title: MicroRNA as biomarkers of mitochondrial toxicity.
abstract: Mitochondrial toxicity can be difficult to detect as most cells can tolerate reduced activity as long as minimal capacity for function is maintained. However, once minimal capacity is lost, apoptosis or necrosis occurs quickly. Identification of more sensitive, early markers of mitochondrial toxicity was the objective of this work. Rotenone, a mitochondrial complex I inhibitor, and 3-nitropropionic acid (3-NP), a mitochondrial complex II inhibitor, were administered daily to male Sprague-Dawley rats at subcutaneous doses of 0.1 or 0.3mg/kg/day and intraperitoneal doses of 5 or 10mg/kg/day, respectively, for 1week. Samples of kidney, skeletal muscle (quadriceps femoris), and serum were collected for analysis of mitochondrial DNA (mtDNA) copy number and microRNA (miRNA) expression patterns. MtDNA was significantly decreased with administration of rotenone at 0.3mg/kg/day and 3-NP at 5 and 10mg/kg/day in the quadriceps femoris and with 3-NP at 10mg/kg/day in the kidney. Additionally, rotenone and 3-NP treatment produced changes to miRNA expression that were similar in direction (i.e. upregulation, downregulation) to those previously linked to mitochondrial functions, such as mitochondrial damage and biogenesis (miR-122, miR-202-3p); regulation of ATP synthesis, abolished oxidative phosphorylation, and loss of membrane potential due to increased reactive oxygen species (ROS) production (miR-338-5p, miR-546, miR-34c); and mitochondrial DNA damage and depletion (miR-546). These results suggest that miRNAs may be sensitive biomarkers for early detection of mitochondrial toxicity.
authors.affiliation: Department of Toxicology, Drug Safety Evaluation, Bristol-Myers Squibb, 4401 Highway 62 East, Mount Vernon, IN 47620, USA. Electronic address: bethany.baumgart@bms.com.
authors.forename: Bethany R
authors.initials: BR
authors.lastname: Baumgart
authors.affiliation: Department of Toxicology, Drug Safety Evaluation, Bristol-Myers Squibb, 4401 Highway 62 East, Mount Vernon, IN 47620, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Gray
authors.affiliation: Department of Pathology, Drug Safety Evaluation, Bristol-Myers Squibb, 4401 Highway 62 East, Mount Vernon, IN 47620, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Woicke
authors.affiliation: Department of Toxicology, Drug Safety Evaluation, Bristol-Myers Squibb, 4401 Highway 62 East, Mount Vernon, IN 47620, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bunch
authors.affiliation: Department of Toxicology, Drug Safety Evaluation, Bristol-Myers Squibb, 4401 Highway 62 East, Mount Vernon, IN 47620, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sanderson
authors.affiliation: Department of Investigative Toxicology and Pathology, Abbvie, 1 N. Waukegan Rd., North Chicago, IL 60064-6123, USA.
authors.forename: Terry R
authors.initials: TR
authors.lastname: Van Vleet
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000633:toxicity*
chemical_list: D004272:DNA, Mitochondrial; D035683:MicroRNAs; D009574:Nitro Compounds; D011422:Propionates; D012402:Rotenone; C015392:3-nitropropionic acid
keywords: Drug safety; MicroRNA; Mitochondria; Toxicity