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Dive into the research topics where Meagan J. McManus is active.

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Featured researches published by Meagan J. McManus.


The Journal of Neuroscience | 2011

The Mitochondria-Targeted Antioxidant MitoQ Prevents Loss of Spatial Memory Retention and Early Neuropathology in a Transgenic Mouse Model of Alzheimer's Disease

Meagan J. McManus; Michael P. Murphy; James L. Franklin

Considerable evidence suggests that mitochondrial dysfunction and oxidative stress contribute to the progression of Alzheimers disease (AD). We examined the ability of the novel mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cycloheexadienl-yl) decyl triphenylphosphonium methanesulfonate]) to prevent AD-like pathology in mouse cortical neurons in cell culture and in a triple transgenic mouse model of AD (3xTg-AD). MitoQ attenuated β-amyloid (Aβ)-induced neurotoxicity in cortical neurons and also prevented increased production of reactive species and loss of mitochondrial membrane potential (Δψm) in them. To determine whether the mitochondrial protection conferred by MitoQ was sufficient to prevent the emergence of AD-like neuropathology in vivo, we treated young female 3xTg-AD mice with MitoQ for 5 months and analyzed the effect on the progression of AD-like pathologies. Our results show that MitoQ prevented cognitive decline in these mice as well as oxidative stress, Aβ accumulation, astrogliosis, synaptic loss, and caspase activation in their brains. The work presented herein suggests a central role for mitochondria in neurodegeneration and provides evidence supporting the use of mitochondria-targeted therapeutics in diseases involving oxidative stress and metabolic failure, namely AD.


Cell | 2012

Heteroplasmy of Mouse mtDNA Is Genetically Unstable and Results in Altered Behavior and Cognition

Mark S. Sharpley; Christine Marciniak; Kristin Eckel-Mahan; Meagan J. McManus; Marco Crimi; Katrina G. Waymire; Chun Shi Lin; Satoru Masubuchi; Nicole Friend; Maya Koike; Dimitra Chalkia; Grant R. MacGregor; Paolo Sassone-Corsi; Douglas C. Wallace

Maternal inheritance of mtDNA is the rule in most animals, but the reasons for this pattern remain unclear. To investigate the consequence of overriding uniparental inheritance, we generated mice containing an admixture (heteroplasmy) of NZB and 129S6 mtDNAs in the presence of a congenic C57BL/6J nuclear background. Analysis of the segregation of the two mtDNAs across subsequent maternal generations revealed that proportion of NZB mtDNA was preferentially reduced. Ultimately, this segregation process produced NZB-129 heteroplasmic mice and their NZB or 129 mtDNA homoplasmic counterparts. Phenotypic comparison of these three mtDNA lines demonstrated that the NZB-129 heteroplasmic mice, but neither homoplasmic counterpart, had reduced activity, food intake, respiratory exchange ratio; accentuated stress response; and cognitive impairment. Therefore, admixture of two normal but different mouse mtDNAs can be genetically unstable and can produce adverse physiological effects, factors that may explain the advantage of uniparental inheritance of mtDNA.


Proceedings of the National Academy of Sciences of the United States of America | 2012

Mouse mtDNA mutant model of Leber hereditary optic neuropathy

Chun Shi Lin; Mark S. Sharpley; Weiwei Fan; Katrina G. Waymire; Alfredo A. Sadun; Valerio Carelli; Fred N. Ross-Cisneros; Peter Baciu; Eric C. Sung; Meagan J. McManus; Billy X. Pan; Daniel W. Gil; Grant R. MacGregor; Douglas C. Wallace

An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atrophy mtDNA ND6 P25L mutation into the mouse. Mice with this mutation exhibited reduction in retinal function by elecroretinogram (ERG), age-related decline in central smaller caliber optic nerve fibers with sparing of larger peripheral fibers, neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I and respiration defects and increased reactive oxygen species (ROS) production, whereas synaptosome analysis revealed decreased complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress.


