Biology subjects

You, P.

Publications and source records attributed to You, P..

3 recordsLinked to original sources

bioRxiv2026

Presenilin 1 (PS1) located at mitochondrial inner membrane regulates mitochondrial cristae junction proteins arrangement and cristae formation in HEK293 cells

Presenilin 1 (PS1), a key pathogenic factor in familial Alzheimers disease, is implicated in regulation of mitochondrial functions, yet its precise sub-mitochondrial localization and underlying mechanisms remain poorly understood. In this study, we generated PS1 knockout (PS1 KO) cell lines to investigate the role of PS1 in mitochondrial structure and function. Our results demonstrated that PS1 is directly localized to the mitochondrial inner membrane. PS1 deficiency led to reduced ATP production, impaired mitochondrial respiration capacity, decreased mitochondrial membrane potential, disrupted Ca2+ homeostasis, and elevated reactive oxygen species (ROS) accumulation. Moreover, loss of PS1 caused abnormal mitochondrial cristae structure. Further analysis revealed that PS1 interacts with mitochondrial inner membrane proteins. Its absence promotes ATAD3A oligomerization and disrupts its arrangement at mitochondrial cristae junctions, leading to expansion of the mitochondria-associated membrane (MAM) and instability of mitochondrial DNA (mtDNA). Our findings demonstrate that PS1 acts as a central regulator of mitochondrial cristae morphogenesis by modulating protein interaction networks at cristae junctions, thereby illuminating fundamental molecular mechanisms contributing to mitochondrial dysfunctions in Alzheimers disease.

cell biology↗

bioRxiv2025

The DDIT4L-TOM40-ATP5A pathway suppresses glioblastoma oncogenesis

The characteristics of glioblastoma (GBM), including resistance to cell death and aberrant energy metabolism, are associated with the function of mitochondria. To date, the inherent suppressors that couple mitochondrial function with cell death remain unclear. DNA damage-inducible transcript 4-like (DDIT4L) expression in human gliomas and its association with patient survival was determined by public databases, western-blot and immunostaining. The role of DDIT4L in regulating tumor growth was analyzed using lentivirus and PDX model. The mechanism of DDIT4L on GBM mitochondrial function was determined by different assays. Here, we show that DDIT4L is an endogenous inhibitor of GBM via suppressing mitochondrial function. DDIT4L was expressed at high levels in GBM and transported into mitochondria via single import channel TOM40 other than the import receptors TOM22, TOM20 or TOM70. Then, DDIT4L interacted with the subunit of ATP synthase, inhibited mitochondrial function and induced tumor cell apoptosis. Furthermore, the synthetic peptide DDIT4LV125-P132 suppressed GBM oncogenesis. Based on these results, DDIT4L suppresses GBM oncogenesis through both TOM40- and ATP5A-dependent mechanisms to curb mitochondrial dynamics and induce cell apoptosis, and the DDIT4LV125-P132 peptide is a potential therapy for GBM.

cancer biology↗

bioRxiv2019

Generating real-world tumor burden endpoints from electronic health record data: Comparison of RECIST, radiology-anchored, and clinician-anchored approaches for abstracting real-world progression in non-small cell lung cancer

Real-world evidence derived from electronic health records (EHRs) is increasingly recognized as a supplement to evidence generated from traditional clinical trials. In oncology, tumor-based Response Evaluation Criteria in Solid Tumors (RECIST) endpoints are collected in clinical trials. The best approach for collecting similar endpoints from EHRs remains unknown. We evaluated the feasibility of a traditional RECIST-based methodology to assess EHR-derived real-world progression (rwP) and explored non-RECIST-based approaches. In this retrospective study, cohorts were randomly selected from Flatiron Healths database of patient-level EHR data in advanced non-small cell lung cancer. A RECIST-based approach was tested for feasibility (N=26). Three non-RECIST abstraction approaches were tested for feasibility, reliability, and validity (N=200): (1) radiology-anchored, (2) clinician-anchored, and (3) combined. RECIST-based cancer progression could be ascertained from the EHRs of 23% of patients (6/26). In 87% of patients (173/200), at least one rwP event was identified using both the radiology- and clinician-anchored approaches. rwP dates matched 90% of the time. In 72% of patients (124/173), the first clinician-anchored rwP event was accompanied by a downstream event (e.g., treatment change); the association was slightly lower for the radiology-anchored approach (67%; 121/180). Median overall survival (OS) was 17 months (95% confidence interval [CI]: 14, 19). Median real-world progression-free survival (rwPFS) was 5.5 (95% CI: 4.6, 6.3) and 4.9 months (95% CI: 4.2, 5.6) for clinician-anchored and radiology-anchored approaches, respectively. Correlations between rwPFS and OS were similar across approaches (Spearmans rho: 0.65-0.66). Abstractors preferred the clinician-anchored approach as it provided more comprehensive context. RECIST cannot adequately assess cancer progression in EHR-derived data due to missing data and lack of clarity in radiology reports. We found a clinician-anchored approach supported by radiology report data to be the optimal, and most practical, method for characterizing tumor-based endpoints from EHR-sourced data.

bioinformatics↗