Introduction: While mitochondrial dynamics and mitophagy are recognized as significant factors in the development and progression of liver diseases, there has been a lack of studies assessing the impact of mitochondrial stress in liver allografts experiencing T-cell-mediated rejection (TCMR). This study aims to fill this gap by investigating the role of mitochondrial stress and mitophagy in liver transplant patients diagnosed with acute TCMR.
Methods: Sixty-six recipients diagnosed with TCMR were enrolled in the study. A total of 132 biopsies were analyzed, with 66 being initial biopsies diagnosed as acute TCMR and the rest being follow-up biopsies. OPA1 and PINK1 immunostaining for mitophagy were performed on all 132 biopsies, evaluating expressions in hepatocytes, bile ducts, and inflammatory cells. PINK1 expression in sinusoids was additionally assessed. Cases were analyzed based on the presence or absence of increased OPA1 and PINK1 expression between diagnostic and follow-up biopsies. The histopathological and immunohistochemical differences between the initial and follow-up biopsies were correlated with concurrently measured liver function tests, clinical findings, new fibrosis development, new steatosis development, and graft and patient survival.
Results: Persistently elevated serum AST, ALT, and GGT levels (p<0.001, p<0.001, p=0.006 respectively), new fibrosis, and new steatosis development (p<0.001) in follow-up biopsies, along with an unchanged total RAI score (p=0.003), were statistically associated with shorter 10-year patient survival. Hepatic OPA 1 expression significantly correlated with augmented lobular necrosis, new steatosis, and fibrosis development in follow-up biopsies. (p<0.014, p<0.001, p<0.001 respectively) Elevated PINK1 staining in inflammatory cells was linked to increased lobular necrosis, persistent lobular inflammation, cholestasis, and new steatosis and fibrosis development (p=0.021, p=0.034, p=0.034, p=0.003, p=0.041 respectively) in the follow-up. Increased PINK1 staining in sinusoids was significantly associated with the development of new steatosis (p=0.003) during follow-up. Higher percentages of OPA1 staining in hepatocytes (p<0.001) and increased percentages of PINK1 staining in inflammatory cells (p<0.001)  and sinusoids (p=0.001) were statistically associated with more prolonged survival in terms of the 10-year survival time.
Conclusion: To our knowledge, no similar study has investigated the impact of mitochondrial stress on graft survival after liver transplantation, making our study pioneering in this field. In conclusion, our study suggests that mitochondrial stress and dynamics in post-liver transplant follow-up can significantly influence post-transplant prognosis and survival. These findings provide a crucial foundation for future research and clinical applications in the field of liver transplantation.