Preeclampsia (PE) is a pregnancy associated hypertensive disease. It is one of the major causes o... more Preeclampsia (PE) is a pregnancy associated hypertensive disease. It is one of the major causes of pregnancy-related maternal/perinatal adverse health outcomes, with a lack of highly effective preventative strategies and/or therapeutic interventions. Our group has previously identified distinct subclasses of pathophysiology underlying a PE diagnosis, one of which exhibits heightened immune activation at the gestational parent-fetal interface, identified as inflammatory-driven PE. In non-pregnant populations, chronic inflammation is associated with reduced cellular availability of NAD+, a vitamin B3-derived metabolite involved in energy metabolism and mitochondrial function. Interestingly, specifically in placentas from women with inflammatory-driven PE, we observed increased activity of NAD+-consuming PARP enzymes and reduced NAD+content. Moreover, these placentas had decreased expression of several mitochondrial oxidative phosphorylation (OXPHOS) proteins and evidence of oxidative ...
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Glucose uptake in muscle cells in response to insulin is a fundamental mechanism for metabolism. ... more Glucose uptake in muscle cells in response to insulin is a fundamental mechanism for metabolism. The inability of cells to mobilize the specific glucose transporter GLUT4 is believed to be at least partially accountable for diseases, like diabetes, where cells do not respond to an insulin stimulus. In this work, a microchip is used to detect electrochemically glucose uptake from C2C12 myoblasts cultured on a patch of paper upon exposure to insulin. More importantly, the data suggest a new role for dynamin, a molecular motor which would be involved in GLUT4 translocation by facilitating exocytosis. It is also shown in vivo that dynamin is involved in the response to glucose in a completely distinct organism, namely the nematode Caenorhabditis elegans. The new mechanism for dynamin could therefore be more generally relevant in vivo and may play a role in insulin resistance. Insight, innovation, integration Developing new quantitative techniques and in vivo or in vitro models are crucial steps to extend our understanding of life sciences and to facilitate biomedical research. In this article, a versatile microfluidic system, fitted with an electrochemical sensor, is used to investigate glucose uptake from artificial tissues built on paper. The fundamental finding that dynamin is involved in this process was further extended in an organism-on-a-chip system, thus showing that dynamin also controls the response of C. elegans to high glucose levels. Overall, beyond the importance of the biological results, this work shows that carefully designed bioanalytical microsystems allow for the study of a specific phenomenon at a wide range of samples.
Protein lysine acetylation is a post-translational modification that regulates protein structure ... more Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5 skm−/−) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.
Annual Review of Pharmacology and Toxicology, Jan 6, 2018
Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy ... more Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy harvesting through oxidative phosphorylation. Alterations of mitochondrial function not only impact on cellular metabolism but also critically influence whole-body metabolism, health, and life span. Diseases defined by mitochondrial dysfunction have also expanded from rare monogenic disorders in a strict sense to now also include many common polygenic diseases, including metabolic, cardiovascular, neurodegenerative, and neuromuscular diseases. This has led to an intensive search for new therapeutic and preventive strategies aimed at invigorating mitochondrial function by exploiting key components of mitochondrial biogenesis, redox metabolism, dynamics, mitophagy, and the mitochondrial unfolded protein response. As such, new findings linking mitochondrial function to the progression or outcome of this ever-increasing list of diseases has stimulated the discovery and development of the first true mitochondrial drugs, which are now entering the clinic and are discussed in this review. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 58 is January 6, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Nicotinamide Adenine Dinucleotide (NAD+) plays an important role in energy metabolism and signali... more Nicotinamide Adenine Dinucleotide (NAD+) plays an important role in energy metabolism and signaling pathways controlling crucial cellular functions. The increased interest in NAD+ metabolism and NAD+-boosting therapies has reinforced the necessity for accurate NAD+ quantification. To examine the published NAD(P)(H) measures across mammalian tissues, we performed a meta-analysis of the existing data. An Ovid MEDLINE database search identified articles with NAD(P)(H) quantification results obtained from mammalian tissues published between 1961 and 2021. We screened 4890 records and extracted quantitative data, as well as the quantification methods, pre-analytical conditions, and subject characteristics. The extracted physiological NAD(P)(H) concentrations in various tissues from mice, rats, and humans, revealed an important inter- and intra-method variability that extended to recent publications. This highlights the relatively poor potential for cross-experimental analyses for NAD(P)(...
The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational-paren... more The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational-parent/fetal exchange and ultimately fetal development and growth. Not surprisingly, in cases of placental dysfunction - where aspects of placental development or function become compromised - adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero-placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunct...
