Multiple mechanisms underlying troglitazone-induced mitochondrial permeability transition

Area of Science:

• Biochemistry
• Toxicology
• Pharmacology

Background:

• Troglitazone, a withdrawn antidiabetic drug, caused severe hepatotoxicity.
• This toxicity is partly linked to mitochondrial permeability transition (MPT).

Purpose of the Study:

• Investigate the precise mechanisms of troglitazone-induced mitochondrial toxicity in isolated rat liver mitochondria.
• Differentiate the pathways of MPT induced by varying troglitazone concentrations.

Main Methods:

• Isolated rat liver mitochondria were used to assess mitochondrial swelling and oxygen consumption.
• Experiments involved varying troglitazone concentrations (10 μM and 50 μM) and using inhibitors like bromoenol lactone (BEL), cyclosporin A (CsA), and antioxidants.
• Calcium (Ca2+) presence/absence was also manipulated.

Main Results:

• Low troglitazone (10 μM) induced swelling sensitive to Ca2+ absence and CsA, indicating Ca2+-dependent MPT regulated by Ca2+-independent phospholipase A2 (iPLA2).
• High troglitazone (50 μM) induced swelling exacerbated by BEL and partially reduced by antioxidants, suggesting reactive oxygen species involvement.
• High troglitazone-induced swelling was CsA-insensitive, indicating different MPT pore opening mechanisms.
• Oxygen consumption was decreased by troglitazone but unaffected by BEL.

Conclusions:

• Troglitazone-induced MPT occurs via distinct mechanisms at different concentrations.
• Low-dose troglitazone toxicity involves iPLA2 activation, Ca2+ accumulation, and CsA-sensitive MPT pores.
• High-dose troglitazone toxicity involves reactive oxygen species and CsA-insensitive MPT pores.