Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1

Filippis, Bianca De; Valenti, Daniela; Bari, Lidia de; Rasmo, Domenico De; Musto, Mattia; Fabbri, Alessia; Ricceri, Laura; Fiorentini, Carla; Laviola, Giovanni; Vacca, Rosa Anna

doi:10.1016/j.freeradbiomed.2015.02.014

Cited by 73 publications

(105 citation statements)

References 64 publications

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“…4 D ). Given mitochondrial respiratory deficits were usually accompanied by increased ROS production (44), we determined whether CypD deficiency inhibits oxidative stress in STZ mouse brains. Brain ROS levels were measured by highly selective and sensitive EPR, which detects the presence of unpaired electrons and provides an excellent technique for measuring intracellular free radicals (39,40).…”

Section: Resultsmentioning

confidence: 99%

F1F0 ATP Synthase–Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline

Yan

et al. 2016

Diabetes

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Mitochondrial abnormalities are well known to cause cognitive decline. However, the underlying molecular basis of mitochondria-associated neuronal and synaptic dysfunction in the diabetic brain remains unclear. Here, using a mitochondrial single-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif −/−) with streptozotocin-induced diabetes, we observed an increase in the probability of Ca2+-induced mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, which was further confirmed by mitochondrial swelling and cytochrome c release induced by Ca2+ overload. Diabetes-induced elevation of CypD triggers enhancement of F1F0 ATP synthase–CypD interaction, which in turn leads to mPTP opening. Indeed, in patients with diabetes, brain cypD protein levels were increased. Notably, blockade of the F1F0 ATP synthase–CypD interaction by CypD ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress, and mitochondria dysfunction. Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learning, and memory in diabetic mice. Thus, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic intervention in diabetic encephalopathy.

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Section: Resultsmentioning

confidence: 99%

F1F0 ATP Synthase–Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline

Yan

et al. 2016

Diabetes

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“…Further, they raise the possibility that impaired mitochondrial function could indeed play a contributing rather than passive role in RTT pathogenic progression. Finally, the decreased ATP levels that have been observed in the symptomatic MeCP2-null mouse brain (Saywell et al, 2006), in the female Mecp2 308 mouse brain (De Filippis et al, 2015), and in isolated Mecp2 −/y microglia (Jin et al, 2015) provides further evidence that the absence of MeCP2 leads to impaired mitochondrial function.…”

Section: Introductionmentioning

confidence: 95%

Mitochondrial Dysfunction in the Pathogenesis of Rett Syndrome: Implications for Mitochondria-Targeted Therapies

Shulyakova

Andreazza

Mills

et al. 2017

Front. Cell. Neurosci.

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First described over 50 years ago, Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by mutations of the X-linked MECP2 gene. RTT affects predominantly females, and has a prevalence of roughly 1 in every 10,000 female births. Prior to the discovery that mutations of MECP2 are the leading cause of RTT, there were suggestions that RTT could be a mitochondrial disease. In fact, several reports documented altered mitochondrial structure, and deficiencies in mitochondrial enzyme activity in different cells or tissues derived from RTT patients. With the identification of MECP2 as the causal gene, interest largely shifted toward defining the normal function of MeCP2 in the brain, and how its absence affects the neurodevelopment and neurophysiology. Recently, though, interest in studying mitochondrial function in RTT has been reignited, at least in part due to observations suggesting systemic oxidative stress does play a contributing role in RTT pathogenesis. Here we review data relating to mitochondrial alterations at the structural and functional levels in RTT patients and model systems, and present a hypothesis for how the absence of MeCP2 could lead to altered mitochondrial function and elevated levels of cellular oxidative stress. Finally, we discuss the prospects for treating RTT using interventions that target specific aspects of mitochondrial dysfunction and/or oxidative stress.

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“…Furthermore, comparative gene-array analyses on patient lymphomonoytes indicated a differential expression of various genes pivotal to mitochondrial function and/or organization [25]. In mouse models of RTT, symptomatic animals also showed reduced enzyme activities of respiratory chain complexes II, III, IV, and ANT1, as well as reduced glutathione levels in the brain and/or skeletal muscle [26–29]. Furthermore, the ANT1 gene encoding the mitochondrial adenine nucleotide translocase is highly upregulated in the Mecp2 −/y mouse brain and Rett patient fibroblasts [30], the latter of which also show clear signs of metabolic mitochondrial dysregulation, oxidative stress, and diminished redox-balancing capabilities [31].…”

Section: Introductionmentioning

confidence: 99%

Increased Mitochondrial Mass and Cytosolic Redox Imbalance in Hippocampal Astrocytes of a Mouse Model of Rett Syndrome: Subcellular Changes Revealed by Ratiometric Imaging of JC‐1 and roGFP1 Fluorescence

Bebensee

Can

Müller

2017

Oxidative Medicine and Cellular Longevity

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Rett syndrome (RTT) is a neurodevelopmental disorder with mutations in the MECP2 gene. Mostly girls are affected, and an apparently normal development is followed by cognitive impairment, motor dysfunction, epilepsy, and irregular breathing. Various indications suggest mitochondrial dysfunction. In Rett mice, brain ATP levels are reduced, mitochondria are leaking protons, and respiratory complexes are dysregulated. Furthermore, we found in MeCP2-deficient mouse (Mecp2−/y) hippocampus an intensified mitochondrial metabolism and ROS generation. We now used emission ratiometric 2-photon imaging to assess mitochondrial morphology, mass, and membrane potential (ΔΨm) in Mecp2−/y hippocampal astrocytes. Cultured astrocytes were labeled with the ΔΨm marker JC-1, and semiautomated analyses yielded the number of mitochondria per cell, their morphology, and ΔΨm. Mecp2−/y astrocytes contained more mitochondria than wild-type (WT) cells and were more oxidized. Mitochondrial size, ΔΨm, and vulnerability to pharmacological challenge did not differ. The antioxidant Trolox opposed the oxidative burden and decreased the mitochondrial mass, thereby dampening the differences among WT and Mecp2−/y astrocytes; mitochondrial size and ΔΨm were not markedly affected. In conclusion, mitochondrial alterations and redox imbalance in RTT also involve astrocytes. Mitochondria are more numerous in Mecp2−/y than in WT astrocytes. As this genotypic difference is abolished by Trolox, it seems linked to the oxidative stress in RTT.

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Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1

Cited by 73 publications

References 64 publications

F1F0 ATP Synthase–Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline

F1F0 ATP Synthase–Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline

Mitochondrial Dysfunction in the Pathogenesis of Rett Syndrome: Implications for Mitochondria-Targeted Therapies

Increased Mitochondrial Mass and Cytosolic Redox Imbalance in Hippocampal Astrocytes of a Mouse Model of Rett Syndrome: Subcellular Changes Revealed by Ratiometric Imaging of JC‐1 and roGFP1 Fluorescence

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