Proceedings of the National Academy of Sciences of the United States of America | 2015

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

Martin Picard; Meagan J. McManus; Jason D. Gray; Carla Nasca; Cynthia Moffat; Piotr K. Kopinski; Erin L. Seifert; Bruce S. McEwen; Douglas C. Wallace

Significance In humans and animals, stress triggers multisystemic physiological responses that vary in nature and magnitude. The organism’s response to stress, rather than actual stressors, leads to allostatic load that predisposes to disease. This study in mice demonstrates that a specific cellular component that sustains life via energy transformation and intracellular signaling—the mitochondrion—influences the organism’s integrated response to psychological stress. Each component of the stress response assessed was modified by at least one mitochondrial defect. When analyzed collectively, stress-induced neuroendocrine, inflammatory, metabolic, and transcriptional responses coalesced into unique signatures that distinguish groups based on their mitochondrial genotype. This work shows that mitochondria can regulate complex whole-body physiological responses, impacting stress perception at the cellular and organismal levels. The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases.


Nature Communications | 2015

Trans-mitochondrial coordination of cristae at regulated membrane junctions

Martin Picard; Meagan J. McManus; György Csordás; Péter Várnai; Gerald W. Dorn; Dewight Williams; György Hajnóczky; Douglas C. Wallace

Reminiscent of bacterial quorum sensing, mammalian mitochondria participate in inter-organelle communication. However, physical structures that enhance or enable interactions between mitochondria have not been defined. Here we report that adjacent mitochondria exhibit coordination of inner mitochondrial membrane cristae at inter-mitochondrial junctions (IMJs). These electron-dense structures are conserved across species, resistant to genetic disruption of cristae organization, dynamically modulated by mitochondrial bioenergetics, independent of known inter-mitochondrial tethering proteins mitofusins and rapidly induced by the stable rapprochement of organelles via inducible synthetic linker technology. At the associated junctions, the cristae of adjacent mitochondria form parallel arrays perpendicular to the IMJ, consistent with a role in electrochemical coupling. These IMJs and associated cristae arrays may provide the structural basis to enhance the propagation of intracellular bioenergetic and apoptotic waves through mitochondrial networks within cells.


Journal of Applied Physiology | 2013

Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle

Martin Picard; Benoit J. Gentil; Meagan J. McManus; Kathryn White; Kyle St. Louis; Sarah E. Gartside; Douglas C. Wallace; Douglass M. Turnbull

A unique property of mitochondria in mammalian cells is their ability to physically interact and undergo dynamic events of fusion/fission that remodel their morphology and possibly their function. In cultured cells, metabolic perturbations similar to those incurred during exercise influence mitochondrial fusion and fission processes, but it is unknown whether exercise acutely alters mitochondrial morphology and/or membrane interactions in vivo. To study this question, we subjected mice to a 3-h voluntarily exercise intervention following their normal physical activity patterns, and quantified mitochondrial morphology and membrane interactions in the soleus using a quantitative electron microscopy approach. A single exercise bout effectively decreased blood glucose (P < 0.05) and intramyocellular lipid content (P < 0.01), indicating increased muscle metabolic demand. The number of mitochondria spanning Z-lines and proportion of electron-dense contact sites (EDCS) between adjacent mitochondrial membranes were increased immediately after exercise among both subsarcolemmal (+116%, P < 0.05) and intermyofibrillar mitochondria (+191%, P < 0.001), indicating increased physical interactions. Mitochondrial morphology, and abundance of the mitochondrial pro-fusion proteins Mfn2 and OPA1 were unchanged. Collectively, these results support the notion that mitochondrial membrane dynamics are actively remodelled in skeletal muscle, which may be regulated by contractile activity and the metabolic state. Future studies are required to understand the implications of mitochondrial dynamics in skeletal muscle physiology during exercise and inactivity.


