<i>In vivo</i> and <i>in vitro</i> assessment of brain bioenergetics in aging rats

Vančová, Oľga; Bačiak, Ladislav; Kašparová, Svatava; Kucharská, J; Palacios, Hector H.; Horecký, J; Aliev, Gjumrakch

doi:10.1111/j.1582-4934.2009.00879.x

Cited by 19 publications

(19 citation statements)

References 60 publications

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“…This same pattern of mitochondrial lesions is observed in human AD brain biopsy samples [53,59]. The reduced expression of both mtDNA and nuclear DNA encoded genes is consistent with a physiological down–regulation of the mitochondria respiratory chain in response to declining neuronal activity [49,50,51,52,53,54,55,56,57,58,61,62,64]. However, the role of somatic cells and mtDNA mutations in the pathogenesis of mitochondria failure during AD is still controversial [50,58,61,62].…”

Section: The Role Of Mitochondrial Abnormalities During the Develosupporting

confidence: 59%

Oxidative Stress Induced Mitochondrial Failure and Vascular Hypoperfusion as a Key Initiator for the Development of Alzheimer Disease

et al. 2010

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Mitochondrial dysfunction may be a principal underlying event in aging, including age-associated brain degeneration. Mitochondria provide energy for basic metabolic processes. Their decay with age impairs cellular metabolism and leads to a decline of cellular function. Alzheimer disease (AD) and cerebrovascular accidents (CVAs) are two leading causes of age-related dementia. Increasing evidence strongly supports the theory that oxidative stress, largely due to reactive oxygen species (ROS), induces mitochondrial damage, which arises from chronic hypoperfusion and is primarily responsible for the pathogenesis that underlies both disease processes. Mitochondrial membrane potential, respiratory control ratios and cellular oxygen consumption decline with age and correlate with increased oxidant production. The sustained hypoperfusion and oxidative stress in brain tissues can stimulate the expression of nitric oxide synthases (NOSs) and brain endothelium probably increase the accumulation of oxidative stress products, which therefore contributes to blood brain barrier (BBB) breakdown and brain parenchymal cell damage. Determining the mechanisms behind these imbalances may provide crucial information in the development of new, more effective therapies for stroke and AD patients in the near future.

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Section: The Role Of Mitochondrial Abnormalities During the Develosupporting

confidence: 59%

Oxidative Stress Induced Mitochondrial Failure and Vascular Hypoperfusion as a Key Initiator for the Development of Alzheimer Disease

et al. 2010

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“…There is growing evidence for abnormalities of high‐energy substance levels and/or altered kinetics in various diseases across multiple biological systems such as brain, liver, muscle, and heart . Our method can be applied to any of those listed above (i.e., it is not restricted to brain), but we recommend caution when using

T_{1}^{i n t}

values from the literature.…”

Section: Discussionmentioning

confidence: 99%

“…In realistic experimental conditions, this is unlikely. Despite the essential role of accurate metabolite quantification, especially for determining the metabolic rates (or fluxes) of CK and ATPase reactions, most studies have ignored the chemical exchange and T 1 relaxation effects on metabolite quantification . Hence, a more advanced correction method that is capable of considering T 1 relaxation as well as chemical exchange effects would be required.…”

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confidence: 99%

“…Despite the essential role of accurate metabolite quantification, especially for determining the metabolic rates (or fluxes) of CK and ATPase reactions, most studies have ignored the chemical exchange and T 1 relaxation effects on metabolite quantification. [13][14][15][16][17] Hence, a more advanced correction method that is capable of considering T 1 relaxation as well as chemical exchange effects would be required. 31 P magnetization transfer, in particular magnetization saturation transfer (MST) spectroscopy has been widely used for measuring the reaction kinetics of enzymes noninvasively to provide insights into the biological mechanism of disease.…”

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confidence: 99%

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Rapid and simultaneous measurement of phosphorus metabolite pool size ratio and reaction kinetics of enzymes in vivo

