Adaptation within mitochondrial oxidative phosphorylation supercomplexes and membrane viscosity during degeneration of dopaminergic neurons in an animal model of early Parkinson's disease

Kuter, Katarzyna; Kratochwil, Manuela; Berghauzen-Maciejewska, Klemencja; Głowacka, Urszula; Sugawa, M.; Ossowska, Krystyna; Dencher, Norbert A.

doi:10.1016/j.bbadis.2016.01.022

Cited by 42 publications

(32 citation statements)

References 65 publications

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“…Stereotaxic brain operations were performed according to Kuter et al [ 53 ], with modifications, under ketamine and xylazine anesthesia (65–50 and 10–3 mg/kg im , Biowet, Puławy, Poland). Desipramine (30 mg/kg ip , Sigma-Aldrich, Germany) was administered 30 min before lesioning to protect the noradrenergic terminals.…”

Section: Methodsmentioning

confidence: 99%

Prolonged Dysfunction of Astrocytes and Activation of Microglia Accelerate Degeneration of Dopaminergic Neurons in the Rat Substantia Nigra and Block Compensation of Early Motor Dysfunction Induced by 6-OHDA

2017

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Progressive degeneration of dopaminergic neurons in the substantia nigra (SN) is the underlying cause of Parkinson’s disease (PD). The disease in early stages is difficult to diagnose, because behavioral deficits are masked by compensatory processes. Astrocytic and microglial pathology precedes motor symptoms. Besides supportive functions of astrocytes in the brain, their role in PD is unrecognized. Prolonged dysfunction of astrocytes could increase the vulnerability of dopaminergic neurons and advance their degeneration during aging. The aim of our studies was to find out whether prolonged dysfunction of astrocytes in the SN is deleterious for neuronal functioning and if it influences their survival after toxic insult or changes the compensatory potential of the remaining neurons. In Wistar rat model, we induced activation, prolonged dysfunction, and death of astrocytes by chronic infusion of fluorocitrate (FC) into the SN, without causing dopaminergic neuron degeneration. Strongly enhanced dopamine turnover in the SN after 7 days of FC infusion was induced probably by microglia activated in response to astrocyte stress. The FC effect was reversible, and astrocyte pool was replenished 3 weeks after the end of infusion. Importantly, the prolonged astrocyte dysfunction and microglia activation accelerated degeneration of dopaminergic neurons induced by 6-hydroxydopamine and blocked the behavioral compensation normally observed after moderate neurodegeneration. Impaired astrocyte functioning, activation of microglia, diminishing compensatory capability of the dopaminergic system, and increasing neuronal vulnerability to external insults could be the underlying causes of PD. This animal model of prolonged astrocyte dysfunction can be useful for in vivo studies of glia–microglia–neuron interaction.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-017-0529-z) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Prolonged Dysfunction of Astrocytes and Activation of Microglia Accelerate Degeneration of Dopaminergic Neurons in the Rat Substantia Nigra and Block Compensation of Early Motor Dysfunction Induced by 6-OHDA

2017

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“…Since complex I needs to be assembled into the NADH oxidase supercomplex for its optimal redox activity (Stroh et al 2004), it can be speculated that reduced complex I redox energy leads to lower proton translocation across the IMM, resulting in lower membrane potential and decreased respiration with NADH-dependent substrates. Moreover, mitochondrial dysfunction and deficiency of respiratory supercomplexes are correlated to the mitochondrial aging phenotype and in the etiopathology of several diseases like Parkinson's and Alzheimer's (Seelert et al 2009, Frenzel et al 2010, Kuter et al 2016). On the other hand, complex II does not form part of respiratory supercomplexes, which is in agreement with lack of alterations in FADH 2 -linked respiration and further supports the putative involvement of supercomplex destabilization induced by loss of ovarian hormones.…”

Section: Figurementioning

confidence: 99%

Hormone deprivation alters mitochondrial function and lipid profile in the hippocampus

