al. 2014). Development of an appropriate therapy has been hampered due to the lack of understanding of events involved in progression of the disease. Underlying genetic defect in X-ALD is a mutation or deletion in ABCD1 gene (Berger et al. 2014). ABCD1 encodes a peroxisomal integral membrane protein-adrenoleukodystrophy protein (ALDP) responsible for transport of very long chain fatty acids (VLCFA; C > 22 : 0) into the peroxisome for b-oxidation (Contreras

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