Single-cell transcriptome atlas reveals mitophagy dynamics in acute chemical injury model and the role of MSCs transplantation.

BACKGROUND AND PURPOSE: Mitochondrial autophagy, also referred to as mitophagy, clears damaged mitochondria and has dual functions in disease development and liver homeostasis in response to liver pathologies. Mesenchymal stem/stromal cells (MSCs) are most commonly used to treat liver failure because they are easy to obtain and present no ethical problems. However, the molecular mechanisms by which MSCs promote liver failure progression are not fully understood. This study explored the distinct mitophagy states in hepatocytes and macrophages during MSCs therapy. EXPERIMENTAL APPROACH: To investigate tissue-specific mitophagy in acute liver failure (ALF), we generated a single-cell transcriptome (scRNA-seq) atlas of liver tissue from healthy mice, ALF mice and human umbilical cord mesenchymal stem/stromal cell (hUC-MSC)-transplanted mice. KEY RESULTS: The data revealed the complex cellular landscape of liver tissue during ALF progression, revealing alterations in metabolic fluxes and mitophagy activation. Through the intersection of single-cell sequencing data with mitophagy-related genes (MRGs), a total of 24 differentially expressed MRGs were identified. Gene Ontology (GO) analysis further revealed that the ubiquitinating enzyme Arih1 was significantly upregulated after MSC transplantation, whereas the mitophagy genes Bnip3L/NIX and Beciln1 were significantly downregulated in mononuclear phagocytes(MPs). CONCLUSIONS AND IMPLICATIONS: Our research demonstrated that during the development of ALF, mitophagy within hepatocytes is suppressed, whereas in MPs, mitophagy is excessively activated. MSCs are capable of alleviating disease progression by modulating the distinct mitophagy states of cells, providing an important resource for investigating mitophagy regulation in hepatic homeostasis and disease development.