ABSTRACTMaintaining mitochondrial function is critical to an improved health span and lifespan. I... more ABSTRACTMaintaining mitochondrial function is critical to an improved health span and lifespan. Introducing mild stress by inhibiting mitochondrial translation invokes the mitochondrial unfolded protein response (UPRmt) and increases lifespan in several animal models. Notably, lower mitochondrial ribosomal protein (MRP) expression also correlates with increased lifespan in a reference population of mice. In this study, we tested whether partially reducing the expression of a critical MRP,Mrpl54, reduced mitochondrial DNA-encoded protein content, induced the UPRmt, and affected lifespan or metabolic health using germline heterozygousMrpl54mice. Despite reducedMrpl54expression in multiple organs and a reduction in mitochondrial-encoded protein expression in myoblasts, we identified few significant differences between male or femaleMrpl54+/-and wild type mice in initial body composition, respiratory parameters, energy intake and expenditure, or ambulatory motion. We also observed no di...
The present invention relates to agents that prevent or reverse process of stem cell senescence. ... more The present invention relates to agents that prevent or reverse process of stem cell senescence. Further, the invention relates to methods and compositions useful in the prevention and/or treatment of stem senescence
In recent years the role of acetylation has gained ground as an essential modulator of intermedia... more In recent years the role of acetylation has gained ground as an essential modulator of intermediary metabolism in skeletal muscle. Imbalance in energy homeostasis or chronic cellular stress, due to diet, aging or disease, translate into alterations in the acetylation levels of key proteins which governs bioenergetics, cellular substrate use and/or changes in mitochondrial content and function. For example, cellular stress induced by exercise or caloric restriction can alter the coordinated activity of acetyltransferases and deacetylases to increase mitochondrial biogenesis and function in order to adapt to low energetic levels. The natural duality of these enzymes, as metabolic sensors and effector proteins, have helped biologists understand how the body can integrate seemingly distinct signaling pathways to control mitochondrial biogenesis, insulin sensitivity, glucose transport, reactive oxygen species handling, angiogenesis and muscle satellite cell proliferation/differentiation....
This work identifies a novel role for the acetyltransferase GCN5 in regulating muscle integrity t... more This work identifies a novel role for the acetyltransferase GCN5 in regulating muscle integrity through inhibition of DNA binding activity of the transcriptional repressor YY1. Here we report that in mice a muscle-specific knockout of GCN5 (Gcn5skm-/-) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. Supporting our observation, a meta-analysis between the differential transcriptome ofGcn5skm-/-muscle and all available open-access data sets identified top correlations with musculoskeletal diseases in humans. GCN5 was found to acetylate YY1 at two residues (K392 and K393), which disrupts the interaction between the YY1 zinc-finger region and DNA. De/acetylation mimics for these YY1 post-translational modifications modulated muscle structural gene expression and DNA binding. Analysis of human GTEx data also found positive and negative correlations between fiber diameter and GCN5 and YY1 respectively. Collectively, our results demons...
In recent years, the role of acetylation has gained ground as an essential modulator of intermedi... more In recent years, the role of acetylation has gained ground as an essential modulator of intermediary metabolism in skeletal muscle. Imbalance in energy homeostasis or chronic cellular stress, due to diet, aging, or disease, translate into alterations in the acetylation levels of key proteins which govern bioenergetics, cellular substrate use, and/or changes in mitochondrial content and function. For example, cellular stress induced by exercise or caloric restriction can alter the coordinated activity of acetyltransferases and deacetylases to increase mitochondrial biogenesis and function in order to adapt to low energetic levels. The natural duality of these enzymes, as metabolic sensors and effector proteins, has helped biologists to understand how the body can integrate seemingly distinct signaling pathways to control mitochondrial biogenesis, insulin sensitivity, glucose transport, reactive oxygen species handling, angiogenesis, and muscle satellite cell proliferation/differentia...
Glutathione is an important antioxidant that regulates cellular redox status and is disordered in... more Glutathione is an important antioxidant that regulates cellular redox status and is disordered in many disease states. Glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase that plays a pivotal role in redox control by catalyzing reversible protein deglutathionylation. As oxidized glutathione (GSSG) can stimulate mitochondrial fusion, we hypothesized that Grx2 may contribute to the maintenance of mitochondrial dynamics and ultrastructure. Here, we demonstrate that Grx2 deletion results in decreased GSH:GSSG, with a marked increase of GSSG in primary muscle cells isolated from C57BL/6 Grx2−/− mice. The altered glutathione redox was accompanied by increased mitochondrial length, consistent with a more fused mitochondrial reticulum. Electron microscopy of Grx2−/− skeletal muscle fibers revealed decreased mitochondrial surface area, profoundly disordered ultrastructure, and the appearance of multi-lamellar structures. Immunoblot analysis revealed that autophagic flux was augme...
