Deciphering novel mitochondrial signatures: multi-omics analysis uncovers cross-disease markers and oligodendrocyte pathways in Alzheimer's disease and Glioblastoma

Xuan Xu ^1,2* Jiaqi Wang ^1,2 Tong Chen ^1,3 Shuaibin Wang ³ Fei Wang ⁴ Junwen He ⁵ Xiang-Yu Meng ⁶ Yin Shen ^1,3*

• ¹ Anhui Medical University, Hefei, China
• ² School of Life Sciences, Anhui Medical University, Hefei, Anhui Province, China
• ³ School of Biomedical Engineering, Anhui Medical University, Hefei, Anhui Province, China
• ⁴ School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui Province, China
• ⁵ College of Informatics, Huazhong Agricultural University, Wuhan, Hubei Province, China
• ⁶ School of Medicine, Hubei Minzu University, Enshi, China

Introduction: Alzheimer's Disease (AD) and Glioblastoma (GBM) are severe neurological disorders that pose significant global healthcare challenges. Despite extensive research, the molecular mechanisms, particularly those involving mitochondrial dysfunction, remain poorly understood. A major limitation in current studies is the lack of cell-specific markers that effectively represent mitochondrial dynamics in AD and GBM.In this study, we analyzed single-cell transcriptomic data using ten machine learning algorithms to identify mitochondria-associated cell-specific markers. We validated these markers through the integration of gene expression and methylation data across diverse cell types. Our dataset comprised single-nucleus RNA sequencing (snRNA-seq) from AD patients, single-cell RNA sequencing (scRNA-seq) from GBM patients, and additional DNA methylation and transcriptomic data from the ROSMAP, ADNI, TCGA, and CGGA cohorts.Results: Our analysis identified four significant cross-disease mitochondrial markers: EFHD1, SASH1, FAM110B, and SLC25A18. These markers showed both shared and unique expression profiles in AD and GBM, suggesting a common mitochondrial mechanism contributing to both diseases. Additionally, oligodendrocytes and their interactions with astrocytes were implicated in disease progression, particularly through the APP signaling pathway. Key hub genes, such as HS6ST3 and TUBB2B, were identified across different cellular subpopulations, highlighting a cellspecific co-expression network linked to mitochondrial function.These findings provide novel insights into mitochondrial roles in AD and GBM, with significant implications for targeted therapies. This research delivers a comprehensive characterization of mitochondrial signatures in these diseases, potentially guiding more precise diagnostic and therapeutic interventions to mitigate disease progression.