Aging Selectively Decreases Oxidative Capacity in Rat Heart Interfibrillar Mitochondria

Fannin, Stephen W.; Lesnefsky, Edward J.; Slabe, Thomas J.; Hassan, Mehat O.; Hoppel, Charles L.

doi:10.1006/abbi.1999.1508

Cited by 232 publications

(247 citation statements)

References 29 publications

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“…5B) was observed in aged rat heart mitochondrial fragments, which may reflect preserved expression of functionally active mtDNA encoded subunits. These results are consistent with findings reported in mitochondrial fragments from aged rat hearts (Fannin et al, 1999) but different from those described in brain and liver mitochondria from old rats where a 24-28% reduction in Complex IV activity was demonstrated (Navarro and Boveris, 2004). This discrepancy in the effect of aging on Complex IV activity could be related to tissue specific differences in isoenzymes of Complex IV or other complexes (Capaldi et al, 1988) that may respond differently to aging.…”

Section: Discussionsupporting

confidence: 90%

“…In addition, methodological differences such as the use of polarographic determination of cytochrome c oxidase activity demonstrating reduced Complex IV activity in aged cardiac mitochondria may explain some of the reported differences (Navarro and Boveris, 2007). 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).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Preston¹,

Oberlin²,

Holmuhamedov³

et al. 2008

Mechanisms of Ageing and Development

124

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Aging is associated with progressive decline in energetic reserves compromising cardiac performance and tolerance to injury. Although deviations in mitochondrial functions have been documented in senescent heart, the molecular bases for the decline in energy metabolism are only partially understood. Here, high-throughput transcription profiles of genes coding for mitochondrial proteins in ventricles from adult (6-months) and aged (24-months) rats were compared using microarrays. Out of 614 genes encoding for mitochondrial proteins, 94 were differentially expressed with 95% downregulated in the aged. The majority of changes affected genes coding for proteins involved in oxidative phosphorylation (39), substrate metabolism (14) and tricarboxylic acid cycle (6). Compared to adult, gene expression changes in aged hearts translated into a reduced mitochondrial functional capacity, with decreased NADH-dehydrogenase and F0F1-ATPase complex activities and capacity for oxygen-utilization and ATP synthesis. Expression of genes coding for transcription co-activator factors involved in the regulation of mitochondrial metabolism and biogenesis were downregulated in aged ventricles without reduction in mitochondrial density. Thus, aging induces a selective decline in activities of oxidative phosphorylation complexes I and V within a broader transcriptional downregulation of mitochondrial genes, providing a substrate for reduced energetic efficiency associated with senescence.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Preston¹,

Oberlin²,

Holmuhamedov³

et al. 2008

Mechanisms of Ageing and Development

124

View full text Add to dashboard Cite

show abstract

“…Although some authors emphasize the involvement of the vascular NADPH oxidase in this pathology (Oudot et al 2006), others point out the prominent responsibility of the mitochondrial reactive oxygen species (ROS) (Lesfnefsky and Hoppel 2003) through the wellknown ROS-induced release process (Zorov et al 2006). Due to cardiolipin oxidation by ROS attack, interfibrillar mitochondria of the senescent heart display lower oxidative capacities and increased ROS release (Fannin et al 1999;Lesnefsky et al 2001a;Hoppel et al 2002). Ischemia further amplifies these abnormalities (Lesnefsky et al 2001b;Lesnefsky and Hoppel 2008;Lesnefsky et al 2009), but only in the aged myocardium.…”