Molecular and Cellular Neuroscience | 2014

Mitochondria-derived reactive oxygen species mediate caspase-dependent and -independent neuronal deaths

Meagan J. McManus; Michael P. Murphy; James L. Franklin

Mitochondrial dysfunction and oxidative stress are implicated in many neurodegenerative diseases. Mitochondria-targeted drugs that effectively decrease oxidative stress, protect mitochondrial energetics, and prevent neuronal loss may therefore lend therapeutic benefit to these currently incurable diseases. To investigate the efficacy of such drugs, we examined the effects of mitochondria-targeted antioxidants MitoQ10 and MitoE2 on neuronal death induced by neurotrophin deficiency. Our results indicate that MitoQ10 blocked apoptosis by preventing increased mitochondria-derived reactive oxygen species (ROS) and subsequent cytochrome c release, caspase activation, and mitochondrial damage in nerve growth factor (NGF)-deprived sympathetic neurons, while MitoE2 was largely ineffective. In this paradigm, the most proximal point of divergence was the ability of MitoQ10 to scavenge mitochondrial superoxide (O2(-)). MitoQ10 also prevented caspase-independent neuronal death in these cells demonstrating that the mitochondrial redox state significantly influences both apoptotic and nonapoptotic pathways leading to neuronal death. We suggest that mitochondria-targeted antioxidants may provide tools for delineating the role and significance of mitochondrial ROS in neuronal death and provide a new therapeutic approach for neurodegenerative conditions involving trophic factor deficits and multiple modes of cell death.


Proceedings of the National Academy of Sciences of the United States of America | 2017

Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

Ryan M. Morrow; Martin Picard; Olga Derbeneva; Jeremy Leipzig; Meagan J. McManus; Gilles Gouspillou; Sébastien Barbat-Artigas; Carlos Dos Santos; Russell T. Hepple; Deborah G. Murdock; Douglas C. Wallace

Significance Mitochondrial dysfunction is associated with type II diabetes and metabolic syndrome, but whether it is cause or consequence is debated. By showing that increased mitochondrial respiration can impart glucose tolerance, insulin sensitivity, and resistance to high fat diet (HFD) toxicity, we provide evidence that mitochondria contributes to the etiology of metabolic disease. Inactivation of adenine nucleotide translocator isoform 1 (ANT1) results in proliferation of partially uncoupled muscle mitochondrial respiration, creating a sink for excess calories. Although ANT1-deficient muscle induces expression of Fgf21, FGF21 level is not elevated in blood, and FGF21 and UCP1 mRNAs are not increased in liver or brown adipose tissue (BAT). If increased mitochondrial respiration prevents HFD toxicity, then decreased mitochondrial respiration may contribute to metabolic disease. Diabetes is associated with impaired glucose metabolism in the presence of excess insulin. Glucose and fatty acids provide reducing equivalents to mitochondria to generate energy, and studies have reported mitochondrial dysfunction in type II diabetes patients. If mitochondrial dysfunction can cause diabetes, then we hypothesized that increased mitochondrial metabolism should render animals resistant to diabetes. This was confirmed in mice in which the heart–muscle–brain adenine nucleotide translocator isoform 1 (ANT1) was inactivated. ANT1-deficient animals are insulin-hypersensitive, glucose-tolerant, and resistant to high fat diet (HFD)-induced toxicity. In ANT1-deficient skeletal muscle, mitochondrial gene expression is induced in association with the hyperproliferation of mitochondria. The ANT1-deficient muscle mitochondria produce excess reactive oxygen species (ROS) and are partially uncoupled. Hence, the muscle respiration under nonphosphorylating conditions is increased. Muscle transcriptome analysis revealed the induction of mitochondrial biogenesis, down-regulation of diabetes-related genes, and increased expression of the genes encoding the myokines FGF21 and GDF15. However, FGF21 was not elevated in serum, and FGF21 and UCP1 mRNAs were not induced in liver or brown adipose tissue (BAT). Hence, increased oxidation of dietary-reducing equivalents by elevated muscle mitochondrial respiration appears to be the mechanism by which ANT1-deficient mice prevent diabetes, demonstrating that the rate of mitochondrial oxidation of calories is important in the etiology of metabolic disease.


