Stem Cell Modeling of Neuroferritinopathy Reveals Iron as a Determinant of Senescence and Ferroptosis during Neuronal Aging

Abstract

Summary: Neuroferritinopathy (NF) is a movement disorder caused by alterations in the L-ferritin gene that generate cytosolic free iron. NF is a unique pathophysiological model for determining the direct consequences of cell iron dysregulation. We established lines of induced pluripotent stem cells from fibroblasts from two NF patients and one isogenic control obtained by CRISPR/Cas9 technology. NF fibroblasts, neural progenitors, and neurons exhibited the presence of increased cytosolic iron, which was also detectable as: ferritin aggregates, alterations in the iron parameters, oxidative damage, and the onset of a senescence phenotype, particularly severe in the neurons. In this spontaneous senescence model, NF cells had impaired survival and died by ferroptosis. Thus, non-ferritin-bound iron is sufficient per se to cause both cell senescence and ferroptotic cell death in human fibroblasts and neurons. These results provide strong evidence supporting the primary role of iron in neuronal aging and degeneration. : In this article Sonia Levi and colleagues show that non-ferritin-bound iron is able to cause cell senescence and ferroptotic cell death in human fibroblasts and neurons, underlining the primary role of iron in accelerating the processes of aging and neurodegeneration. These findings provide implications for studies investigating the role of iron in a more general context of neurodegenerative diseases. Keywords: iron, induced pluripotent stem cells, senescence, ferroptosis, neurodegeneration, aging