Age-related changes in mitochondrial respiration and oxidative damage in the cerebral cortex of the Fischer 344 rat

Abstract

SummaryThis study probed possible age-related changes in mitochondrial bioenergetics in naïve Fischer 344 rats. Synaptic and extrasynaptic mitochondria were isolated from the cortex of one hemisphere of young (3-5 mos), middle (12-14 mos), or aged (22-24 mos) rats. Respiration parameters were obtained using a Clarke-type electrode. Aged rats displayed no significant alterations in respiration, indicating mitochondria must be more resilient to the aging process than previously thought. Synaptic mitochondria displayed lower respiration capacities than the extrasynaptic fraction. Aged F344 rats appear capable of normal electron transport chain function without declines in ability to produce ATP. Markers of cortical oxidative damage (3-nitrotyrosine [3-NT], 4-hydroxynonenal [4-HNE], and protein carbonyls [PC]) were collected from the post mitochondrial supernatant (PMS) from the contralateral hemisphere, and from mitochondrial samples following respiration analysis. Agerelated increases in PC and 3-NT levels were found in synaptic mitochondria, whereas significant extrasynaptic elevations were only found in middle aged rats. These findings support an age-related increase in oxidative damage in the cortex, while proposing the two fractions of mitochondria are differentially affected by the aging process. Levels of oxidative damage that accumulates in the cortex with age does not appear to significantly impair cortical mitochondrial respiration of F344 rats.

Age-Related Mitochondrial Changes after Traumatic Brain Injury

“…Some groups report extensive age-related declines in mitochondrial respiration (Chiu and Richardson, 1980;Cocco et al, 2005;Navarro et al, 2005Navarro et al, , 2008Petrosillo et al, 2008a,b). Our laboratory and others (Bustamante et al, 2008;Deshmukh et al, 1980;Gilmer et al, 2010;Leslie et al, 1985;Meng et al, 2007) previously reported no significant age-related changes in cortical mitochondrial bioenergetics in naïve rats, while significant elevations in oxidative damage were apparent (Gilmer et al, 2010). It is possible that under naïve conditions the subtle age-related declines in mitochondrial respiration are not sufficient to impair resting energy demands, but perhaps when the system is challenged deficits become more apparent.…”

“…A Student-Newman-Keuls post-hoc analysis was used with alpha set at 0.05. Previous work by our laboratory has shown that mitochondrial respiration does not decline with normal aging in F344 rats (Gilmer et al, 2010), therefore respiration data collected from the contralateral hemisphere of young and aged rats were used as internal controls, respectively.…”

“…ROS can cause oxidative damage to several components of mitochondria, including the electron transport chain (ETC) (Dencher et al, 2007;Lesnefsky and Hoppel 2006;Van Remmen and Richardson 2001), lipid membranes (Hoch, 1992), and DNA (Richter, 1995). Oxidative damage to mitochondrial components has been shown to accumulate in an age-dependent manner in certain mitochondrial fractions (Gilmer et al, 2010), and can alter several mitochondrial and cellular functions (Stowe, 2009). This accumulation of oxidative damage in mitochondria is associated with an increase in ROS production in several regions of the brain (Driver et al, 2000).…”

“…The extent of mitochondrial decline that occurs with normal aging is much less pronounced than that seen in pathological conditions (Finsterer, 2008). There is an ongoing debate concerning the magnitude of decline in mitochondrial respiration that occurs during normal aging (Gilmer et al, 2010). Some groups report extensive age-related declines in mitochondrial respiration (Chiu and Richardson, 1980;Cocco et al, 2005;Navarro et al, 2005Navarro et al, , 2008Petrosillo et al, 2008a,b).…”

“…The theory suggested by Signorini and associates (1999), that the repair mechanisms of the brain decline with age, may implicate mitochondria as an important variable. Higher levels of oxidative damage to machinery inside mitochondria of aged subjects, particularly in the synaptic fraction (Gilmer et al, 2010), may impede their ability to produce ATP, resulting in greater cellular dysfunction. Increased mitochondrial dysfunction may be a mechanistic explanation as to why aged individuals require longer recovery times and experience increased morbidity and mortality following many different neurological insults.…”