Kim

Chen

Öngür

et al. 2017

Magnetic Resonance Imaging

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Purpose: The metabolites phosphocreatine (PCr), adenosine triphosphate (ATP), and in-organic phosphate (Pi) are biochemically coupled. Their pool sizes, assessed by their magnetization ratios, have been extensively studied and reflect bioenergetics status in vivo. However, most such studies have ignored chemical exchange and T 1 relaxation effects. In this work, we aimed to extend the T nom 1 method to simultaneously quantify the reaction rate constants as well as phosphorus metabolite pool size ratios under partially relaxed conditions. Materials and Methods: Modified Bloch-McConnell equations were used to simulate the effects of chemical exchanges on T 1 relaxation times and magnetization ratios among PCr, c-ATP, and Pi. The T nom 1 method with iteration approach was used to measure both reaction constants and metabolite pool size ratios. To validate our method, in vivo data from rat brains (N 5 8) at 9.4 Tesla were acquired under two conditions, i.e., approximately full relaxation (TR 5 9 s) and partial relaxation (TR 5 3 s). We compared metabolite pool size ratios and reaction constants before and after correcting the chemical exchange and T 1 relaxation effects. Results: There were significant errors in underestimation of PCr/cATP by 12 % (P 5 0.03) and overestimation of ATP/Pi ratios by 14 % (P 5 0.04) when not considering chemical exchange effects. These errors were minimized using our iteration approach, resulting in no significant differences (PCr/cATP, P 5 0.47; ATP/Pi, P 5 0.81) in metabolite pool size ratios and reaction constants between the two measurements (i.e., short versus long TR conditions). Conclusion: Our method can facilitate broad biomedical applications of 31 P magnetization saturation transfer spectroscopy, requiring high temporal and/or spatial resolution for assessment of altered bioenergetics. P hosphorus magnetic resonance spectroscopy ( 31 P-MRS) provides insight into bioenergetic impairment and mitochondrial dysfunction in vivo under various physiological and pathological conditions. 1-5 Major phosphorus-containing metabolites related to bioenergetics detected by in vivo 31 P-MRS include phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP) with the a-, b-, and c-resonances. These metabolites compose a chemical exchange network (PCr$ATP$Pi) catalyzed by the enzymes creatine kinase (CK) and ATP synthase (ATPase). These chemical reactions are crucial for regulating ATP metabolism and maintaining normal ATP functionality. The phosphorus metabolite levels or pool sizes assessed by their magnetization ratios such as PCr to c-ATP (PCr/c-ATP), c-ATP to Pi (c-ATP/Pi), and PCr to Pi (PCr/Pi) have been extensively studied in various disease states in vivo, for instance in the brain, 6-8 heart, 9,10 and muscle. 2,11 For measuring phosphorus-containing metabolite levels using a conventional MRS approach, Ernst and Anderson 12 suggested that large improvements in signal-to-noise ratio (SNR) per unit sampling time could be achieved by the use of short inter-pulse del...

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“…Aging is associated with reductions in mitochondrially derived energy production [1], global increases in oxidative load (reviewed by [2,3]), and a concomitant decline in correlates of cognitive function, specifically neuronal and astroglial function [4][5][6]. Dysregulation of mitochondrial function, including diminished ATP synthesis, excessive free radical production, and apoptosis, is part of the etiology of many age-related human diseases, including neurodegenerative disorders such as Alzheimer's disease [7,8].…”

Section: Introductionmentioning

confidence: 99%

Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

et al. 2019

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Age-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~75%) were depleted in adult male Igf1 f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited~60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~50%) were decreased and hippocampal oxidative stress (protein carbonylation and F 2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function. Highlights Circulating IGF-1 deficiency: • Has pleiotropic effects on central and peripheral tissues. • Induces impairments in hippocampal learning and memory. • Decreases hippocampal mitochondrial oxygen coupling efficiency. • Increases stress response and oxidative damage in brain.

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In vivo and in vitro assessment of brain bioenergetics in aging rats

Cited by 19 publications

References 60 publications

Oxidative Stress Induced Mitochondrial Failure and Vascular Hypoperfusion as a Key Initiator for the Development of Alzheimer Disease

Oxidative Stress Induced Mitochondrial Failure and Vascular Hypoperfusion as a Key Initiator for the Development of Alzheimer Disease

Rapid and simultaneous measurement of phosphorus metabolite pool size ratio and reaction kinetics of enzymes in vivo

Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

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