Carbon monoxide-releasing molecules (CO-RMs) modulate respiration in isolated mitochondria.
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.
Sandouka
A
A
Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, HA1 3UJ, United Kingdom.
Balogun
E
E
Foresti
R
R
Mann
B E
BE
Johnson
T R
TR
Tayem
Y
Y
Green
C J
CJ
Fuller
B
B
Motterlini
R
R
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
D006427:Hemin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat