Polyamines are important polycations that play critical roles in mammalian cells. ATP13A2 belongs to the orphan P5B adenosine triphosphatases (ATPase) family and has been established as a lysosomal polyamine exporter to maintain the normal function of lysosomes and mitochondria. Previous studies have reported that several human neurodegenerative disorders are related to mutations in the ATP13A2 gene. However, the transport mechanism of ATP13A2 in the lysosome remains unclear. Here, we report the cryo-electron microscopy (cryo-EM) structures of three distinct intermediates of the human ATP13A2, revealing key insights into the spermine (SPM) transport cycle in the lysosome. The transmembrane domain serves as a substrate binding site and the C-terminal domain is essential for protein stability and may play a regulatory role. These findings advance our understanding of the polyamine transport mechanism, the lipid-associated regulation, and the disease-associated mutants of ATP13A2.

Educational level (EL), an important component for socioeconomic status, can potentially influence health, disease or mortality. Unfortunately, the detailed relationship between educational level and all cause or disease specific mortality in general population has not been elucidated, especially in Americans, which could impact public health policy. Here we analyzed association of EL with mortality in a nationally representative cohort from NHANES. This cohort study used National Health and Nutrition Examination Survey data from 1999 through 2018 and linked mortality information until 2019. Data were analyzed from April 1 through July 15, 2024. This study included 34,673 American adults aged 20-80 years old. During a median (IQR) follow-up of 9.9 (5.2-15.2) years, 5663 deaths were recorded. We found that higher EL was associated with mortality reduction in all cause, CVD, diabetes, Chronic Lower Respiratory Disease (CLRD), cancer and kidney disease mortality. Stratified analysis revealed that in subgroups <65 years, protection of higher EL was greater for all cause, CVD and cancer mortality. Higher EL was associated with reduction in male, while a risk factor in female for Alzheimer Disease, Influenza and Pneumonia Mortality. Higher EL was associated with mortality reduction in <65 subgroup, while a risk factor in ≥65 for Accidents Mortality. We found higher EL was associated with reduction in all cause, CVD, diabetes, Chronic Lower Respiratory Disease (CLRD), cancer and kidney disease mortality in a representative cohort in U.S. This study proved clear association between education level and disease specific mortality in a large nationally representative cohort in U.S., which may impact future public health policy making.