Published online Jan 27, 2024. doi: 10.4254/wjh.v16.i1.65
Peer-review started: September 30, 2023
First decision: October 23, 2023
Revised: November 3, 2023
Accepted: November 28, 2023
Article in press: November 28, 2023
Published online: January 27, 2024
Processing time: 114 Days and 23.7 Hours
It is clinically important to develop therapeutic strategies to enhance liver regeneration (LR) or support the liver in its attempt to restore its functional integrity under pathophysiological circumstances. However, the complexity of the regulatory mechanisms of LR, together with our limited understanding of the functional priorities of the hepatocytes have rendered difficult the identification of targets for therapeutic interventions.
Prohibitin 1 (Phb1) is a ubiquitously expressed highly conserved protein among eukaryotes. Previous research has proposed that Phb1 was involved in many cellular processes. Phb1 was reported to mainly localize in mitochondria, with its expression upregulated by mitochondrial stress and downregulated during cellular senescence. Therefore, Phb1 is thought to have a crucial role in mitochondrial function. One study identified a novel function of Phb1 in the maintenance of mitochondrial DNA (mtDNA). In Phb1-knockdown cells, the status of mtDNA is altered in several ways. Despite such information, our understanding of the overall functions of Phb1 in mitochondria remains incomplete and its potential role during LR is largely unexplored. LR is a very complicated biological procedure involving various signal transduction pathways and molecular events. Thus, we hypothesized that Phb1 could play a crucial role during LR.
This study aimed to further investigate the function of Phb1 in mitochondria during changes in Phb1 expression, mitochondrial mass and ultrastructure, and the subcellular distribution of Phb1 at 24, 72 and 168 h post 70% partial hepatectomy (PHx) in rat liver. Using RNA-interference-mediated knockdown of Phb1 (PHBi), we also analyzed the potential functions of Phb1.
We examined changes in Phb1 mRNA and protein levels, subcellular distribution, and abundance in rat liver during LR following 70% PHx. We also evaluated mitochondrial changes and apoptosis levels using electron microscopy and flow cytometry. PHBi was performed in BRL-3A cells.
Compared with sham-operation control groups, Phb1 mRNA and protein levels in 70% PHx test groups were downregulated at 24 h, then upregulated at 72 and 168 h. Phb1 was mainly located in mitochondria, showed a reduced abundance at 24 h, significantly increased at 72 h, and almost recovered to normal at 168 h. Phb1 was also present in nuclei, with continuous increase in abundance observed at 72 and 168 h after 70% PHx. The altered ultrastructure and reduced mass of mitochondria during LR had almost completely recovered to normal at 168 h. PHBi in BRL-3A cells resulted in increased S-phase entry, a higher number of apoptotic cells, and disruption of mitochondrial membrane potential.
In summary, our results demonstrate that Phb1 plays two roles in the LR process: one is to regulate cell cycle and apoptosis, and the other is to regulate and maintain mitochondrial stability.
Whether the two effects are directly linked or show two different effects remains unclear. Further in-depth studies will aid in us better understanding the complexities and roles of Phb1 in the LR process.