SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse

Fischer, Lindsey R.; Igoudjil, Anissa; Magrané, Jordi; Li, Yingjie; Hansen, Jason M.; Manfredi, Giovanni; Glass, Jonathan D.

doi:10.1093/brain/awq314

Cited by 115 publications

(113 citation statements)

References 72 publications

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“…These findings imply that the mitochondrial redox environment plays a central role in regulating skeletal muscle mitochondrial function. In support of this, the physiological and functional importance of maintaining redox homeostasis within the MIS was recently highlighted in a transgenic model that exclusively expressed SOD1 within the MIS (mitoSOD1,Sod1 −/− ) from SOD1 −/− mice 23. The transgenic approach used in the mitoSOD1,Sod1 −/− model prevented the morphological and biochemical defects associated with progressive motor axonopathy in skeletal muscle of the SOD1 −/− rodents,23 highlighting the importance of SOD1 redox regulatory enzyme expression in the MIS, and implicated oxidative damage initiated at mitochondrial sites in the pathogenesis of motor axon degeneration.…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 89%

“…The impact of altered redox homeostasis in loss of neuromuscular integrity and function with ageing has been investigated in several murine models, which have undergone genetic modifications of redox signalling/homeostasis components 19, 23, 25, 29, 30, 31, 32, 33, 34, 240, 241, 242. Transgenic murine models have provided insight into the importance of RONS regulatory systems in lifespan and neuromuscular ageing, and it has been reported that SOD2 −/− ,243 GRX3 −/− ,244 GPX4 −/− ,245 TRX1 −/− ,246 TRX2 −/− ,247 TR1 −/− 248 and TR2 −/− 249 murine models are embryonically lethal.…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

“…Increased oxidative damage and compensatory up‐regulation of redox regulatory enzymes, stress responses and adaptive signalling pathways observed in muscle from SOD1 −/− mice30, 33 were not present in the neuron‐specific transgenic SynTgSOD1 −/− model. Moreover, the accelerated degeneration in NMJ structure, including both presynaptic and postsynaptic NMJ features,23, 276 failure of neuromuscular transmission29, 278 and impaired in situ muscle‐force generation34, 277 that occur in the whole body SOD1 −/− model were completely rescued in the nerve rescue model 29…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

“…Many reports19, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 have examined skeletal muscle of rodents lacking and/or overexpressing various key regulatory enzyme systems (in homo/heterozygotic and tissue‐specific models) involved in the reduction and/or generation of oxidants to determine whether specific defects in antioxidant protection and the resultant changes in redox homeostasis influence the onset and/or rate of age‐related muscle atrophy and functional deficits.…”

Section: Introductionmentioning

confidence: 99%

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Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age‐related muscle atrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributor to morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population (estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associated with neuromuscular ageing, will inevitably increase. Despite the importance of this ‘epidemic’ problem, the primary biochemical and molecular mechanisms underlying age‐related deficits in neuromuscular integrity and function have not been fully determined. Skeletal muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources, and age‐associated oxidative damage has been suggested to be a major factor contributing to the initiation and progression of muscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, and disruption of these events over time due to altered redox control has been proposed as an underlying mechanism of ageing. The role of oxidants in ageing has been extensively examined in different model organisms that have undergone genetic manipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function of RONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redox homeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken in murine models to examine the role of redox regulation in age‐related muscle atrophy and weakness.

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Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 89%

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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“…Preparation of Mitochondrial Subcompartments and Proteinase K Protection Assays-For protein localization, pure brain mitochondria were isolated using a Percoll gradient as described previously (29). 500 g of mitochondria (10 mg/ml) were resuspended in MS-EGTA (225 mM mannitol, 75 mM sucrose, 5 mM HEPES, 1 mM EGTA, pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

Acı́n-Pérez

Russwurm

Günnewig

et al. 2011

Journal of Biological Chemistry

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120

133

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Mitochondria are central organelles in cellular energy metabolism, apoptosis, and aging processes. A signaling network regulating these functions was recently shown to include soluble adenylyl cyclase as a local source of the second messenger cAMP in the mitochondrial matrix. However, a mitochondrial cAMPdegrading phosphodiesterase (PDE) necessary for switching off this cAMP signal has not yet been identified. Here, we describe the identification and characterization of a PDE2A isoform in mitochondria from rodent liver and brain. We find that mitochondrial PDE2A is located in the matrix and that the unique N terminus of PDE2A isoform 2 specifically leads to mitochondrial localization of this isoform. Functional assays show that mitochondrial PDE2A forms a local signaling system with soluble adenylyl cyclase in the matrix, which regulates the activity of the respiratory chain. Our findings complete a cAMP signaling cascade in mitochondria and have implications for understanding the regulation of mitochondrial processes and for their pharmacological modulation.Mitochondria play central roles in cellular energy metabolism, as well as in the regulation of cell cycle progression, apoptosis, and aging processes (1, 2). Despite their importance, signaling into, from, and within mitochondria is still not well understood. Emerging signaling mechanisms in mitochondria and between the organelle and its environment include reversible protein deacetylation (3, 4), redox regulation and reactive oxygen species formation (5-7), and cyclic adenosine monophosphate (cAMP) signaling (8, 9).cAMP-dependent effects and proteins of cAMP signaling systems, such as cAMP-responsive element-binding protein (CREB), protein kinase A (PKA), and A-kinase anchoring proteins (AKAPs), 3 have been described in mitochondria (10 -12). In addition to these effector proteins, a complete cAMP signaling microdomain requires enzymes for synthesis and degradation of the second messenger. Although an intramitochondrial cAMP source has been identified recently (8), there is no known cAMP-degrading enzyme in this organelle. Cyclic AMP is formed inside mitochondria by soluble adenylyl cyclase (sAC) (8), a member of Class III of the nucleotidyl cyclase family, which also comprises the G-protein-regulated transmembrane adenylyl cyclases (13). Unique from transmembrane adenylyl cyclases, sAC is activated by bicarbonate (14), and it appears to act as a metabolic sensor (15), whose mitochondrial form(s) seems to modulate PKA-mediated regulation of respiration (8) and apoptosis (16).The opponents of the cyclic nucleotide-forming cyclases are cyclic nucleotide monophosphate (cNMP)-degrading phosphodiesterases (PDEs). Mammalian cells contain a varying subset of members of the classical PDE family, which comprises 11 PDE gene families (PDE1-11) (17, 18) and non-generic PDEs such as the protein human Prune (19,20). The isoforms of the generic PDEs comprise homologous catalytic domains, fused to varying regulatory domains, making them sensitive to a variety of signals s...

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Maintenance of small molecule redox homeostasis in mitochondria

Jacobs

Riemer

2022

FEBS Letters

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Compartmentalisation of eukaryotic cells enables fundamental otherwise often incompatible cellular processes. Establishment and maintenance of distinct compartments in the cell relies not only on proteins, lipids and metabolites but also on small redox molecules. In particular, small redox molecules such as glutathione, NAD(P)H and hydrogen peroxide (H 2 O 2 ) cooperate with protein partners in dedicated machineries to establish specific subcellular redox compartments with conditions that enable oxidative protein folding and redox signalling. Dysregulated redox homeostasis has been directly linked with a number of diseases including cancer, neurological disorders, cardiovascular diseases, obesity, metabolic diseases and ageing. In this review, we will summarise mechanisms regulating establishment and maintenance of redox homeostasis in the mitochondrial subcompartments of mammalian cells.

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SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse

Cited by 115 publications

References 72 publications

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

Maintenance of small molecule redox homeostasis in mitochondria

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