Zárate

Astiz

Magnani

et al. 2017

Journal of Endocrinology

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Mitochondrial dysfunction is a common hallmark in aging. In the female, reproductive senescence is characterized by loss of ovarian hormones, many of whose neuroprotective effects converge upon mitochondria. The functional integrity of mitochondria is dependent on membrane fatty acid and phospholipid composition, which are also affected during aging. The effect of long-term ovarian hormone deprivation upon mitochondrial function and its putative association with changes in mitochondrial membrane lipid profile in the hippocampus, an area primarily affected during aging and highly responsive to ovarian hormones, is unknown. To this aim, Wistar adult female rats were ovariectomized or sham-operated. Twelve weeks later, different parameters of mitochondrial function (O uptake, ATP production, membrane potential and respiratory complex activities) as well as membrane phospholipid content and composition were evaluated in hippocampal mitochondria. Chronic ovariectomy reduced mitochondrial O uptake and ATP production rates and induced membrane depolarization during active respiration without altering the activity of respiratory complexes. Mitochondrial membrane lipid profile showed no changes in cholesterol levels but higher levels of unsaturated fatty acids and a higher peroxidizability index in mitochondria from ovariectomized rats. Interestingly, ovariectomy also reduced cardiolipin content and altered cardiolipin fatty acid profile leading to a lower peroxidizability index. In conclusion, chronic ovarian hormone deprivation induces mitochondrial dysfunction and changes in the mitochondrial membrane lipid profile comparable to an aging phenotype. Our study provides insights into ovarian hormone loss-induced early lipidomic changes with bioenergetic deficits in the hippocampus that may contribute to the increased risk of Alzheimer's disease and other age-associated disorders observed in postmenopause.

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“…Mitochondrial supercomplexes are being actively studied to elucidate their physiological role, and their importance in the pathogenesis of numerous human diseases, whether they are acquired or genetic mitochondrial diseases 3,7,9,10,11,12,13,14 . In order to obtain reliable results, several aspects need to be considered.…”

Section: Discussionmentioning

confidence: 99%

“…These supramolecular structures are thought to decrease ROS production, stabilize or assist in the assembly of individual complexes, regulate respiratory chain activity, and prevent protein aggregation in the protein rich inner mitochondrial membrane 5,6,7,8 . Their remodelling ability upon variation in energy demand and their importance in the pathogenesis of diseases is being investigated in several labs 3,7,9,10,11,12,13,14 . Studies have demonstrated that pathological changes in SCs assembly are present in a variety of disorders, including, but not limited to, genetic defect in cardiolipin synthesis 15 , heart failure 16 , ischemia-reperfusion 17 , diabetes 12 , and aging 18 .…”

Section: Introductionmentioning

confidence: 99%

Hybrid Clear/Blue Native Electrophoresis for the Separation and Analysis of Mitochondrial Respiratory Chain Supercomplexes

Cuillerier

Burelle

2019

JoVE

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Complexes of the oxidative phosphorylation machinery form supramolecular protein arrangements named supercomplexes (SCs), which are believed to confer structural and functional advantages to mitochondria. SCs have been identified in many species, from yeast to mammal, and an increasing number of studies report disruption of their organization in genetic and acquired human diseases. As a result, an increasing number of laboratories are interested in analyzing SCs, which can be methodologically challenging. This article presents an optimized protocol that combines the advantages of Blue-and Clear-Native PAGE methods to resolve and analyze SCs in a time-effective manner. With this hybrid CN/BN-PAGE method, mitochondrial SCs extracted with optimal amounts of the mild detergent digitonin are exposed briefly to the anionic dye Coomassie Blue (CB) at the beginning of the electrophoresis, without exposure to other detergents. This short exposure to CB allows to separate and resolve SCs as effectively as with traditional BN-PAGE methods, while avoiding the negative impact of high CB levels on in-gel activity assays, and labile protein-protein interactions within SCs. With this protocol it is thus possible to combine precise and rapid in gel activity measurements with analytical techniques involving 2D electrophoresis, immuno-detection, and/or proteomics for advanced analysis of SCs.

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Adaptation within mitochondrial oxidative phosphorylation supercomplexes and membrane viscosity during degeneration of dopaminergic neurons in an animal model of early Parkinson's disease

Cited by 42 publications

References 65 publications

Prolonged Dysfunction of Astrocytes and Activation of Microglia Accelerate Degeneration of Dopaminergic Neurons in the Rat Substantia Nigra and Block Compensation of Early Motor Dysfunction Induced by 6-OHDA

Prolonged Dysfunction of Astrocytes and Activation of Microglia Accelerate Degeneration of Dopaminergic Neurons in the Rat Substantia Nigra and Block Compensation of Early Motor Dysfunction Induced by 6-OHDA

Hormone deprivation alters mitochondrial function and lipid profile in the hippocampus

Hybrid Clear/Blue Native Electrophoresis for the Separation and Analysis of Mitochondrial Respiratory Chain Supercomplexes

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