Loss of AMP-activated protein kinase induces mitochondrial dysfunction and proinflammatory response in unstimulated Abcd1-knockout mice mixed glial cells
Recommended Citation
Singh J, Suhail H, and Giri S. Loss of AMP-Activated Protein Kinase Induces Mitochondrial Dysfunction and Proinflammatory Response in Unstimulated Abcd1-Knockout Mice Mixed Glial Cells. Mediators Inflamm 2015; 2015:176983.
Document Type
Article
Publication Date
1-1-2015
Publication Title
Mediators of inflammation
Abstract
X-linked adrenoleukodystrophy (X-ALD) is caused by mutations and/or deletions in the ABCD1 gene. Similar mutations/deletions can give rise to variable phenotypes ranging from mild adrenomyeloneuropathy (AMN) to inflammatory fatal cerebral adrenoleukodystrophy (ALD) via unknown mechanisms. We recently reported the loss of the anti-inflammatory protein adenosine monophosphate activated protein kinase (AMPKα1) exclusively in ALD patient-derived cells. X-ALD mouse model (Abcd1-knockout (KO) mice) mimics the human AMN phenotype and does not develop the cerebral inflammation characteristic of human ALD. In this study we document that AMPKα1 levels in vivo (in brain cortex and spinal cord) and in vitro in Abcd1-KO mixed glial cells are similar to that of wild type mice. Deletion of AMPKα1 in the mixed glial cells of Abcd1-KO mice induced spontaneous mitochondrial dysfunction (lower oxygen consumption rate and ATP levels). Mitochondrial dysfunction in ALD patient-derived cells and in AMPKα1-deleted Abcd1-KO mice mixed glial cells was accompanied by lower levels of mitochondrial complex (1-V) subunits. More importantly, AMPKα1 deletion induced proinflammatory inducible nitric oxide synthase levels in the unstimulated Abcd1-KO mice mixed glial cells. Taken together, this study provides novel direct evidence for a causal role for AMPK loss in the development of mitochondrial dysfunction and proinflammatory response in X-ALD.
Medical Subject Headings
AMP-Activated Protein Kinases; ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Adrenoleukodystrophy; Animals; Cells, Cultured; Humans; Inflammation; Mice; Mice, Knockout; Mitochondria; Neuroglia
PubMed ID
25861159
Volume
2015
First Page
176983