Section: Introductionmentioning

confidence: 99%

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Mourmoura

Leguen

Dubouchaud

et al. 2010

AGE

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Aging compromises restoration of the cardiac mechanical function during reperfusion. We hypothesized that this was due to an ampler release of mitochondrial reactive oxygen species (ROS). This study aimed at characterising ex vivo the mitochondrial ROS release during reperfusion in isolated perfused hearts of middle-aged rats. Causes and consequences on myocardial function of the observed changes were then evaluated. The hearts of rats aged 10-or 52-week old were subjected to global ischemia followed by reperfusion. Mechanical function was monitored throughout the entire procedure. Activities of the respiratory chain complexes and the ratio of aconitase to fumarase activities were determined before ischemia and at the end of reperfusion. H 2 O 2 release was also evaluated in isolated mitochondria. During ischemia, middle-aged hearts displayed a delayed contracture, suggesting a maintained ATP production but also an increased metabolic proton production. Restoration of the mechanical function during reperfusion was however reduced in the middle-aged hearts, due to lower recovery of the coronary flow associated with higher mitochondrial oxidative stress indicated by the aconitase to fumarase ratio in the cardiac tissues. Surprisingly, activity of the respiratory chain complex II was better maintained in the hearts of middle-aged animals, probably because of an enhanced preservation of its membrane lipid environment. This can explain the higher mitochondrial oxidative stress observed in these conditions, since cardiac mitochondria produce much more H 2 O 2 when they oxidize FADH 2 -linked substrates than when they use NADH-linked substrates. In conclusion, the lower restoration of the cardiac mechanical activity during reperfusion in the middle-aged hearts was due to an impaired recovery of the coronary flow and an insufficient oxygen supply. The deterioration AGE (2011) of the coronary perfusion was explained by an increased mitochondrial ROS release related to the preservation of complex II activity during reperfusion.

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“…Biochemically speaking, aging selectively alters IFM, with the protein yield and rate of oxidative phosphorylation being decreased, but SSM remain unaffected (Fannin et al, 1999). Despite these biochemical differences, transmission electron microscopy does not reveal any obvious morphologic changes in cardiac mitochondria associated with aging (Fannin et al, 1999).Osmium extraction of tissues and pellets of isolated mitochondria combined with high resolution scanning electron microscopy (HRSEM) permits the examination of the interior of these organelles. Our use of osmium extraction-HRSEM allowed us to establish the threedimensional structure of cristae in more than a thousand in situ and isolated cardiac mitochondria in or derived from young adult Sprague-Dawley rats (Riva et al, 2005).…”

mentioning

confidence: 99%

Structure of cristae in cardiac mitochondria of aged rat

Riva

Tandler

Lesnefsky

et al. 2006

Mechanisms of Ageing and Development

Self Cite

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Interfibrillar mitochondria (IFM) of the heart in aged Fischer 344 rats show a biochemical defect which might be reflected in their morphology. We examined by high resolution scanning electron microscopy over 5,500 mitochondria to determine if a concomitant structural alteration existed. This methodology provides a means of examining mitochondrial cristae in three dimensions. Cristae of in situ subsarcolemmal mitochondria (SSM) and of IFM in both 6 and 24 month old Fischer rats are predominantly lamelliform. When isolated, these organelles, whether of SSM or IFM origin, display enhanced heterogeneity, but they have similar crista morphology irrespective of the age of the rat. Crista configuration does not play a major role in age-related cardiac mitochondrial defects.Cardiac mitochondria exist in two functionally distinct populations. Subsarcolemmal mitochondria (SSM) are situated beneath the sarcolemma, whereas interfibrillar mitochondria (IFM) reside between the myofibrils (Palmer et al., 1977). Biochemically speaking, aging selectively alters IFM, with the protein yield and rate of oxidative phosphorylation being decreased, but SSM remain unaffected (Fannin et al., 1999). Despite these biochemical differences, transmission electron microscopy does not reveal any obvious morphologic changes in cardiac mitochondria associated with aging (Fannin et al., 1999).Osmium extraction of tissues and pellets of isolated mitochondria combined with high resolution scanning electron microscopy (HRSEM) permits the examination of the interior of these organelles. Our use of osmium extraction-HRSEM allowed us to establish the threedimensional structure of cristae in more than a thousand in situ and isolated cardiac mitochondria in or derived from young adult Sprague-Dawley rats (Riva et al., 2005). SSM contain largely lamelliform cristae; in contrast, cristae in IFM display mostly tubular morphology (Riva et al., 2005). This result provides a morphological underpinning for the Corresponding Author: Charles L. Hoppel, M.D., Case Western Reserve University School of Medicine, Department of Pharmacology, 10900 Euclid Avenue, Cleveland, Phone: (216) FAX: (216) 368-3395, E-mail: charles.hoppel@case.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. previous biochemical studies of rat heart mitochondria that had shown functional differences between SSM and IFM. NIH Public AccessWe now turn our attention to the Fisher 344 rat, a long-established model for aging studies (Coleman et al., 1977). In this aging model, there is a disconnect between metabolic changes, which are highly si...

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Aging Selectively Decreases Oxidative Capacity in Rat Heart Interfibrillar Mitochondria

Cited by 232 publications

References 29 publications

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

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

Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

Structure of cristae in cardiac mitochondria of aged rat

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