Astrocytes of ABCD1 deficient mouse, adrenoleukodystrophy model have functional deficits but not respective brain mitochondria

Abstract

The neurodegenerative X‐ALD (X‐linked adrenoleukodystrophy) has symptoms caused by VLCFA. ABCD1 dysfunction results in VLCFA accumulation in patients. VLCFA accumulation is considered the X‐ALD pathogenic factor. We aim to understand the molecular mechanism underlying X‐ALD pathogenesis. A mouse model for X‐ALD, the Abcd1‐knockout mouse, displays biochemical abnormalities, reduced VLCFA ß‐oxidation and accumulation of VLCFA. We thank Aurora Pujol (Barcelona, Spain) for the Abcd1‐/‐ animals used here. Isolated brain mitochondria from Abcd1‐/‐ and wild‐type mice respond similarly to VLCFA, indicated as rise in ROS generation, impaired oxidative ATP synthesis and diminished Ca2+ uptake capacity. Remarkably, in mitochondria from adult wild‐type and one‐year‐old Abcd1‐/‐ deficient mice, the response of ATP synthesis to VLCFA was comparable. However, astrocytes from wild‐type and Abcd1‐knockout mice, exposed to supraphysiological concentrations of the C22:0, C24:0 and C26:0 exhibit impairments of energy metabolism. Long‐term exposure to VLCFA enhances ROS generation, in situ depolarization of mitochondria. Moreover, the VLCFA‐induced intracellular Ca2+ response is diminished in Abcd1‐/‐ astrocytes. VLCFA promote cell death in astrocytes. Important for understanding the X‐ALD pathogenic mechanism is the finding that in Abcd1‐/‐ astrocytes, the capability to revert oxidized pyridine nucleotides to NAD(P)H is diminished. Defective ABCD1 exerts no adaptive pressure on mitochondria. We suggest that detrimental activities of VLCFA in astrocytes involve defective functions besides mitochondria. Astrocytes from Abcd1‐/‐ mice respond more sensitively to VLCFA than from wild‐type mice. The antioxidative defense is diminished in Abcd1‐/‐.