Key result
Six-gene mitochondrial model distinguishes HCM from normal tissue with ~0.96 validation AUC.
Why the study?
Mitochondrial DNA is implicated in hypertrophic cardiomyopathy development, leading researchers to identify valuable mtDNAs that contribute to HCM.
A 6-gene mitochondrial expression signature accurately differentiates hypertrophic cardiomyopathy tissue from healthy controls, highlighting the role of mitochondrial dysfunction and immune microenvironment alterations in HCM pathogenesis.
High tissue discrimination supports mitochondrial roles in HCM; hypothesis-generating for non-invasive validation before clinical use.
Mitochondrial DNA is implicated in hypertrophic cardiomyopathy (HCM) development. We aimed to identify valuable mtDNAs that contribute to the development of HCM. Differentially expressed mitochondrial DNAs (DEMGs) between HCM and controls were screened. GO and KEGG functional enrichment analyses were performed, and the optimum genes were explored using the LASSO regression mode and SVM-RFE model. A diagnostic scoring model was constructed and verified using ROC curves. Mitochondria-based subtypes were identified. Immune performance among the subtypes including immune cells, immune checkpoint genes, and HLA family genes was analyzed. Finally, an mRNA-transcription factor (TF)-miRNA network was constructed using Cytoscape software. Twelve DEMGs in HCM were selected. Among them, 6 DEMGs, including PDK4, MGST1, TOMM40, LYPLAL1, GATM, and CPT1B were demonstrated as DEMGs at the point of intersection of Lasso regression and SVM-RFE. The ROC of the model for the training and validation datasets was 0.999 and 0.958, respectively. Two clusters were divided, and 4 immune cell types were significantly different between the 2 clusters, including resting mast cells, macrophages M2, and plasma cells. Nine upregulated KEGG pathways were enriched in cluster 1 vs. cluster 2 including O-glycan biosynthesis, the ErbB signaling pathway, and the GnRH signaling pathway. Meanwhile, 49 down-regulated pathways were enriched such as the toll-like signaling pathway and natural killer cell-mediated cytotoxicity pathway. The 6 gene-based mRNA-TF-miRNA networks included other 133 TFs and 18 miRNAs. Six DEMGs in HCM, including PDK4, MGST1, TOMM40, LYPLAL1, GATM, and CPT1B, can be indicative of HCM prognosis or disease progression.
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Liao et al. (2023) studied Hypertrophic cardiomyopathy (n=339). Mitochondrial gene expression (6-gene signature) vs. Healthy controls was evaluated on Diagnostic accuracy (ROC AUC) of the mitochondrial gene scoring model (AUC 0.999 in training dataset, 0.958 in validation dataset). A 6-gene mitochondrial diagnostic model (PDK4, MGST1, TOMM40, LYPLAL1, GATM, CPT1B) distinguished hypertrophic cardiomyopathy from normal tissues with an AUC of 0.999 in the training dataset and 0.958 in the validation dataset.
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