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

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

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

Methods: 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.

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

Results: 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.

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

Strengths & Limitations: 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.

Conclusion: 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.