Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence ...alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins. For instance, ferritin (iron storage) levels provided a robust biomarker of cellular senescence, for associated iron accumulation and for resistance to iron-induced toxicity. Cellular senescence preceded iron accumulation and was not perturbed by sustained iron chelation (deferiprone). Iron accumulation in senescent cells was driven by impaired ferritinophagy, a lysosomal process that promotes ferritin degradation and ferroptosis. Lysosomal dysfunction in senescent cells was confirmed through several markers, including the build-up of microtubule-associated protein light chain 3 (LC3-II) in autophagosomes. Impaired ferritin degradation explains the iron accumulation phenotype of senescent cells, whereby iron is effectively trapped in ferritin creating a perceived cellular deficiency. Accordingly, senescent cells were highly resistant to ferroptosis. Promoting ferritin degradation by using the autophagy activator rapamycin averted the iron accumulation phenotype of senescent cells, preventing the increase of TfR1, ferritin and intracellular iron, but failed to re-sensitize these cells to ferroptosis. Finally, the enrichment of senescent cells in mouse ageing hepatic tissue was found to accompany iron accumulation, an elevation in ferritin and mirrored our observations using cultured senescent cells.
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•Altered iron homeostasis in senescent cells is driven by impaired ferritinophagy.•Impaired ferritinophagy causes functional cellular iron deficiency.•senescent cells are resistant to iron mediated cell death including ferroptosis.
Purpose
To develop a patient‐specific respiratory motion correction technique with true 100% acquisition efficiency.
Methods
A short training scan consisting of a series of single heartbeat images, ...each acquired with a preceding diaphragmatic navigator, was performed to fit a model relating the patient‐specific 3D respiratory motion of the heart‐to‐diaphragm position. The resulting motion model was then used to update the imaging plane in real‐time to correct for translational motion based on respiratory position provided by the navigator. The method was tested in a group of 11 volunteers with 5 separate free‐breathing acquisitions: FB, no motion correction; FB‐TF, free breathing with a linear tracking factor; Nav Gate, navigator gating; Nav Gate‐TF, navigator gating with a tracking factor; and PROCO, prospective motion correction (proposed). Each acquisition lasted for 50 accepted heartbeats, where non‐gated scans had a 100% acceptance rate, and gated scans accepted data only within a ±4 mm navigator window. Retrospective image registration was used to measure residual motion and determine the effectiveness of each method.
Results
PROCO reduced the range/RMSE of residual motion to 4.08 ± 1.4/0.90 ± 0.3 mm, compared to 10.78 ± 6.9/2.97 ± 2.2 mm for FB, 5.32 ± 2.92/1.24 ± 0.8 mm for FB‐TF, 4.08 ± 1.6/0.93 ± 0.4 mm for Nav Gate, and 2.90 ± 1.0/0.63 ± 0.2 mm for Nav Gate‐TF. Nav Gate and Nav Gate‐TF reduced scan efficiency to 48.84 ± 9.31% and 54.54 ± 10.12%, respectively.
Conclusion
PROCO successfully limited the residual motion in single‐shot imaging to the level of traditional navigator gating while maintaining 100% acquisition efficiency.
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