Date Published: January 25, 2017
Publisher: Public Library of Science
Author(s): Paul Holvoet, Maarten Vanhaverbeke, Benjamine Geeraert, Dieuwke De Keyzer, Maarten Hulsmans, Stefan Janssens, Elena Aikawa.
Cytochrome oxidase IV complex regulates energy production in mitochondria. Therefore, we determined the relation of COX genes with atherosclerosis in mice and pigs.
First, we compared atherosclerosis in the aortic arch of age-matched (24 weeks) C57BL/6J control (n = 10), LDL-receptor deficient (n = 8), leptin-deficient ob/ob (n = 10), and double knock-out (lacking LDL-receptor and leptin) mice (n = 12). Low aortic mitochondria-encoded cytochrome oxidase 1 in obese diabetic double knock-out mice was associated with a larger plaque area and higher propensity of M1 macrophages and oxidized LDL. Caloric restriction increased mitochondria-encoded cytochrome oxidase 1 and reduced plaque area and oxidized LDL. This was associated with a reduction of titer of anti-oxidized LDL antibodies, a proxy of systemic oxidative stress. Low of mitochondria-encoded cytochrome oxidase 1 was related to low expression of peroxisome proliferative activated receptors α, δ, and γ and of peroxisome proliferative activated receptor, gamma, co-activator 1 alpha reflecting mitochondrial dysfunction. Caloric restriction increased them. To investigate if there was a diabetic/obesity requirement for mitochondria-encoded cytochrome oxidase 1 to be down-regulated, we then studied atherosclerosis in LAD of hypercholesterolemic pigs (n = 37). Pigs at the end of the study were divided in three groups based on increasing LAD plaque complexity according to Stary (Stary I: n = 12; Stary II: n = 13; Stary III: n = 12). Low mitochondria-encoded cytochrome oxidase 1 in isolated plaque macrophages was associated with more complex coronary plaques and oxidized LDL. Nucleus-encoded cytochrome oxidase 4I1 and cytochrome oxidase 10 did not correlate with plaque complexity and oxidative stress. In mice and pigs, MT-COI was inversely related to insulin resistance.
Low MT-COI is related to mitochondrial dysfunction, oxidative stress and atherosclerosis and plaque complexity.
It has been proposed that mitochondrial decline resulting in mitochondrial oxidative stress contributes to the development of age-related metabolic and cardiovascular diseases . Impairment of the cytochrome c oxidase (COX), or complex IV, results in reactive oxygen intermediates promoting oxidative stress . This bigenomic complex is composed of subunits coded by both mitochondrial and nuclear DNA. A coordinated expression of these subunits provides cells with different modes of regulation of enzyme content in mitochondria. Of the thirteen subunits of the mammalian complex IV, the mitochondrial genome encodes subunits 1, 2 and 3, which form the catalytic core of the enzyme . MT-COI is the first gene in the polycistronic mitochondrial DNA and a single missense mutation in mouse Mt-co1 was associated with loss of COX activity , despite normal assembly of the complex IV, and with increased mitochondrial oxidative stress in cells in vitro .
In conclusion, we found that the expression of low MT-COI was associated with high oxidative stress and increased plaque burden in mice and pigs.