Comprehensive analysis of mitochondrial dysfunction and necroptosis in intracranial aneurysms from the perspective of predictive, preventative, and personalized  medicine

Abstract

Mitochondrial dysfunction and necroptosis are closely associated, and play vital roles in the medical strategy of multiple cardiovascular diseases. However, their implications in intracranial aneurysms (IAs) remain unclear. In this study, we aimed to explore whether mitochondrial dysfunction and necroptosis could be identified as valuable starting points for predictive, preventive, and personalized medicine for IAs. The transcriptional profiles of 75 IAs and 37 control samples were collected from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs), weighted gene co-expression network analysis, and least absolute shrinkage and selection operator (LASSO) regression were used to screen key genes. The ssGSEA algorithm was performed to establish phenotype scores. The correlation between mitochondrial dysfunction and necroptosis was evaluated using functional enrichment crossover, phenotype score correlation, immune infiltration, and interaction network construction. The IA diagnostic values of key genes were identified using machine learning. Finally, we performed the single-cell sequencing (scRNA-seq) analysis to explore mitochondrial dysfunction and necroptosis at the cellular level. In total, 42 IA-mitochondrial DEGs and 15 IA-necroptosis DEGs were identified. Screening revealed seven key genes invovled in mitochondrial dysfunction (KMO, HADH, BAX, AADAT, SDSL, PYCR1, and MAOA) and five genes involved in necroptosis (IL1B, CAMK2G, STAT1, NLRP3, and BAX). Machine learning confirmed the high diagnostic value of these key genes for IA. The IA samples showed higher expression of mitochondrial dysfunction and necroptosis. Mitochondrial dysfunction and necroptosis exhibited a close association. Furthermore, scRNA-seq indicated that mitochondrial dysfunction and necroptosis were preferentially up-regulated in monocytes/macrophages and vascular smooth muscle cells (VSMCs) within IA lesions. In conclusion, mitochondria-induced necroptosis was involved in IA formation, and was mainly up-regulated in monocytes/macrophages and VSMCs within IA lesions. Mitochondria-induced necroptosis may be a novel potential target for diagnosis, prevention, and treatment of IA.

Causal relationship between mitochondrial-associated proteins and cerebral aneurysms: a Mendelian randomization study

“…Apoptosis-inducing factor 1(AIF1), initially discovered as a flavoprotein located in the mitochondrial intermembrane space, was first identified as a cell apoptosis-inducing factor ( 27 , 28 ). After translocation from mitochondria to the nucleus, AIF1 can induce DNA fragmentation and cell apoptosis through a caspase-independent mechanism, leading to apoptosis within the cell or affecting cell survival by modulating mitochondrial function ( 29 , 30 ), and the mitochondria-necrotic apoptosis axis is one of the pathogenic mechanisms of cerebral aneurysms ( 8 ). Numerous experimental studies have demonstrated that AIF is the primary cause of ischemic and traumatic neuronal death.…”

“…Abnormal mitochondrial ultrastructure, defects in the electron transport chain, increased reactive oxygen species (ROS), oxidative stress, and unique dynamic characteristics play crucial roles in regulating the process of cellular apoptosis ( 7 ). Notably, mitochondria-induced necrotic apoptosis is implicated in the formation of cerebral aneurysms ( 8 ). and mitochondrial apoptosis triggered by respiratory chain dysfunction serves as a pathological mechanism of cerebral aneurysms ( 9 ).…”

A novel mitochondrial function-associated programmed cell death-related prognostic signature for predicting the prognosis of early breast cancer

“…Total 19 PCD patterns and key regulatory genes were collected through literature search ( Chen et al, 2023 ; Hu et al, 2023 ), and after removing duplicates, total 1583 PCD-related genes were obtained. Besides, 1,136 mitochondrial function-related genes were obtained from MitoCarta 3.0 database ( Rath et al, 2021 ).…”

Current understanding of macrophages in intracranial aneurysm: relevant etiological manifestations, signaling modulation and therapeutic strategies

“…The blocking of GM-CSF significantly inhibited M1 macrophages and MMP-9 secretion ( 75 ). In addition, the STAT signaling is an important clue in modulating macrophage M1/M2 polarization ( 99 , 100 ). The intervention of STAT signaling could significantly decrease the M1 macrophages polarization in IA ( 15 ).…”