Preeclampsia (PE) is a pregnancy associated hypertensive disease. It is one of the major causes o... more Preeclampsia (PE) is a pregnancy associated hypertensive disease. It is one of the major causes of pregnancy-related maternal/perinatal adverse health outcomes, with a lack of highly effective preventative strategies and/or therapeutic interventions. Our group has previously identified distinct subclasses of pathophysiology underlying a PE diagnosis, one of which exhibits heightened immune activation at the gestational parent-fetal interface, identified as inflammatory-driven PE. In non-pregnant populations, chronic inflammation is associated with reduced cellular availability of NAD+, a vitamin B3-derived metabolite involved in energy metabolism and mitochondrial function. Interestingly, specifically in placentas from women with inflammatory-driven PE, we observed increased activity of NAD+-consuming PARP enzymes and reduced NAD+content. Moreover, these placentas had decreased expression of several mitochondrial oxidative phosphorylation (OXPHOS) proteins and evidence of oxidative ...
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Glucose uptake in muscle cells in response to insulin is a fundamental mechanism for metabolism. ... more Glucose uptake in muscle cells in response to insulin is a fundamental mechanism for metabolism. The inability of cells to mobilize the specific glucose transporter GLUT4 is believed to be at least partially accountable for diseases, like diabetes, where cells do not respond to an insulin stimulus. In this work, a microchip is used to detect electrochemically glucose uptake from C2C12 myoblasts cultured on a patch of paper upon exposure to insulin. More importantly, the data suggest a new role for dynamin, a molecular motor which would be involved in GLUT4 translocation by facilitating exocytosis. It is also shown in vivo that dynamin is involved in the response to glucose in a completely distinct organism, namely the nematode Caenorhabditis elegans. The new mechanism for dynamin could therefore be more generally relevant in vivo and may play a role in insulin resistance. Insight, innovation, integration Developing new quantitative techniques and in vivo or in vitro models are crucial steps to extend our understanding of life sciences and to facilitate biomedical research. In this article, a versatile microfluidic system, fitted with an electrochemical sensor, is used to investigate glucose uptake from artificial tissues built on paper. The fundamental finding that dynamin is involved in this process was further extended in an organism-on-a-chip system, thus showing that dynamin also controls the response of C. elegans to high glucose levels. Overall, beyond the importance of the biological results, this work shows that carefully designed bioanalytical microsystems allow for the study of a specific phenomenon at a wide range of samples.
Protein lysine acetylation is a post-translational modification that regulates protein structure ... more Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5 skm−/−) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.
Annual Review of Pharmacology and Toxicology, Jan 6, 2018
Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy ... more Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy harvesting through oxidative phosphorylation. Alterations of mitochondrial function not only impact on cellular metabolism but also critically influence whole-body metabolism, health, and life span. Diseases defined by mitochondrial dysfunction have also expanded from rare monogenic disorders in a strict sense to now also include many common polygenic diseases, including metabolic, cardiovascular, neurodegenerative, and neuromuscular diseases. This has led to an intensive search for new therapeutic and preventive strategies aimed at invigorating mitochondrial function by exploiting key components of mitochondrial biogenesis, redox metabolism, dynamics, mitophagy, and the mitochondrial unfolded protein response. As such, new findings linking mitochondrial function to the progression or outcome of this ever-increasing list of diseases has stimulated the discovery and development of the first true mitochondrial drugs, which are now entering the clinic and are discussed in this review. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 58 is January 6, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Nicotinamide Adenine Dinucleotide (NAD+) plays an important role in energy metabolism and signali... more Nicotinamide Adenine Dinucleotide (NAD+) plays an important role in energy metabolism and signaling pathways controlling crucial cellular functions. The increased interest in NAD+ metabolism and NAD+-boosting therapies has reinforced the necessity for accurate NAD+ quantification. To examine the published NAD(P)(H) measures across mammalian tissues, we performed a meta-analysis of the existing data. An Ovid MEDLINE database search identified articles with NAD(P)(H) quantification results obtained from mammalian tissues published between 1961 and 2021. We screened 4890 records and extracted quantitative data, as well as the quantification methods, pre-analytical conditions, and subject characteristics. The extracted physiological NAD(P)(H) concentrations in various tissues from mice, rats, and humans, revealed an important inter- and intra-method variability that extended to recent publications. This highlights the relatively poor potential for cross-experimental analyses for NAD(P)(...
The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational-paren... more The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational-parent/fetal exchange and ultimately fetal development and growth. Not surprisingly, in cases of placental dysfunction - where aspects of placental development or function become compromised - adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero-placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunct...
