Mitochondria controlled by UCP2 determine hypoxia-induced synaptic remodeling in the cortex and hippocampus

Varela, Luis; Schwartz, Michael L.; Horváth, Tamas L.

doi:10.1016/j.nbd.2016.01.004

Cited by 21 publications

(12 citation statements)

References 30 publications

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“…We found that mitochondria of the hippocampus, generally consumed oxygen and synthesized ATP at lower rates, when compared to mitochondria of the other two regions. These observations of low hippocampal oxygen consumption is in line with several other reports of isolated mitochondria (Burtscher et al, 2015;Cardoso et al, 2010;Czerniczyniec et al, 2015;Dagani et al, 1988;Sims, 1990;Varela et al, 2016) and brain homogenates (Sims, Finegan, & Blass, 1986;Sims & Pulsinelli, 1987). However, it was also observed that hippocampal mitochondria exhibited comparable ATP/O 2 ratios to the other regions, suggesting an overall general lower mitochondrial activity in this region (Dagani et al, 1988).…”

Section: Regional Differences In Mitochondrial Ocr and Atp Synthesisupporting

confidence: 91%

“…Compared to the literature, these values signify well-functioning mitochondria, validating the quality of our preparation (Burtscher, Zangrandi, Schwarzer, & Gnaiger, 2015;Cardoso, Santos, Seica, & Moreira, 2010;Czerniczyniec et al, 2015;Dagani et al, 1988;Lai et al, 1977;Sauerbeck et al, 2011;Sims, 1990;Varela, Schwartz, & Horvath, 2016). We observed that hippocampal mitochondria exhibited a larger proton leak, with both substrate conditions, resulting in reduced RCR values for this region.…”

Section: Mitochondrial Isolation and Functionsupporting

confidence: 84%

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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: Regional Differences In Mitochondrial Ocr and Atp Synthesisupporting

confidence: 91%

Section: Mitochondrial Isolation and Functionsupporting

confidence: 84%

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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“…For example, caloric restriction increased the expression of UCP4 in the cerebral cortex of adult rats [35]. Consistent with the general notion that UCP expression is increased in response to physiological metabolic challenges such as exercise and dietary energy restriction, exposure of animals to mild hypoxia increases the expression of UCP2 in the cerebral cortex and hippocampus [75]. A ketogenic diet has also been reported to increase UCP2 expression in the brain [76].…”

Section: Chemical Uncouplers and Neuroprotectionmentioning

confidence: 62%

DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya

Geisler¹,

Marosi

Halpern

et al. 2016

Alzheimer's & Dementia

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Recent findings have elucidated roles for mitochondrial uncoupling proteins (UCPs) in neuronal plasticity and resistance to metabolic and oxidative stress. UCPs are induced by bioenergetic challenges such as caloric restriction and exercise, and may protect neurons against dysfunction and degeneration. The pharmacological uncoupler 2,4-dinitrophenol (DNP), which was once prescribed to over 100,000 people as a treatment for obesity, stimulates several adaptive cellular stress response signaling pathways in neurons including those involving the neurotrophic factor BDNF, the transcription factor CREB, and autophagy. Preclinical data show that low doses of DNP can protect neurons and improve functional outcome in animal models of Alzheimer’s and Parkinson’s diseases, epilepsy and cerebral ischemic stroke. Repurposing of DNP and the development of novel uncoupling agents with hormetic mechanisms of action provide opportunities for new breakthrough therapeutic interventions in a range of acute and chronic insidious neurodegenerative/neuromuscular conditions, all paradoxically at body weight-preserving doses.

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“…Other mtDNA variants, including in the aforementioned MT-ATP6 gene, have also been associated with SCZ outright (Ueno et al, 2009). Interestingly, alteration in the levels of the mitochondrial protein uncoupling protein 2 (UCP2), which controls substrate oxidation of the mitochondria in neurons (Andrews et al, 2008), as well as mitochondrial fidelity overall, have significant impact on cortical structure and function (Hermes et al, 2016; Kann and Kovacs, 2007; Li et al, 2004; Varela et al, 2016). These findings illustrate that mitochondrial function can facilitate neuropsychiatric disorders, including major depressive disorder (Cai et al, 2015; Converge Consortium, 2015) and intellectual and developmental disability (Ouyang et al, 2016), and substantiate the need for further investigations into similar neurodevelopmental disorders such as ASD.…”

Section: Discussionmentioning

confidence: 99%

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development

Tebbenkamp

Varela

Choi

et al. 2018

Cell

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SUMMARY Despite the known causality of copy number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each genes’ contribution to the constellation of neural phenotypes remains elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with the decreased integrity of oxidative phosphorylation supercomplexes and ATP synthase dimers we observed in WS. Thus, we reveal DNAJC30 as a novel auxiliary component of ATP synthase machinery, and link mitochondrial maladies as underlying certain defects in brain development and function associated with WS.

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Mitochondria controlled by UCP2 determine hypoxia-induced synaptic remodeling in the cortex and hippocampus

Cited by 21 publications

References 30 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

DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development

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