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Updated: Jun 6, 2026
Extended 78% Hepatectomy in a Mouse Surgical Model
Published on: May 24, 2024
NIM811 prevents mitochondrial dysfunction, attenuates liver injury, and stimulates liver regeneration after massive
Hasibur Rehman1, Junjiang Sun, Yanjun Shi
1Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA.
Background:
Massive hepatectomy (MHX) leads to failure of remnant livers. Excessive metabolic burden in remnant livers may cause mitochondrial dysfunction. This study investigated whether blockade of the mitochondrial permeability transition (MPT) with N-methyl-4-isoleucine cyclosporine (NIM811) improves the outcome of MHX.
Methods:
Mice were gavaged with NIM811 (10 mg/kg before surgery and 5 mg/kg daily afterward) and underwent sham-operation or approximately 90% partial hepatectomy.
Results:
Serum alanine aminotransferase, necrosis, and apoptosis increased, respectively, to approximately 1200 U/L, 6.1%, and 7% after MHX. NIM811 decreased peak alanine aminotransferase release, necrosis, and apoptosis by 70%, 100%, and 42%, respectively. 5-Bromo-2'-deoxyuridine incorporation, proliferating cell nuclear antigen expression, and the remnant liver weights were all increased significantly by NIM811 treatment, indicating improved liver regeneration. NIM811 also blunted hyperbilirubinemia by 54%, increased serum albumin by 51%, and improved survival from 6% to 40% after MHX. Hepatic mitochondrial depolarization, cell death, and MPT were detected by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. Mitochondrial depolarization occurred in many viable hepatocytes (13 cells/high-power field), and nonviable hepatocytes increased slightly to approximately 1 cell/high-power field at 3 hr after MHX. Entry of calcein into mitochondria after MHX indicated MPT onset. Importantly, NIM811 decreased mitochondria depolarization by more than 60%, blocked MPT onset, and prevented cell death. Decreases of hepatic ATP, mitochondrial cytochrome c release, and caspase-3 activation after MHX were also partially blocked by NIM811.
Conclusions:
NIM811 minimized liver injury and improved liver regeneration after MHX, at least in part, by preventing MPT onset and subsequent compromised energy supply and proapoptotic cytochrome c release.
Insights
N-methyl-4-isoleucine cyclosporine (NIM811) significantly improved liver regeneration and survival after massive hepatectomy (MHX) in mice. This was achieved by blocking mitochondrial permeability transition (MPT) and reducing liver injury.
Area of Science:
- Hepatology
- Mitochondrial Biology
- Surgical Research
Background:
- Massive hepatectomy (MHX) often results in remnant liver failure due to excessive metabolic burden.
- Mitochondrial dysfunction is a key factor contributing to liver injury post-MHX.
- The mitochondrial permeability transition (MPT) pore opening is implicated in cell death following liver resection.
Purpose of the Study:
- To investigate the therapeutic potential of blocking MPT with N-methyl-4-isoleucine cyclosporine (NIM811).
- To evaluate the effects of NIM811 on liver injury, regeneration, and survival after MHX.
Main Methods:
- Mice were treated with NIM811 (10 mg/kg pre-surgery, 5 mg/kg daily post-surgery) or placebo.
- Animals underwent either sham operation or approximately 90% partial hepatectomy (MHX).
- Liver injury, regeneration markers, mitochondrial function, and MPT were assessed using biochemical assays and microscopy.
Main Results:
- NIM811 treatment significantly reduced serum alanine aminotransferase, necrosis, and apoptosis by 70%, 100%, and 42%, respectively.
- Improved liver regeneration was evidenced by increased DNA synthesis, cell proliferation markers, and remnant liver weight.
- NIM811 blunted hyperbilirubinemia, increased serum albumin, improved survival from 6% to 40%, and prevented mitochondrial depolarization and MPT onset.
Conclusions:
- NIM811 effectively minimized liver injury and promoted liver regeneration following massive hepatectomy.
- The protective effects of NIM811 are attributed to the prevention of MPT pore opening.
- Blocking MPT with NIM811 preserves energy supply and inhibits pro-apoptotic cytochrome c release, enhancing post-resection outcomes.
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