Single-cell transcriptome analyses reveal the mechanism of mitochondrial activity in erectile dysfunction

Erectile dysfunction (ED) is a multifactorial disorder, with mitochondrial dysfunction increasingly recognized as an important contributor to its pathogenesis.

This study aimed to characterize the single-cell landscape of ED and investigate the impact of mitochondrial function on cellular heterogeneity.

We performed single-cell RNA sequencing analysis on ED samples (GSE206528), screened for ED-related mitochondrial genes, evaluated mitochondrial activity using area under the curve cell scoring at the single-cell level, and conducted subclustering, cell-cell communication, pseudotime trajectory, and pathway enrichment analyses to systematically characterize key cell populations.

The principal finding is that fibroblasts (FB) and endothelial cells (EC) display significant mitochondrial heterogeneity associated with ED.

A total of 64 993 high-quality cells were classified into seven major cell types. Among these, FB and EC exhibited significant mitochondrial heterogeneity. Seventy-three ED-related mitochondrial genes were identified, with 11 and six mitochondrial activity-associated genes in FB and EC, respectively. Subclustering analysis revealed six FB and four EC subpopulations, with distinct functional pathways. Cell-cell communication analysis indicated increased tumor necrosis factor, TNF-related apoptosis-inducing ligand, and wingless/integrated signaling in high-mitochondrial-activity groups. Pseudotime analysis suggested FB0 and EC1 as progenitor states, progressing toward FB4 and EC0, respectively. Pathway enrichment highlighted shared metabolic and stress-response pathways in FB and EC.

These results suggest that targeting mitochondrial dysfunction in FB and EC may offer novel therapeutic approaches for ED.

The study's strengths lie in its comprehensive single-cell characterization and functional annotation, while limitations include sample representativeness and the lack of direct experimental validation.

This study provides a comprehensive single-cell landscape of ED, identifying mitochondrial dysfunction as a key contributor to cellular heterogeneity. FB and EC emerged as critical regulators, with potential implications for targeted therapeutic strategies.