Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells

Abstract

Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

“…In particular, the WDR45 protein, by binding to phosphatidylinositol-3-phosphate (PtdIns3P), regulates autophagosome formation [ 149 , 150 , 151 ]. In this way, defective autophagic flux associated with WDR45 mutations have been described in different cellular and animal studies [ 147 , 152 , 153 , 154 , 155 ]. KO mice for Wdr45 show an impaired autophagic flux with accumulation of SQSTM1- and ubiquitin-positive aggregates in neurons and swollen axons.…”

A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities

“…Genetic variants in the PARK2 gene in humans and mice deficient in parkin, also show increased susceptibility to intracellular pathogens such as salmonella and mycobacteria. A common variant in ATG16L1, identified as a risk factor for Crohn’s disease, is associated with reduced autophagy (Kaser and Blumberg, 2014; Murthy et al , 2014), and hemizygous and heterozygous mutations in WIPI4 have been identified in sporadic patients with BPAN (β-propeller associated neurodegeneration)—a neurological condition that is a subtype of NBIA (neurodegeneration with brain iron accumulation), characterized by childhood onset psychomotor delay, iron deposits in the brain and patients becoming bedridden (Haack et al , 2012; Hayflick et al 2013; Saitsu et al , 2013; Seibler et al , 2018).…”

MitophAging: Mitophagy in Aging and Disease

“…In line with these observations, WIPI3 or WIPI4 knockout mice show neurological defects, possibly caused by defective neuronal autophagy (Zhao et al, 2015;Ji et al, 2019). WIPI3 and −4 knockout mice display mitochondrial dysmorphology, which was also evident in WIPI4 mutant human fibroblast cells (Zhao et al, 2015;Seibler et al, 2018;Ji et al, 2019). The patient phenotypes caused by mutations in the WIPI genes highlight the importance of the WIPI protein members for neuronal function, however, the contribution of WIPI-mediated clearance of mitochondria in neurodegeneration remains unclear.…”