Isoniazid-induced cell death is precipitated by underlying mitochondrial complex I dysfunction in mouse hepatocytes

Area of Science:

• Hepatology
• Mitochondrial Biology
• Pharmacology

Background:

• Isoniazid (INH) is a key antituberculosis drug.
• Idiosyncratic liver injury is a known side effect of INH.
• The mechanisms of INH-induced liver injury are not fully understood, but mitochondrial dysfunction is suspected.

Purpose of the Study:

• To investigate if impaired mitochondrial complex I function sensitizes hepatocytes to INH-induced injury.
• To determine the role of hydrazine, a major INH metabolite, in this process.

Main Methods:

• Primary mouse hepatocyte cultures were used.
• Cells were exposed to INH alone, complex I inhibitors (rotenone, piericidin A), or combinations.
• Mitochondrial function (respiration, ATP levels) and cell viability were assessed.
• Experiments were also conducted with Ndufs4(+/-) mice lacking a complex I subunit.

Main Results:

• Isoniazid alone did not cause cell injury but reduced respiration and ATP levels.
• Combined exposure to INH and complex I inhibitors led to severe ATP depletion and cell death.
• Hydrazine, but not INH, directly inhibited complex II activity.
• Mice with reduced complex I subunit expression were not sensitized to INH.

Conclusions:

• Underlying mitochondrial complex I inhibition can precipitate INH-induced hepatocellular injury.
• Hydrazine appears to be the primary toxic metabolite involved.
• Mitochondrial dysfunction is a key factor in the idiosyncratic liver injury caused by INH.