1. Academic Validation
  2. The mTOR inhibitor sirolimus suppresses renal, hepatic, and cardiac tissue cellular respiration

The mTOR inhibitor sirolimus suppresses renal, hepatic, and cardiac tissue cellular respiration

  • Int J Physiol Pathophysiol Pharmacol. 2015 Mar 20;7(1):54-60.
Alia Albawardi 1 Saeeda Almarzooqi 1 Dhanya Saraswathiamma 1 Hidaya Mohammed Abdul-Kader 2 Abdul-Kader Souid 3 Ali S Alfazari 2
Affiliations

Affiliations

  • 1 Department of Pathology, UAE University Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
  • 2 Department of Medicine, UAE University Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
  • 3 Department of Pediatrics, UAE University Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
PMID: 26069529
Abstract

The purpose of this in vitro study was to develop a useful biomarker (e.g., cellular respiration, or mitochondrial O2 consumption) for measuring activities of mTOR inhibitors. It measured the effects of commonly used immunosuppressants (sirolimus - rapamycin, tacrolimus, and cyclosporine) on cellular respiration in target tissues (kidney, liver, and heart) from C57BL/6 mice. The mammalian target of rapamycin (mTOR), a serine/threonine kinase that supports nutrient-dependent cell growth and survival, is known to control energy conversion processes within the mitochondria. Consistently, inhibitors of mTOR (e.g., rapamycin, also known as sirolimus or Rapamune®) have been shown to impair mitochondrial function. Inhibitors of the calcium-dependent serine/threonine phosphatase Calcineurin (e.g., tacrolimus and cyclosporine), on the other hand, strictly prevent lymphokine production leading to a reduced T-cell function. Sirolimus (10 μM) inhibited renal (22%, p = 0.002), hepatic (39%, p < 0.001), and cardiac (42%, p = 0.005) cellular respiration. Tacrolimus and cyclosporine had no or minimum effects on cellular respiration in these tissues. Thus, these results clearly demonstrate that impaired cellular respiration (bioenergetics) is a sensitive biomarker of the immunosuppressants that target mTOR.

Keywords

O2 consumption; cyclosporine; mTOR; oxidative phosphorylation; rapamycin; sirolimus; tacrolimus.

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