A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease.

Dysregulated iron or Ca2+ homeostasis has been reported in Parkinson's disease (PD) models. Here, we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+ overflow, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU). In PD neurons, iron accumulation-triggered Ca2+ influx across the mitochondrial surface leads to spatially confined Ca2+ elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover Food and Drug Administration-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology and drug targets and candidates coupled with a convenient stratification method.

SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1.

PTOV1 is an oncogenic protein, initially identified in prostate cancer, that promotes proliferation, cell motility, and invasiveness. However, the mechanisms that regulate PTOV1 remain unclear. Here, we identify 14-3-3 as a PTOV1 interactor and show that high levels of 14-3-3 expression, like PTOV1, correlate with prostate cancer progression. We discover an SGK2-mediated phosphorylation of PTOV1 at S36, which is required for 14-3-3 binding. Disruption of the PTOV1-14-3-3 interaction results in an accumulation of PTOV1 in the nucleus and a proteasome-dependent reduction in PTOV1 protein levels. We find that loss of 14-3-3 binding leads to an increase in PTOV1 binding to the E3 ubiquitin ligase HUWE1, which promotes proteasomal degradation of PTOV1. Conversely, our data suggest that 14-3-3 stabilizes PTOV1 protein by sequestering PTOV1 in the cytosol and inhibiting its interaction with HUWE1. Finally, our data suggest that stabilization of the 14-3-3-bound form of PTOV1 promotes PTOV1-mediated expression of cJun, which drives cell-cycle progression in cancer. Together, these data provide a mechanism to understand the regulation of the oncoprotein PTOV1. IMPLICATIONS: These findings identify a potentially targetable mechanism that regulates the oncoprotein PTOV1.