AMPK activator acadesine fails to alleviate isoniazid-caused mitochondrial instability in HepG2 cells

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Isoniazid (INH), a key anti-tuberculosis drug, can cause liver damage (hepatotoxicity).
• Mitochondrial dysfunction is increasingly recognized as a factor in INH-induced hepatotoxicity.
• Maintaining mitochondrial homeostasis, through biogenesis and autophagy, is crucial for cellular health.

Purpose of the Study:

• To investigate the effect of the AMP-activated protein kinase (AMPK) activator acadesine (AICAR) on isoniazid-induced mitochondrial dysfunction.
• To explore the role of the SIRT1-PGC1α pathway and autophagy in AICAR's effects on mitochondrial homeostasis during INH treatment.

Main Methods:

• Utilized HepG2 cells as a model system.
• Administered isoniazid (INH) and acadesine (AICAR) to cells.
• Assessed mitochondrial biogenesis, autophagy flux, mitochondrial stability, and apoptosis.

Main Results:

• AICAR treatment activated the SIRT1-PGC1α pathway, enhancing mitochondrial biogenesis and partially mitigating INH-induced impairment.
• However, AICAR unexpectedly decreased INH-induced autophagy, a critical cellular process for removing damaged mitochondria.
• This inhibition of autophagy led to persistent mitochondrial instability and apoptosis, despite improved biogenesis.

Conclusions:

• While AICAR can boost mitochondrial biogenesis via the SIRT1-PGC1α pathway, its inhibitory effect on autophagy prevents it from alleviating INH-induced mitochondrial instability and cell death in HepG2 cells.
• Targeting both mitochondrial biogenesis and autophagy may be necessary for effective therapeutic strategies against INH hepatotoxicity.