title: Inhibition of mammalian target of rapamycin induces renal mitochondrial uncoupling in rats.
abstract: The mechanisms underlying diabetic nephropathy are not fully understood. However, recent research indicates mitochondria dysfunction as a contributing factor. Mammalian target of rapamycin (mTOR) is a known regulator of mitochondria function and could therefore also be involved in the development of diabetic nephropathy. The present study investigates the role of mTOR for controlling the function of mitochondria isolated from normal and diabetic rat kidneys. Control and streptozotocin-induced diabetic rats were treated with the mTOR inhibitor rapamycin (0.2 mg/day) by oral gavage for 14 days, after which mitochondria function was investigated using high-resolution respirometry. Mitochondrial uncoupling was defined as increased oxygen usage unrelated to ATP production. mTOR inhibition induced mitochondria uncoupling in control rats, but did not affect the already occurring uncoupling in kidney mitochondria from diabetic animals. Inhibition of mTOR using rapamycin induces mitochondria uncoupling in control rats, suggesting a role of mTOR as a moderator of mitochondria efficiency. No effect of mTOR inhibition was observed in mitochondria from diabetic animals, suggesting that there are other pathways in addition to the mTOR pathway regulating mitochondria function in diabetes. The functional significance of the mTOR pathway in regulating mitochondria efficiency warrants further attention.
authors.affiliation: Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University, Uppsala, 571, 751 23, Sweden. Ebba.sivertsson@mcb.uu.se.
authors.forename: Ebba
authors.initials: E
authors.lastname: Sivertsson
authors.affiliation: Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University, Uppsala, 571, 751 23, Sweden.
authors.forename: Malou
authors.initials: M
authors.lastname: Friederich-Persson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D010100:Oxygen; D020123:Sirolimus