title: Carbon monoxide-releasing molecules (CO-RMs) modulate respiration in isolated mitochondria.
abstract: Emerging evidence reveals that heme oxygenase-1 (HO-1) and its product carbon monoxide (CO) can exert diverse biological and cytoprotective effects. Our group has recently identified a new class of compounds (CO-releasing molecules or CO-RMs) that can carry and deliver CO to biological systems and can be used to examine the physiological properties of CO. Here, we evaluated the influence of endogenously-generated CO (via HO-1 induction by hemin) and CO liberated from exogenously supplied CO-RMs on mitochondrial function. Renal mitochondria were isolated either from rats with increased HO-1 or from untreated animals, the latter being exposed to different concentrations of CO-RMs (10-100 microM). We found that mitochondrial oxygen uptake was significantly reduced in kidneys after HO-1 induction and, in a similar fashion, CO-RMs inhibited mitochondrial function in a concentration-dependent manner. Specifically, a marked depression of state 3 was observed resulting in a significant decrease in respiratory control index (RCI) values. When mitochondria were incubated with the inactive forms of CO-RMs, which are devoid of CO, the respiratory parameters remained unchanged. In summary, the results indicate that HO-1 induction and enhanced CO decrease renal oxygen consumption and alter mitochondrial function suggesting that CO could be a physiological regulator of mitochondrial oxidative phosphorylation.
authors.affiliation: Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, HA1 3UJ, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Sandouka
authors.forename: E
authors.initials: E
authors.lastname: Balogun
authors.forename: R
authors.initials: R
authors.lastname: Foresti
authors.forename: B E
authors.initials: BE
authors.lastname: Mann
authors.forename: T R
authors.initials: TR
authors.lastname: Johnson
authors.forename: Y
authors.initials: Y
authors.lastname: Tayem
authors.forename: C J
authors.initials: CJ
authors.lastname: Green
authors.forename: B
authors.initials: B
authors.lastname: Fuller
authors.forename: R
authors.initials: R
authors.lastname: Motterlini
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D019069:Cell Respiration / Q000187:drug effects*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006427:Hemin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat