TY - JOUR
T1 - Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart
AU - Preston, Claudia C.
AU - Oberlin, Andrew S.
AU - Holmuhamedov, Ekhson L.
AU - Gupta, Anu
AU - Sagar, Sandeep
AU - Syed, Rashad H.Khazi
AU - Siddiqui, Sabeeh A.
AU - Raghavakaimal, Sreekumar
AU - Terzic, Andre
AU - Jahangir, Arshad
N1 - Funding Information:
Arshad Jahangir is supported by grants from the National Institute on Aging (AG-21201), National Heart, Lung and Blood Institute (HL089542), the Mayo Clinic Robert and Arlene Kogod Program on Aging and the Marriott Mitochondrial Medicine Award. Current address for Ekhson L. Holmuhamedov is Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill. We are grateful to Dr. Petras Dzeja for technical advice.
PY - 2008/6
Y1 - 2008/6
N2 - 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.
AB - 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.
KW - ATP
KW - Aging
KW - Gene expression
KW - Mitochondria
KW - Myocardium
KW - Oxidative phosphorylation
KW - Transcription factors
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U2 - 10.1016/j.mad.2008.02.010
DO - 10.1016/j.mad.2008.02.010
M3 - Article
C2 - 18400259
AN - SCOPUS:43449114455
SN - 0047-6374
VL - 129
SP - 304
EP - 312
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
IS - 6
ER -