Introduction: Stem cells play a pivotal role in immunomodulation and tissue repair, and their functions can be influenced by TLR signaling. The Toll/interleukin-1 receptor domain-containing protein C (TcpC), secreted by Uropathogenic Escherichia coli, can inhibit host immunity by interfering with TLR pathways. As mitochondria are crucial for stem cell function, there may be links between TcpC and mitochondrial homeostasis. Methods: We isolated MSC mitochondria using magnetic beads coated with a monoclonal antibody against the outer mitochondrial membrane protein OMP25 and conducted a proteomic study to examine the MSC mitochondrial proteome with or without TcpC. Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and proteinprotein interaction (PPI) network analysis, were employed. Results: A total of 33 proteins with significant changes in abundance were identified: 4 increased in abundance, including glycolytic enzymes (Pkm FC=1.6599, p=0.0217) and stress response proteins (Ywhaq FC=1.4666, p=0.04502); and 29 decreased, mainly related to mitochondrial oxidative phosphorylation (e.g., Atp5f1e FC=0.001, p=0.00120, Ndufa11 FC=0.001, p=0.00674) and protein quality control (e.g., Grpel1 FC=0.46663, p=0.02083, Hspa9 FC=0.48089, p=0.0435, Pitrm1 FC=0.12764, p=0.01388). Discussion: The possible effects of TcpC on the MSC mitochondrial proteome are reported here for the first time. This information provides a clearer understanding of MSCs in the context of infectious disease and offers a scientific basis for future stem cell therapy research. Conclusion: TCP-C intervention leads to a series of differentially expressed proteins in MSC mitochondria, which are involved in several functional clusters, including oxidative phosphorylation, respiratory electron transport, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism, branched-chain amino acid catabolism, and cristae formation.
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