Figure 1.

Ultrastructural changes in cells undergoing ferroptosis and oxytosis comprise prominent but diverse mitochondrial abnormalities while nuclear integrity is preserved. Electron micrographs of (A) mouse embryonic fibroblasts (MEF) showing a time-dependent outer mitochondrial membrane rupture (yellow arrows) upon ferroptosis induction using RSL3 (50 nM; scale bars 2 μm top row, 200 nm bottom row) while nuclear integrity is preserved, (B) of BJeLR cells treated with DMSO (10 h) or erastin (37 μM, 10 h) showing shrinkage and increased electron density of the mitochondria. (C) Similar morphological changes as in (B) in response to RSL3 in MEF. (D) HT22 cells after control treatment (panels 1/2) and after 5 mM glutamate for 10 h (panels 3–5). Panels 3/4: low- and high-power micrographs, respectively, of the same region of the same cell. Arrows indicate mitochondria. Bars in panel 1 = 5 μm; panels 2, 3, and 5 = 2 μm; and panel 4 = 1 μm. Glutamate-induced oxytosis is also characterized by preserved nuclear structure in addition to prominent swelling of the endoplasmic reticulum, Golgi apparatus and mitochondria as well as cytoplasmic vacuolization. Mitochondria showed loss of the cristae. (E) Oxytosis induced by glutamate in HT4 cells. (E, left) HT4 cells with no glutamate. Mitochondria have a regular shape and optical density. (E, middle and right) glutamate-treated cell (10 mM for 8 h). The mitochondria appeared to be swollen and degraded with low optical density. Mitochondrial outer membrane disruption is observed. Scale bars 1.85 μm (left and middle), 0.21 μm (right). [Modified and reproduced with permission from (A) (Friedmann Angeli et al., 2014), (B) (Dixon et al., 2012), (C) (Doll et al., 2017), (D) (Tan et al., 1998b), and (E) (Tirosh et al., 2000)].