Neurochemistry International | 2017

An X-chromosome linked mouse model (Ndufa1(S55A)) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases.

Chul Kim; Prasanth Potluri; Ahmed Khalil; Daria Gaut; Meagan J. McManus; Douglas C. Wallace; Nagendra Yadava

&NA; The respiratory chain Complex I deficiencies are the most common cause of mitochondrial diseases. Complex I biogenesis is controlled by 58 genes and at least 47 of these cause mitochondrial disease in humans. Two of these are X‐chromosome linked nuclear (nDNA) genes (NDUFA1 and NDUFB11), and 7 are mitochondrial (mtDNA, MT‐ND1‐6, ‐4L) genes, which may be responsible for sex‐dependent variation in the presentation of mitochondrial diseases. In this study, we describe an X‐chromosome linked mouse model (Ndufa1S55A) for systemic partial Complex I deficiency. By homologous recombination, a point mutation T > G within 55th codon of the Ndufa1 gene was introduced. The resulting allele Ndufa1S55A introduced systemic serine‐55‐alanine (S55A) mutation within the MWFE protein, which is essential for Complex I assembly and stability. The S55A mutation caused systemic partial Complex I deficiency of ˜50% in both sexes. The mutant males (Ndufa1S55A/Y) displayed reduced respiratory exchange ratio (RER) and produced less body heat. They were also hypoactive and ate less. They showed age‐dependent Purkinje neurons degeneration. Metabolic profiling of brain, liver and serum from males showed reduced heme levels in mutants, which correlated with altered expressions of Fech and Hmox1 mRNAs in tissues. This is the first genuine X‐chromosome linked mouse model for systemic partial Complex I deficiency, which shows age‐dependent neurodegeneration. The effect of Complex I deficiency on survival patterns of males vs. females was different. We believe this model will be very useful for studying sex‐dependent predisposition to both spontaneous and stress‐induced neurodegeneration, cancer, diabetes and other diseases. Graphical abstract Figure. No caption available. HighlightsNdufa1S55A mouse model is the first genuine X‐chromosome linked animal model for systemic partial Complex I deficiency.Ndufa1S55A/Y mice are hypometabolic, hypoactive and hypophagic, and display age‐dependent Purkinje neurons degeneration.Partial Complex I deficiency results in heme deficiency that correlates with decreased ferrochelatase (Fech) expression in liver and increased heme oxygenase 1 (Hmox1) expression in brain and liver.Systemic partial Complex I deficiency has sex‐dependent effect on survival.


Archive | 2016

Mitochondrial Signaling and Neurodegeneration

Martin Picard; Meagan J. McManus

The endosymbiosis of mitochondria and the resulting increase in energy supply thus conferred upon the eukaryotic cell enabled the evolution of multicellular organisms and complex organs, such as the brain. As a result, the brain and other organs with high energy demands, depend heavily upon mitochondrial metabolism for normal function, and as a consequence, defects in mitochondrial function lead to neurodegenerative disorders. However, the mechanisms linking mitochondrial defects to hallmarks of neurodegeneration, such as the protein aggregates are also extracellular epigenetic alterations, abnormal gene expression, systemic inflammation, and protein aggregates, remain unclear.

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Douglas C. Wallace

Children's Hospital of Philadelphia

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Martin Picard

Columbia University Medical Center

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Prasanth Potluri

University of Pennsylvania

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Alessia Angelin

University of Pennsylvania

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Carla Nasca

Rockefeller University

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Erin L. Seifert

Thomas Jefferson University

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Jagat Narula

Icahn School of Medicine at Mount Sinai

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