Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria

Area of Science:

• Pharmacology
• Nephrology
• Mitochondrial Biology

Background:

• Tacrolimus and sirolimus are crucial immunosuppressants in organ transplantation.
• Tacrolimus is suspected to affect mitochondrial respiration, but sirolimus's effects remain unevaluated.
• Understanding these drugs' mitochondrial impact is vital for managing transplant patient outcomes.

Purpose of the Study:

• To investigate the in vitro effects of tacrolimus and sirolimus on oxidative phosphorylation in isolated rat kidney mitochondria.
• To determine if these immunosuppressants alter mitochondrial respiration at therapeutic concentrations.
• To explore potential cellular consequences and clinical implications, including nephrotoxicity.

Main Methods:

• Isolated rat kidney mitochondria were utilized for in vitro experiments.
• Oxygen consumption was measured using a Clark-type electrode to assess mitochondrial respiration.
• The effects on state 3 and state 4 respiration, respiratory control ratio, and EC50 values were quantified.

Main Results:

• Both tacrolimus and sirolimus increased resting mitochondrial respiration (state 4) but did not significantly affect ADP-stimulated respiration (state 3).
• A concentration-dependent decrease in respiratory control ratio was observed, with maximal inhibition of 20% for tacrolimus and 14% for sirolimus.
• An uncoupling effect on oxidative phosphorylation was noted, linked to reduced inner mitochondrial membrane fluidity.

Conclusions:

• Tacrolimus and sirolimus exhibit an uncoupling effect on mitochondrial oxidative phosphorylation at therapeutic concentrations.
• These findings suggest a potential mechanism for long-term nephrotoxicity associated with tacrolimus and raise concerns about sirolimus potentiating cyclosporine A-induced nephrotoxicity.