BID links ferroptosis to mitochondrial cell death pathways

Abstract

Ferroptosis has been defined as an oxidative and iron-dependent pathway of regulated cell death that is distinct from caspase-dependent apoptosis and established pathways of death receptor-mediated regulated necrosis. While emerging evidence linked features of ferroptosis induced e.g. by erastin-mediated inhibition of the Xc- system or inhibition of glutathione peroxidase 4 (Gpx4) to an increasing number of oxidative cell death paradigms in cancer cells, neurons or kidney cells, the biochemical pathways of oxidative cell death remained largely unclear. In particular, the role of mitochondrial damage in paradigms of ferroptosis needs further investigation.In the present study, we find that erastin-induced ferroptosis in neuronal cells was accompanied by BID transactivation to mitochondria, loss of mitochondrial membrane potential, enhanced mitochondrial fragmentation and reduced ATP levels. These hallmarks of mitochondrial demise are also established features of oxytosis, a paradigm of cell death induced by Xc- inhibition by millimolar concentrations of glutamate. Bid knockout using CRISPR/Cas9 approaches preserved mitochondrial integrity and function, and mediated neuroprotective effects against both, ferroptosis and oxytosis. Furthermore, the BID-inhibitor BI-6c9 inhibited erastin-induced ferroptosis, and, in turn, the ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 prevented mitochondrial dysfunction and cell death in the paradigm of oxytosis. These findings show that mitochondrial transactivation of BID links ferroptosis to mitochondrial damage as the final execution step in this paradigm of oxidative cell death.

Ferritinophagy/ferroptosis: Iron‐related newcomers in human diseases

“…The upregulation of the NRF2/HO‐1 pathway is involved in interrupting ferroptotic cell death and induced a neuroprotective effect (Adedoyin et al, ; Kim et al, ; Roh et al, ). In particular, the ferroptosis inhibitor of ferrostatin‐1 prevents mitochondrial dysfunction and oxidative cell death, mediating neuroprotective effects (Neitemeier et al, ). Therefore, ferroptosis is likely to exacerbate AD via targeting the HIF‐1α and HO‐1 pathways.…”

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

“…The immunomodulatory role of ferroptosis has also been investigated and discussed [164]. A member of the BCL-2 family, BH3-interacting domain death agonist (BID), which is truncated (tBID) during extrinsic apoptosis has been required for ferroptosis in neurons [165], suggesting an interconnection between ferroptotic and apoptotic cell death signaling pathways. More universally, ferroptosis is triggered in response to inhibition of glutathione (GSH) biosynthesis or inhibition of selenoprotein glutathione peroxidase 4 (GPX4) (Figure 4).…”

JN403, an alpha-7-nicotine-acetylcholine-receptor agonist, reduces alpha-synuclein induced inflammatory parameters ofin vitromicroglia but fails to attenuate the reduction of TH positive nigral neurons in a focal alpha-synuclein overexpression mouse model of Parkinson’s disease

“…The viability of microglial cells was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT; Sigma-Aldrich, Steinheim, Germany) assay as described previously [36]. MTT was added to the cells at a final concentration of 0.5 mg/ml in the cell culture medium, and the cells were incubated for 30 min at 37 °C.…”