ABSTRACTMaintaining mitochondrial function is critical to an improved health span and lifespan. I... more ABSTRACTMaintaining mitochondrial function is critical to an improved health span and lifespan. Introducing mild stress by inhibiting mitochondrial translation invokes the mitochondrial unfolded protein response (UPRmt) and increases lifespan in several animal models. Notably, lower mitochondrial ribosomal protein (MRP) expression also correlates with increased lifespan in a reference population of mice. In this study, we tested whether partially reducing the expression of a critical MRP,Mrpl54, reduced mitochondrial DNA-encoded protein content, induced the UPRmt, and affected lifespan or metabolic health using germline heterozygousMrpl54mice. Despite reducedMrpl54expression in multiple organs and a reduction in mitochondrial-encoded protein expression in myoblasts, we identified few significant differences between male or femaleMrpl54+/-and wild type mice in initial body composition, respiratory parameters, energy intake and expenditure, or ambulatory motion. We also observed no di...
The present invention relates to agents that prevent or reverse process of stem cell senescence. ... more The present invention relates to agents that prevent or reverse process of stem cell senescence. Further, the invention relates to methods and compositions useful in the prevention and/or treatment of stem senescence
In recent years the role of acetylation has gained ground as an essential modulator of intermedia... more In recent years the role of acetylation has gained ground as an essential modulator of intermediary metabolism in skeletal muscle. Imbalance in energy homeostasis or chronic cellular stress, due to diet, aging or disease, translate into alterations in the acetylation levels of key proteins which governs bioenergetics, cellular substrate use and/or changes in mitochondrial content and function. For example, cellular stress induced by exercise or caloric restriction can alter the coordinated activity of acetyltransferases and deacetylases to increase mitochondrial biogenesis and function in order to adapt to low energetic levels. The natural duality of these enzymes, as metabolic sensors and effector proteins, have helped biologists understand how the body can integrate seemingly distinct signaling pathways to control mitochondrial biogenesis, insulin sensitivity, glucose transport, reactive oxygen species handling, angiogenesis and muscle satellite cell proliferation/differentiation....
This work identifies a novel role for the acetyltransferase GCN5 in regulating muscle integrity t... more This work identifies a novel role for the acetyltransferase GCN5 in regulating muscle integrity through inhibition of DNA binding activity of the transcriptional repressor YY1. Here we report that in mice a muscle-specific knockout of GCN5 (Gcn5skm-/-) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. Supporting our observation, a meta-analysis between the differential transcriptome ofGcn5skm-/-muscle and all available open-access data sets identified top correlations with musculoskeletal diseases in humans. GCN5 was found to acetylate YY1 at two residues (K392 and K393), which disrupts the interaction between the YY1 zinc-finger region and DNA. De/acetylation mimics for these YY1 post-translational modifications modulated muscle structural gene expression and DNA binding. Analysis of human GTEx data also found positive and negative correlations between fiber diameter and GCN5 and YY1 respectively. Collectively, our results demons...
In recent years, the role of acetylation has gained ground as an essential modulator of intermedi... more In recent years, the role of acetylation has gained ground as an essential modulator of intermediary metabolism in skeletal muscle. Imbalance in energy homeostasis or chronic cellular stress, due to diet, aging, or disease, translate into alterations in the acetylation levels of key proteins which govern bioenergetics, cellular substrate use, and/or changes in mitochondrial content and function. For example, cellular stress induced by exercise or caloric restriction can alter the coordinated activity of acetyltransferases and deacetylases to increase mitochondrial biogenesis and function in order to adapt to low energetic levels. The natural duality of these enzymes, as metabolic sensors and effector proteins, has helped biologists to understand how the body can integrate seemingly distinct signaling pathways to control mitochondrial biogenesis, insulin sensitivity, glucose transport, reactive oxygen species handling, angiogenesis, and muscle satellite cell proliferation/differentia...
Glutathione is an important antioxidant that regulates cellular redox status and is disordered in... more Glutathione is an important antioxidant that regulates cellular redox status and is disordered in many disease states. Glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase that plays a pivotal role in redox control by catalyzing reversible protein deglutathionylation. As oxidized glutathione (GSSG) can stimulate mitochondrial fusion, we hypothesized that Grx2 may contribute to the maintenance of mitochondrial dynamics and ultrastructure. Here, we demonstrate that Grx2 deletion results in decreased GSH:GSSG, with a marked increase of GSSG in primary muscle cells isolated from C57BL/6 Grx2−/− mice. The altered glutathione redox was accompanied by increased mitochondrial length, consistent with a more fused mitochondrial reticulum. Electron microscopy of Grx2−/− skeletal muscle fibers revealed decreased mitochondrial surface area, profoundly disordered ultrastructure, and the appearance of multi-lamellar structures. Immunoblot analysis revealed that autophagic flux was augme...
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