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

International Journal of Physiology, Pathophysiology and Pharmacology

Ali S Alfazari¹  Hidaya Mohammed Abdul-Kader¹  Abdul-Kader Souid¹  Saeeda Almarzooqi¹  Dhanya Saraswathiamma¹  Alia Albawardi¹ 

关键词: mTOR;    rapamycin;    sirolimus;    tacrolimus;    cyclosporine;    O2 consumption;    oxidative phosphorylation;   

DOI  :  

学科分类：生理学与病理学

来源: e-Century Publishing Corporation

【 摘 要 】

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.

【 授权许可】

Unknown