Ferroptosis

2022-06-16: reference:

Ferroptosis #

(NOT ferritinophagy but I’m gonna be annoying and alias it for now since they’re related)

• Iron-driven cell death characterized by accumulation of lipid peroxides. Ferritinophagy, meanwhile, a component of ferroptosis, is the turnover of ferritin for the purpose of releasing vast amounts of iron - to commit suicide - and is the only known mechanism by which iron bound to ferritin can be released.
• Iron overload inhibits late stage autophagic flux leading to insulin resistance
  • Leads to a decrease in AKT->TSC2 and Rheb-mediated mTORC1 activation on autolysosomes, thereby inhibiting autophagic-lysosome regeneration.
    • Very confused with the semantics. Are we talking both or can I just say it inhibited AKT? Which will be seen in insulin resistance.
  • How tf does mTORC1-UVRAG inhibition lead to a ‘profound autophagy defect’? This will be interesting.
• IRON METABOLISM AND AUTOPHAGY: A POORLY EXPLORED RELATIONSHIP THAT HAS IMPORTANT CONSEQUENCES FOR HEALTH AND DISEASE (pretty short)
• Reduced autophagy leads to an impaired ferritin turnover in senescent fibroblasts
  • Three types of autophagy for the transfer of lysosomes: chaperone-mediated, microautophagy (takes place in just a lysosome), and macroautophagy.
    • Macroautophagy results in the formation of the Autophagosome, which delivers the cursed cargo and goes to fuse with a lysosome to form the autolysosome, wherein protein degradation takes place.
      • During lysosomal dysfunction, autophagosomes build up.
• Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis
  • Rapamycin averted the iron accumulation phenotype of senescent cells, preventing increase in TfR1, ferritin, and intracellular iron. But it failed to re-sensitize cells to ferroptosis.
  • Senescent cells, regardless of stimuli accmumulate up to 30-fold the amounts of intracellular iron
  • Cellular senescence preceded iron accumulation and was not perturbed by sustained iron chelation (deferiprone) and this accumulation was identified as a hallmark of senescence irrespective of the inducing stimuli and it occurred across species.
  • Senescence begins with the p53-p21 effector pathways which the iron accumulation is dependent on.
• Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome
  • Ubiquitination is not required for iron release but is required for disassembly of ferritin nanocages, which is followed by degradation of ferritin by the proteasome.
• Ferritinophagy and ferroptosis in the management of metabolic diseases
  • Both hyperactive and impaired autophagy results in programmed cell death. Ferroptosis is pretty interesting.
  • All types of autophagy really can cause ferroptosis, by means of lipid peroxidation.
  • Maternal hyperandrogenism can cause ferroptosis through MAPK/p38/JNK.
  • NCOA4 is a ‘ferritinophagy receptor’. Deficiency abolishes ferritinophagy. It binds to Ferritin Heavy Chain and then latches onto the autophagosome, and high levels of Fe2+ increase its autophagic degradation, which makes it a simple negative feedback loop.