Age- and brain region-specific differences in mitochondrial bioenergetics in Brown Norway rats

Pandya, Jignesh D.; Royland, Joyce E.; MacPhail, Robert C.; Sullivan, Patrick G.; Kodavanti, Prasada Rao S.

doi:10.1016/j.neurobiolaging.2016.02.027

Cited by 48 publications

(42 citation statements)

References 75 publications

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“…Here, we observed an increased proton leak in isolated hippocampal mitochondria of the mouse brain, however, this was not the case in the striatal mitochondria. Another recent study, likewise performed in rats, showed that regional mitochondrial function fluctuates with age (Pandya, Royland, MacPhail, Sullivan, & Kodavanti, ). The authors reported that cerebral cortical, striatal, and hippocampal mitochondria, isolated from young rats, exhibited comparable bioenergetics profiles, however, particularly hippocampal mitochondrial function declined with increasing age (Pandya et al, ).…”

Section: Discussionmentioning

confidence: 96%

“…Another recent study, likewise performed in rats, showed that regional mitochondrial function fluctuates with age (Pandya, Royland, MacPhail, Sullivan, & Kodavanti, ). The authors reported that cerebral cortical, striatal, and hippocampal mitochondria, isolated from young rats, exhibited comparable bioenergetics profiles, however, particularly hippocampal mitochondrial function declined with increasing age (Pandya et al, ). A relevant extension of this study could include assessment of how regional mitochondrial function in mice is related to age.…”

Section: Discussionmentioning

confidence: 96%

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Distinct differences in rates of oxygen consumption and ATP synthesis of regionally isolated non‐synaptic mouse brain mitochondria

Andersen

Jakobsen

Waagepetersen

2019

J of Neuroscience Research

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Brain mitochondrial dysfunction has been implicated in several neurodegenerative diseases. The distribution and efficiency of mitochondria display large heterogeneity throughout the regions of the brain. This may imply that the selective regional susceptibility of neurodegenerative diseases could be mediated through inherent differences in regional mitochondrial function. To investigate regional cerebral mitochondrial energetics, the rates of oxygen consumption and adenosine‐5′‐triphosphate (ATP) synthesis were assessed in isolated non‐synaptic mitochondria of the cerebral cortex, hippocampus, and striatum of the male mouse brain. Oxygen consumption rates were assessed using a Seahorse XFe96 analyzer and ATP synthesis rates were determined by an online luciferin‐luciferase coupled luminescence assay. Complex I‐ and complex II‐driven respiration and ATP synthesis, were investigated by applying pyruvate in combination with malate, or succinate, as respiratory substrates, respectively. Hippocampal mitochondria exhibited the lowest basal and adenosine‐5′‐diphosphate (ADP)‐stimulated rate of oxygen consumption when provided pyruvate and malate. However, hippocampal mitochondria also exhibited an increased proton leak and an elevated relative rate of oxygen consumption in response to the uncoupler carbonyl cyanide 4‐(trifluoromethoxy)phenylhydrazone (FCCP), showing a large capacity for uncoupled respiration in the presence of pyruvate. When the complex II‐linked substrate succinate was provided, striatal mitochondria exhibited the highest respiration and ATP synthesis rate, whereas hippocampal mitochondria had the lowest. However, the mitochondrial efficiency, determined as ATP produced/O2 consumed, was similar between the three regions. This study reveals inherent differences in regional mitochondrial energetics and may serve as a tool for further investigations of regional mitochondrial function in relation to neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 96%

Distinct differences in rates of oxygen consumption and ATP synthesis of regionally isolated non‐synaptic mouse brain mitochondria

Andersen

Jakobsen

Waagepetersen

2019

J of Neuroscience Research

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“…The increased activity-dependent synaptic plasticity and glutaminergic synaptic activity in the cortex compared with the striatum, as well as brain regional differences in metabolism (Pandya et al, 2016; Sauerbeck et al, 2011), may help to explain different effects of exercise training noted in different brain regions. The relative levels of fission-fusion proteins are known to vary according to body region (Santos-alves et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice

