DMT1 knockout abolishes ferroptosis induced mitochondrial dysfunction in C. elegans amyloid beta proteotoxicity

Abstract

Iron is critical for neuronal activity and metabolism, and iron dysregulation alters these functions in age-related neurodegenerative disorders, such as Alzheimers disease (AD). AD is a chronic neurodegenerative disease characterized by progressive neuronal dysfunction, memory loss and decreased cognitive function. AD patients exhibit elevated iron levels in the brain compared to age-matched non-AD individuals. However, the degree to which iron overload contributes to AD pathogenesis is unclear. Here, we evaluated the involvement of ferroptosis, an iron-dependent cell death process, in mediating AD-like pathologies in C. elegans. Results showed that iron accumulation occurred prior to the loss of neuronal function as worms age. In addition, energetic imbalance was an early event in iron-induced loss of neuronal function. Furthermore, the loss of neuronal function was, in part, due to increased mitochondrial reactive oxygen species mediated oxidative damage, ultimately resulting in ferroptotic cell death. The mitochondrial redox environment and ferroptosis were modulated by pharmacologic processes that exacerbate or abolish iron accumulation both in wild-type worms and worms with increased levels of neuronal amyloid beta (A{beta}). However, neuronal A{beta} worms were more sensitive to ferroptosis-mediated neuronal loss, and this increased toxicity was ameliorated by limiting the uptake of ferrous iron through knockout of divalent metal transporter 1 (DMT1). In addition, DMT1 knockout completely suppressed phenotypic measures of A{beta} toxicity with age. Overall, our findings suggest that iron-induced ferroptosis alters the mitochondrial redox environment to drive oxidative damage when neuronal A{beta} is overexpressed. DMT1 knockout abolishes neuronal A{beta}-associated pathologies by reducing neuronal iron uptake. HighlightsO_LIEnergetic imbalance is an early event in iron-induced loss of neuronal function C_LIO_LINeuronal A{beta} increases susceptibility to ferroptosis mediated oxidative damage C_LIO_LIDivalent metal transporter 1 knockout protects against iron-induced oxidative damage and ferroptosis C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/607074v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@927aaorg.highwire.dtl.DTLVardef@10b121forg.highwire.dtl.DTLVardef@1d2d6aforg.highwire.dtl.DTLVardef@10cb797_HPS_FORMAT_FIGEXP M_FIG C_FIG