ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome

Licznerski, Pawel; Park, Hana; Rolyan, Harshvardhan; Chen, Rongmin; Mnatsakanyan, Nelli; Miranda, Paige; Graham, Morven; Wu, Jing; Cruz-Reyes, Nicole; Mehta, Nikita; Sohail, Sana; Salcedo, Jorge; Song, Erin; Effman, Charles; Effman, Samuel; Brandão, Lucas; Xu, Gulan N.; Braker, Amber; Gribkoff, Valentin K.; Levy, Richard J.; Jonas, Elizabeth A.

doi:10.1016/j.cell.2020.07.008

Cited by 78 publications

(77 citation statements)

References 106 publications

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“…Heteroplasmic levels of the mtDNA 3243A > G mutation associated with ASD are also associated with significant changes in ANT gene expression [ 130 ]. Consistent with this evidence, increased protein leak is also a feature of mitochondrial abnormalities in the Fragile X syndrome mouse, where it is found to directly affect synaptic growth [ 131 ]. Thus, dysregulation in inner membrane proton leak seems to be associated with an ASD phenotype.…”

Section: Long-term Induced Changes In Mitochondrial Function: Adapmentioning

confidence: 74%

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

Frye

Cakir

Rose

et al. 2021

JPM

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We propose that the mitochondrion, an essential cellular organelle, mediates the long-term prenatal environmental effects of disease in autism spectrum disorder (ASD). Many prenatal environmental factors which increase the risk of developing ASD influence mitochondria physiology, including toxicant exposures, immune activation, and nutritional factors. Unique types of mitochondrial dysfunction have been associated with ASD and recent studies have linked prenatal environmental exposures to long-term changes in mitochondrial physiology in children with ASD. A better understanding of the role of the mitochondria in the etiology of ASD can lead to targeted therapeutics and strategies to potentially prevent the development of ASD.

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Section: Long-term Induced Changes In Mitochondrial Function: Adapmentioning

confidence: 74%

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

Frye

Cakir

Rose

et al. 2021

JPM

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“…Any of these mechanisms could indirectly impair the function and/or the composition of the mitochondrial ribosome. A compromised mitochondrial ribosome could account for altered mitochondrial functions observed in Fmr1 -/y cultures [51,[58][59][60][61][62][63][64][65]. Alternatively and/or in addition, we know that loss of FMRP dysregulates synaptic and ion channel protein expression at baseline, and these alterations may lead to altered mitochondrial plasticity during activity deprivation.…”

Section: Discussionmentioning

confidence: 99%

FMRP Attenuates Activity Dependent Modifications in the Mitochondrial Proteome

Bülow

Wenner

Bassell

et al. 2021

Preprint

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Homeostatic plasticity is necessary for the construction and maintenance of functional neuronal networks, but principal molecular mechanisms required for or modified by homeostatic plasticity are not well understood. We recently reported that homeostatic plasticity induced by activity deprivation is dysregulated in cortical neurons from Fragile X Mental Retardation protein (FMRP) knockout mice [1]. These findings led us to hypothesize that identifying proteins sensitive to activity deprivation and/or FMRP expression could reveal pathways required for or modified by homeostatic plasticity. Here, we report an unbiased quantitative mass spectrometry used to quantify steady-state proteome changes following chronic activity deprivation in wild type and Fmr1-/y cortical neurons. Proteome hits responsive to both activity deprivation and the Fmr1-/y genotype were significantly annotated to mitochondria. We found an increased number of mitochondria annotated proteins whose expression was sensitive to activity deprivation in Fmr1-/y cortical neurons as compared to wild type neurons. These findings support a novel role of FMRP in attenuating mitochondrial proteome modifications induced by activity deprivation.

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“…The function of mitochondria is also important for the health of neurons, and the activities of axons and dendritic neuron fibers are highly dependent on mitochondria, which are highly dynamic and exhibit an activity-induced interval distribution (Eisner et al, 2018 ; Bock and Tait, 2020 ). For example, mitochondrial transport to the remote synapse provides sufficient energy for local synaptic activity in the maintenance of ion channels, transporters, and synaptic transmission (Licznerski et al, 2020 ).…”

Section: Mitochondrial Quality Control Systems and Ichmentioning

confidence: 99%

Mitochondria: Novel Mechanisms and Therapeutic Targets for Secondary Brain Injury After Intracerebral Hemorrhage

Chen

Guo

Feng

et al. 2021

Front. Aging Neurosci.

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Intracerebral hemorrhage (ICH) is a destructive form of stroke that often results in death or disability. However, the survivors usually experience sequelae of neurological impairments and psychiatric disorders, which affect their daily functionality and working capacity. The recent MISTIE III and STICH II trials have confirmed that early surgical clearance of hematomas does not improve the prognosis of survivors of ICH, so it is vital to find the intervention target of secondary brain injury (SBI) after ICH. Mitochondrial dysfunction, which may be induced by oxidative stress, neuroinflammation, and autophagy, among others, is considered to be a novel pathological mechanism of ICH. Moreover, mitochondria play an important role in promoting neuronal survival and improving neurological function after a hemorrhagic stroke. This review summarizes the mitochondrial mechanism involved in cell death, reactive oxygen species (ROS) production, inflammatory activation, blood–brain barrier (BBB) disruption, and brain edema underlying ICH. We emphasize the potential of mitochondrial protection as a potential therapeutic target for SBI after stroke and provide valuable insight into clinical strategies.

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ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome

Abstract: Highlights d ATP synthase c-subunit leak in Fragile X causes aberrant metabolism d Changes in ATP synthase component stoichiometry regulate protein synthesis rate d Inhibition of the leak normalizes synaptic spine morphology and Fragile X behavior

Cited by 78 publications

References 106 publications

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

FMRP Attenuates Activity Dependent Modifications in the Mitochondrial Proteome

Mitochondria: Novel Mechanisms and Therapeutic Targets for Secondary Brain Injury After Intracerebral Hemorrhage

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