Mitochondrial Dysfunction in the Senescence Accelerated Mouse (SAM)

Nakahara, Hiroko; Kanno, Tomoko; Inai, Yoko; Utsumi, Kozo; Hiramatsu, Midori; Mori, Akitane; Packer, Lester

doi:10.1016/s0891-5849(97)00164-0

Cited by 114 publications

(70 citation statements)

References 34 publications

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“…5B) and decreased state 3 respiration in malate-pyruvate NAD-dependent substrate. These results are consistent with previous reports indicating a reduction in Complex I activity in mitochondria isolated from old brain, liver, kidney and skeletal muscle (Benzi et al, 1992;Kumaran et al, 2005;Lenaz et al, 1997;Nakahara et al, 1998;Navarro and Boveris, 2004;Sugiyama et al, 1993). These changes may contribute to the reduced energetic reserves and increased susceptibility of the aged heart to stress and oxidative injury (Navarro and Boveris, 2007), underscoring the relevance of the present findings.…”

Section: Discussionsupporting

confidence: 94%

“…The significance of reduction in these factors to mitogenesis in the senescent heart needs to be further explored. However, we did not observe any apparent reduction in the number of mitochondria in cardiomyocytes from senescent heart nor differences in protein content of isolated mitochondria or mitochondrial marker citrate synthase between adult and aged hearts indicating that reduced mitochondrial content was not responsible for the overall reduction in the capacity of mitochondria to synthesize ATP but instead reflects a functional impairment of energy production (Nakahara et al, 1998).…”

Section: Discussioncontrasting

confidence: 59%

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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

126

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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: 94%

Section: Discussioncontrasting

confidence: 59%

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

126

View full text Add to dashboard Cite

show abstract

“…High redox state and increased electron leakage were reported in the brain mitochondria form 3-month-old SAMP8 mice (Liu and Mori, 1993). Some authors have reported the existence of a slight reduction in the respiratory control ratio in SAMP8 mice (Nakahara et al, 1998) that may be significant at the age of 18 months, when these mice may…”

Section: Introductionmentioning

confidence: 99%

“…These data support the existence of a mild deficiency in the mitochondrial electron transport chain (ETC) in young mice before an age-associated mitochondrial dysfunction develops. The reduced (GSH) to disulfide glutathione (GSSG) ratio, a highly sensitive indicator of the cellular redox state (Jones, 2002), shifts toward oxidation during aging in mitochondria from several tissues including heart, liver, lung and kidney of SAMP8 mice (Nakahara et al, 1998;Nishikawa et al, 1998;Park et al, 1996;Rebrin and Sohal, 2004). Anyway, some studies did not report significant differences in mitochondrial respiration between SAMP8 and SAMR1 until 12 months of age (Nomura et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

“…Although mitochondrial production of free radicals increases with advancing age (Nakahara et al, 1998;Nishikawa et al, 1998;Park et al, 1996;Rebrin and Sohal, 2004), it is yet unclear the age at which ROS initiate the senescence stage. Moreover, there are no data regarding the potentially beneficial role of chronic aMT treatment in terms of reducing agedependent mitochondrial oxidative damage, and whether this treatment influences longevity.…”

Section: Introductionmentioning

confidence: 99%

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Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice

Rodríguez

Escames

López

et al. 2008

Experimental Gerontology

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Mouse models for mitochondrial disease

Wallace

2001

Am. J. Med. Genet.

164

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Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes have been implicated in a wide range of neuromuscular diseases. MtDNA base substitution and rearrangement mutations generally inactivate one or more tRNA or rRNA genes and can cause myopathy, cardiomyopathy, cataracts, growth retardation, diabetes, etc. nDNA mutations can cause Leigh syndrome, cardiomyopathy, and nephropathy, due to defects in oxidative phosphorylation (OXPHOS) enzyme complexes; cartilage-hair hypoplasia (CHH) and mtDNA depletion syndrome, through defects in mitochondrial nucleic acid metabolism; and ophthalmoplegia with multiple mtDNA deletions, caused by adenine nucleotide translocator-1 (ANT1) mutations. Mouse models have been prepared that recapitulate a number of these diseases. The mtDNA 16S rRNA chloramphenicol (CAP) resistance mutation was introduced into the mouse female germline and caused cataracts and rod and cone abnormalities in chimeras and neonatal lethal myopathy and cardiomyopathy in mutant animals. A mtDNA deletion was introduced into the mouse germline and caused myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes. The ATP/ADP ratio was implicated in mitochondrial diabetes through transgenic modification of the beta-cell ATP-sensitive K(+) channel (K(ATP)). Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. Inactivation of uncoupler proteins (Ucp) 1-3 revealed that mitochondrial Delta Psi regulated ROS production. The role of mitochondrial ROS toxicity in disease and aging was confirmed by inactivating glutathione peroxidase (GPx1), resulting in growth retardation, and by total and partial inactivation of Mn superoxide dismutase (MnSOD; Sod2), resulting in neonatal lethal dilated cardiomyopathy and accelerated apoptosis in aging, respectively. The importance of mitochondrial ROS in degenerative diseases and aging was confirmed by treating Sod2 -/- mice and C. elegans with catalytic antioxidant drugs.

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Mitochondrial Dysfunction in the Senescence Accelerated Mouse (SAM)

Cited by 114 publications

References 34 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

Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice

Mouse models for mitochondrial disease

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