Hepatic encephalopathy changes mitochondrial dynamics and autophagy in the substantia nigra

Abstract

Hepatic encephalopathy (HE) has been reported in more than 40% of patients with cirrhosis in clinical practice. HE changes mitochondrial dysfunction. Mitochondrial dynamics and autophagy are important for maintaining and removing damaged mitochondria. We used molecular biology and morphology methods to evaluate changes in mitochondrial dynamics and autophagy of the substantia nigra (SN) and prefrontal cortex (PFC) in HE. In this study, we observed that HE increased mitochondrial dynamics and autophagy in the SN, which was not seen in the PFC. HE stimulated dynamin-related protein 1 (DRP1) transformation from the cytosolic to the mitochondria within SN cells, which increased mitochondrial fission and the number of mitochondria. The fusion protein L-OPA1 (long isoforms of OPA1) was increased in the SN of HE mice. HE also increased the levels of autophagy proteins PINK1/PARKIN and P62/LC3-B in the SN, which can selectively remove damaged mitochondria and cell, respectively. Additionally, we used electron microscopy to directly observe changes in mitochondrial morphology in the SN of HE mice and found the number of mitochondria was increased. However, there were no significant changes in the fission, fusion or autophagy proteins in PFC-purified mitochondrial proteins in HE mice. The number of mitochondria also did not show alterations in the PFC of HE mice compared with that in a sham group. These results illustrate that mitochondria can protect themselves by changing the dynamics and autophagy in the SN of HE mice. Changes in the mitochondrial dynamics and autophagy related to HE can help repair damaged mitochondria and provide a further understanding of the mechanisms of hepatic encephalopathy.