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Updated: Aug 23, 2026
Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
Published on: January 7, 2013
Inhibition of tumor necrosis factor-induced apoptosis in transgenic mouse liver expressing creatine kinase
Etsuro Hatano1, Akira Tanaka, Akiyoshi Kanazawa
1Department of Gastroenterological Surgery, Kyoto University, Graduate School of Medicine, Sakyo-ku, Japan. etsu@kuhp.kyoto-u.ac.jp
Background:
The mitochondrion acts as a pivotal decision center in many types of apoptotic responses. To clarify the effects of the enhanced mitochondrial function on tumor necrosis factoralpha (TNFalpha)-induced apoptosis, we studied hepatic injuries in transgenic mice whose livers express creatine kinase (CK).
Methods:
Mice fed a diet containing 10% creatine, came to accumulate phosphocreatine and to enhance hepatic ATP levels and mitochondrial oxidative phosphorylation activities. TNFalpha-mediated hepatic apoptosis in normally fed and Cr-feeding CK transgenic mice were assessed.
Results:
TNFalpha and actinomycin D cause severe liver failure in normally fed transgenic mice, and in the wild-type mice. In contrast, no significant elevations in transaminase levels after injection were observed in Cr feeding transgenic mice. The disruption of the mitochondrial transmembrane potential at 2 h after TNFalpha injection, prior to ATP depletion, activation of caspase 3 like protease, and DNA fragmentation at 4-6 h after injection, were observed in normally fed transgenic mice. These were fully suppressed in Cr feeding transgenic mice. However, anti-Fas antibody-induced apoptosis was not inhibited in both groups.
Conclusions:
The results indicate that TNFalpha-induced apoptosis was inhibited in CK transgenic mice livers by maintaining mitochondrial function.
Insights
Enhanced mitochondrial function protects against tumor necrosis factor-alpha (TNFalpha)-induced liver injury. Creatine kinase (CK) transgenic mice fed creatine showed suppressed TNFalpha-mediated apoptosis, highlighting a protective role for maintained mitochondrial function.
Area of Science:
- Cellular Biology
- Biochemistry
- Hepatology
Background:
- Mitochondria play a critical role in regulating apoptosis.
- Enhanced mitochondrial function may protect against cellular injury.
- Tumor necrosis factor-alpha (TNFalpha) is a key mediator of apoptosis.
Purpose of the Study:
- To investigate the impact of enhanced mitochondrial function on TNFalpha-induced apoptosis in liver cells.
- To assess the protective effects of creatine kinase (CK) expression and creatine supplementation in a mouse model of liver injury.
Main Methods:
- Transgenic mice expressing CK were fed a creatine-rich diet to enhance hepatic ATP levels and mitochondrial oxidative phosphorylation.
- TNFalpha-mediated hepatic apoptosis was induced and assessed in both creatine-fed and normally fed CK transgenic mice, as well as wild-type mice.
- Mitochondrial transmembrane potential, ATP levels, caspase activation, and DNA fragmentation were measured.
Main Results:
- TNFalpha and actinomycin D induced severe liver failure in normally fed mice but not in creatine-fed transgenic mice.
- Creatine supplementation in CK transgenic mice suppressed TNFalpha-induced mitochondrial transmembrane potential disruption, ATP depletion, and caspase activation.
- Anti-Fas antibody-induced apoptosis was not affected, suggesting specificity of the protective mechanism.
Conclusions:
- Maintaining mitochondrial function via creatine supplementation in CK transgenic mice inhibits TNFalpha-induced apoptosis in the liver.
- Enhanced mitochondrial energy metabolism confers protection against TNFalpha-mediated liver injury.
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