Two subpopulations of mitochondria in the aging rat heart display heterogenous levels of oxidative stress

Abstract

Cardiac mitochondria are composed of two distinct subpopulations: one beneath the sarcolemma (subsarcolemmal mitochondria: SSM), and another along the myofilaments (interfibrillary mitochondria: IFM). Previous studies suggest a preferential loss of IFM function with age; however, the age-related changes in oxidative stress in these mitochondrial subpopulations have not been examined. To this end, the changes in mitochondrial antioxidant capacity, oxidant output, and oxidative damage to Complex IV in IFM and SSM from young and old rats were studied. Results show no apparent differences in any parameters examined between IFM and SSM from young rats. However, relative to young, only IFM from old rats had a significantly higher rate of oxidant production and a decline in mitochondrial ascorbate levels and GSH redox status. The age-related decline in mitochondrial antioxidant capacity in IFM was accompanied by a marked loss in glutaredoxin and GSSG reductase activities, suggesting a diminished reductive capacity in IFM with age. Moreover, the loss in Complex IV activity was limited to the IFM of old rats, which was accompanied by a 4-fold increase in 4-hydroxynonenal-modified Complex IV. Thus, mitochondrial decay is not uniform and further indicates that myofibrils may be uniquely under oxidative stress in the aging heart.

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

“…Data from our laboratory indicate that H 2 O 2 production by SSM, but not IFM, increases with age (87). These results are in contrast with previous findings by Suh et al (175) who reported an age-dependent increase in oxidant production by IFM but not SSM isolated from rat hearts. This seemingly opposite evidence could stem from methodological differences between the two studies with regard to the assessment of mitochondrial oxidant production: rate of oxidation of 2'7'-dihydrodichlorofluorescein that detects a variety of intramitochondrial oxidants [including H 2 O 2 and nitric oxide (NO · )] (175) as opposed to the quantification of H 2 O 2 released from intact mitochondria (87).…”

“…It is noteworthy that in IFM from the same animals, Judge et al (87) also observed increased activities of several antioxidant enzymes (SOD, GPX, and catalase), reduced glutathione concentrations, and elevated levels of oxidative damage. These findings may suggest that oxidant production within the matrix of old IFM is greater than in younger counterparts, which is in agreement with the results by Suh et al (175).…”

Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart

“…Moreover, differences in the activities of OxPhos complexes in the literature could result from the use of different subpopulations of mitochondria in different studies (Fannin et al, 1999;Palmer et al, 1977). It has been previously demonstrated that interfibrillar mitochondria exhibit a selective decline in Complex III and IV activity which is not observed in the subsarcolemmal population of mitochondria (Fannin et al, 1999;Lesnefsky and Hoppel, 2006;Suh et al, 2003). In our study, mitochondria were not separated and a mixed population was used, therefore any selective decrease in the activity of ETC complexes in one subpopulation could have been masked.…”

Mitochondria in the pathogenesis of diabetes: a proteomic view

“…However, there are two distinct mitochondrial subpopulations in the cardiac myocytes, SSM and IMF, similar to that found in skeletal muscle. The two populations of mitochondria response differently to physiological stimuli including obesity, diabetes, aging, fasting, apoptosis, and ischemia-reperfusion injury (Lesnefsky et al, 2001;Suh et al, 2003;Ritov et al, 2005;Mollica et al, 2006). John M. Hollander's research group investigated thoroughly the differential response of the two populations of mitochondria in both T1DM and T2DM, using both biochemical and proteomic tools, and thus improved our under- standing of the role of different mitochondrial populations in the pathogenesis of diabetic cardiomyopathy (Dabkowski et al, 2009;Baseler et al, 2010;Dabkowski et al, 2010).…”