title: The mTOR inhibitor sirolimus suppresses renal, hepatic, and cardiac tissue cellular respiration.
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.
authors.affiliation: Department of Pathology, UAE University Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
authors.forename: Alia
authors.initials: A
authors.lastname: Albawardi
authors.affiliation: Department of Pathology, UAE University Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
authors.forename: Saeeda
authors.initials: S
authors.lastname: Almarzooqi
authors.affiliation: Department of Pathology, UAE University Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Saraswathiamma
authors.affiliation: Department of Medicine, UAE University Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
authors.forename: Hidaya Mohammed
authors.initials: HM
authors.lastname: Abdul-Kader
authors.affiliation: Department of Pediatrics, UAE University Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
authors.forename: Abdul-Kader
authors.initials: AK
authors.lastname: Souid
authors.affiliation: Department of Medicine, UAE University Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Alfazari
keywords: O2 consumption; cyclosporine; mTOR; oxidative phosphorylation; rapamycin; sirolimus; tacrolimus