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

Abstract

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.

Effect of aging on formation of reactive oxygen species by mitochondria of rat heart

“…It is generally accepted that mitochondria as a primary site of ROS production are also the major target of their damaging effects. Age-associated mutations of mitochondrial DNA and altered transcription of genes coding for proteins involved in oxidative phosphorylation were demonstrated in rat heart (Wanagat et al 2002;Preston et al 2008). Furthermore, deterioration of function of mitochondrial proteins with age as a consequence of posttranslational oxidative modification was demonstrated in several studies (Choksi and Papaconstantinou 2008;Preston et al 2008) and also in our laboratory (Tatarková et al 2011).…”

Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation

“…Data are expressed in nanomoles per minute per citrate synthase activity and presented as means Ϯ SE; n ϭ 23 for nAF and n ϭ 31 for AF. *P Ͻ 0.05. through regulation of cell death and fibrosis, contributes to the development of the substrate for AF and its progression with aging and aging-associated diseases (39,46,49). Reduction in mitochondrial function has been demonstrated previously in patients with AF; however, the confounding effect of aging or disease conditions such as heart failure, stroke, mitral valve diseases, history of chronic obstructive pulmonary disease, coronary artery disease, hypertension, obstructive sleep apnea, chronic renal failure, diabetes, or obesity on mitochondrial function was not evaluated.…”

“…The functional activity of individual OXPHOS complexes ( Fig. 1) was analyzed spectrophotometrically (46) with the Infinite 200 PRO Plate Reader microplate reader (Tecan US, Research Triangle Park, NC) at 30°C. The activity was calculated as previously described (9) and normalized to CS activity.…”

Cardiohemodynamics and Efficiency of Frank–starling Mechanism During Aging

“…За мітохондріальної та вільно-радикальної теорій старіння дисбаланс між про-та анти-оксидантами є причиною окисного стресу, в результаті якого розвивається глибоке пору-шення метаболізму клітин, фізико-хімічних і функціональних властивостей їх мембран. Зокрема, погіршується ефективність окис-ного фосфорилювання та здатність синтезу аденозинтрифосфату мітохондріями [17,18]. А зменшення його вмісту сприяє розвитку виявленої нами діастолічної дисфункції серця старих щурів і зниженню релаксації та розтяжності міокарда, викликає обмежен-ня функціональних резервів і адаптаційних можливостей серця.…”