Background: Mitochondrial rhomboid protease PARL mediates the cleavage of PINK1 in healthy mitochondria. Results: PARL mediates the cleavage of PGAM5 in damaged mitochondria. Conclusion: PARL regulates differential cleavage of PINK1 and PGAM5 depending on the health status of mitochondria. Significance: This is the first implication of stress-dependent regulation of PARL-mediated RIP.

The use of immune checkpoint inhibitors to treat urothelial carcinoma (UC) is increasing rapidly without clear guidance for validated risk stratification. This multicenter retrospective study collected clinicopathological information on 463 patients, and 11 predefined variables were analyzed to develop a multivariate model predicting overall survival (OS). The model was validated using an independent dataset of 292 patients. Patient characteristics and outcomes were well balanced between the discovery and validation cohorts, which had median OS times of 10.2 and 12.5 mo, respectively. The final validated multivariate model was defined by risk scores based on the hazard ratios (HRs) of independent prognostic factors including performance status, site of metastasis, hemoglobin levels, and the neutrophil‐to‐lymphocyte ratio. The median OS times (95% confidence intervals [CIs]) for the low‐, intermediate‐, and high‐risk groups (discovery cohort) were not yet reached (NYR) (NYR–19.1), 6.8 mo (5.8‐8.9), and 2.3 mo (1.2‐2.6), respectively. The HRs (95% CI) for OS in the low‐ and intermediate‐risk groups vs the high‐risk group were 0.07 (0.04‐0.11) and 0.23 (0.15‐0.37), respectively. The objective response rates for in the low‐, intermediate‐, and high‐risk groups were 48.3%, 28.8%, and 10.5%, respectively. These differential outcomes were well reproduced in the validation cohort and in patients who received pembrolizumab after perioperative or first‐line chemotherapy (N = 584). In conclusion, the present study developed and validated a simple prognostic model predicting the oncological outcomes of pembrolizumab‐treated patients with chemoresistant UC. The model provides useful information for external validation, patient counseling, and clinical trial design.

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Tumor metastasis is the major cause of deaths in cancer patients and is modulated by intertwined stress-responsive signaling cascades. Here we demonstrate that deletion of stress-responsive apoptosis signal-regulating kinase 1 (Ask1) in platelets results in unstable hemostasis and drastic attenuation of tumor lung metastasis, both of which are attributable to platelet dysfunction. Platelet-specific deletion of Ask1 in mice leads to defects in ADP-dependent platelet aggregation, unstable hemostasis and subsequent attenuation of tumor metastasis. We also revealed that activating phosphorylation of Akt is attenuated in Ask1-deficient platelets, contrary to the previous reports suggesting that Akt is negatively regulated by ASK1. Mechanistically, ASK1-JNK/p38 axis phosphorylates an ADP receptor P2Y at Thr345, which is required for the ADP-dependent sustained Akt activity that is vital to normal platelet functions. Our findings offer insight into positive regulation of Akt signaling through P2Y phosphorylation as well as MAPK signaling in platelets by ASK1 and suggest that ASK1-JNK/p38 axis provides a new therapeutic opportunity for tumor metastasis.