Research Article: Mitochondrial electron transport chain functions in long-lived Ames dwarf mice

Date Published: August 7, 2011

Publisher: Impact Journals LLC

Author(s): Kashyap B. Choksi, Jonathan E. Nuss, James H. DeFord, John Papaconstantinou.

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Abstract

The age-associated decline in tissue function has been attributed to ROS-mediated oxidative damage due to mitochondrial dysfunction. The long-lived Ames dwarf mouse exhibits resistance to oxidative stress, a physiological characteristic of longevity. It is not known, however, whether there are differences in the electron transport chain (ETC) functions in Ames tissues that are associated with their longevity. In these studies we analyzed enzyme activities of ETC complexes, CI-CV and the coupled CI-CII and CII-CIII activities of mitochondria from several tissues of young, middle aged and old Ames dwarf mice and their corresponding wild type controls to identify potential mitochondrial prolongevity functions. Our studies indicate that post-mitotic heart and skeletal muscle from Ames and wild-type mice show similar changes in ETC complex activities with aging, with the exception of complex IV. Furthermore, the kidney, a slowly proliferating tissue, shows dramatic differences in ETC functions unique to the Ames mice. Our data show that there are tissue specific mitochondrial functions that are characteristic of certain tissues of the long-lived Ames mouse. We propose that this may be a factor in the determination of extended lifespan of dwarf mice.

Partial Text

The age-associated decline in tissue function has been attributed to ROS-mediated oxidative damage due to mitochondrial dysfunction [1-5]. Mitochondrial ROS are produced by in vivo electron leakage from electron transport chain (ETC) complexes during normal respiration, particularly from Complex I (CI) and Complex III (CIII) [6-9]. This is consistent with the decreased capacity to produce ATP, another characteristic of aging mammalian tissues which is attributed to the selectively diminished activities of CI and CIV [10, 11] and to their vulnerability to oxidative stress [12]. On the other hand, it has been suggested that improved mitochondrial coupling and reduced release or levels of ROS production are the beneficial effects of caloric restriction that mediates longevity [13-15]. However, there is also evidence that lifespan can be increased by reduced mitochondrial ETC function in yeast, nematodes, Drosophila and mice [16-21]. For example, in nematodes, longevity determination is associated with an electron transport chain-mediated function that is linked to the inhibition of CIV activity within a specific tissue (intestine) and at a specific stage of development [22]. In this model the inactivated CIV in the intestine activates the mitochondrial unfolded protein response (UPR) by distal tissues. This physiological response has been proposed to be essential for lifespan extension. This raises the question of the nature of the physiological properties of decreased mitochondrial activity associated with longevity vs. the properties of dysfunctional mitochondria (ROS producing) that are associated with accelerated aging.

The ~40-60% increased lifespan of the long-lived Ames dwarf mouse is attributed to a mutation of the Prop 1 locus that results in poor development of the anterior pituitary and a deficiency of GH, TSH and prolactin [23, 24, 26]. Numerous studies have indicated that the Ames as well as the related Snell dwarf mouse models exhibit an increased level of resistance to oxidative stress generated by extrinsic factors such as hydrogen peroxide, paraquat and 3-NPA [23, 25, 26, 29, 33, 34, 41, 42]; a recent study has identified mitochondrial ETC function(s) that may contribute to the longevity of these mice [36] as well as such factors as oxidative modifications of specific ETC complex proteins in various tissues of aging WT mice [37, 40, 43].

 

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