Gusdon

Callio

Distéfano

et al. 2017

Experimental Gerontology

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Exercise is known to have numerous beneficial effects. Recent studies indicate that exercise improves mitochondrial energetics not only in skeletal muscle but also in other tissues. While exercise elicits positive effects on memory, neurogenesis, and synaptic plasticity, the effects of exercise on brain mitochondrial energetics remain relatively unknown. Herein, we studied the effects of exercise training in old and young mice on brain mitochondrial energetics, in comparison to known effects on peripheral tissues that utilize fatty acid oxidation. Exercise improved the capacity for mucle and liver to oxidize palmitate in old mice, but not young mice. In the brain, exercise increased rates of respiration and reactive oxygen species (ROS) production in the old group only while utilizing complex I substrates, effects that were not seen in the young group. Coupled complex I to III enzymatic activity was significantly increased in old trained versus untrained mice with no effect on coupled II to III enzymatic activity. Mitochondrial protein content and markers of mitochondrial biogenesis (PGC-1α and TFAM) were not affected by exercise training in the brain, in contrast to the skeletal muscle of old mice. Brain levels of the autophagy marker LC3-II and protein levels of other signaling proteins that regulate metabolism or transport (BDNF, HSP60, phosphorylated mTOR, FNDC5, SIRT3) were not significantly altered. Old exercised mice showed a significant increase in DRP1 protein levels in the brain without changes in phosphorylation, while MFN2 and OPA1 protein levels were unchanged. Our results suggest that exercise training in old mice can improve brain mitochondrial function through effects on electron transport chain function and mitochondrial dynamics without increasing mitochondrial biogenesis.

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“…They include analysis of mitochondria-specific proteins, functional interrogation of isolated mitochondria or mitochondria in synaptosome preparations, and manipulation of genes that encode mitochondrial proteins (Grimm and Eckert, 2017). Comparisons of mitochondria isolated from brain tissue of animals reveal numerous age-related alterations, including mitochondrial enlargement or fragmentation (Stahon et al, 2016; Morozov et al, 2017), increased oxidative damage to mitochondrial DNA (Kim and Chan, 2001; Santos et al, 2013), impaired function of the electron transport chain (ETC) (Yao et al, 2010; Pandya et al, 2015, 2016; Pollard et al, 2016), increased numbers of mitochondria with depolarized membranes (Lores-Arnaiz et al, 2016), impaired Ca 2+ handling (Leslie et al, 1985; Pandya et al, 2015), and a reduced threshold for triggering mPTP formation (Brown et al, 2004). The decrement in mitochondrial function during brain aging involves a decline in cellular NAD + levels and the NAD:NADH ratio (Braidy et al, 2014), which would be expected to compromise the activities of NAD + -dependent enzymes critical for neuronal function and viability, including protein deacetylases of the sirtuin family (Fang et al, 2017).…”

Section: Cellular and Molecular Hallmarks Of Brain Agingmentioning

confidence: 99%

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

2018

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During aging, the cellular milieu of the brain exhibits tell-tale signs of compromised bioenergetics, impaired adaptive neuroplasticity and resilience, aberrant neuronal network activity, dysregulation of neuronal Ca2+ homeostasis, the accrual of oxidatively modified molecules and organelles, and inflammation. These alterations render the aging brain vulnerable to Alzheimer’s and Parkinson’s diseases and stroke. Emerging findings are revealing mechanisms by which sedentary overindulgent lifestyles accelerate brain aging, whereas lifestyles that include intermittent bioenergetic challenges (exercise, fasting, and intellectual challenges) foster healthy brain aging. Here we provide an overview of the cellular and molecular biology of brain aging, how those processes interface with disease-specific neurodegenerative pathways, and how metabolic states influence brain health.

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Age- and brain region-specific differences in mitochondrial bioenergetics in Brown Norway rats

Cited by 48 publications

References 75 publications

Distinct differences in rates of oxygen consumption and ATP synthesis of regionally isolated non‐synaptic mouse brain mitochondria

Distinct differences in rates of oxygen consumption and ATP synthesis of regionally isolated non‐synaptic mouse brain mitochondria

Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

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