Dr. Harper’s research focuses on mechanisms that impact the efficiency of energy conversion pathways in mitochondria. Changes in the efficiency of energy conversion can affect the development of diseases and metabolic dysfunction, and her research probes mechanisms in the context of obesity, diabetes, heart failure and cancer. Experimental approaches span from molecular in vitro studies, to mouse models, and to integrative studies in patient populations. Research has been funded by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council (NSERC), Heart and Stroke Foundation, National Institutes of Health (NIH), and the Canadian Cancer Society Research Institute. Dr. Harper holds a University Research Chair; is Director of the NSERC-funded Metabolomics Advanced Training and International Exchange (MATRIX) training program, based at Universities of Ottawa, McGill and Montréal. She was recently appointed as the interim Director of the Ottawa institute of Systems Biology.
Biochimica et biophysica acta. Molecular cell research, 2021
Mitochondria are highly dynamic organelles. Alterations in mitochondrial dynamics are causal or a... more Mitochondria are highly dynamic organelles. Alterations in mitochondrial dynamics are causal or are linked to numerous neurodegenerative, neuromuscular, and metabolic diseases. It is generally thought that cells with altered mitochondrial structure are prone to mitochondrial dysfunction, increased reactive oxygen species generation and widespread oxidative damage. The objective of the current study was to investigate the relationship between mitochondrial dynamics and the master cellular antioxidant, glutathione (GSH). We reveal that mouse embryonic fibroblasts (MEFs) lacking the mitochondrial fusion machinery display elevated levels of GSH, which limits oxidative damage. Moreover, targeted metabolomics and 13C isotopic labeling experiments demonstrate that cells lacking the inner membrane fusion GTPase OPA1 undergo widespread metabolic remodeling altering the balance of citric acid cycle intermediates and ultimately favoring GSH synthesis. Interestingly, the GSH precursor and antioxidant n-acetylcysteine did not increase GSH levels in OPA1 KO cells, suggesting that cysteine is not limiting for GSH production in this context. Post-mitotic neurons were unable to increase GSH production in the absence of OPA1. Finally, the ability to use glycolysis for ATP production was a requirement for GSH accumulation following OPA1 deletion. Thus, our results demonstrate a novel role for mitochondrial fusion in the regulation of GSH synthesis, and suggest that cysteine availability is not limiting for GSH synthesis in conditions of mitochondrial fragmentation. These findings provide a possible explanation for the heightened sensitivity of certain cell types to alterations in mitochondrial dynamics.
SummaryObesity derives from an extended period of positive energy imbalance due to a complex inte... more SummaryObesity derives from an extended period of positive energy imbalance due to a complex interplay of environmental and biological factors. Muscle fiber type and physiology have been hypothesized to affect metabolism and energy expenditure and thus to affect an individual's propensity to gain weight. However, there have been conflicting reports regarding a relationship between muscle fiber type and obesity. Here, we systematically reviewed literature investigating this topic from PubMed, Web of Science, and EMBASE. Of these, 32 articles were included in our final review and analysis. Most studies (22/32) reported a significant relationship between muscle fiber‐type proportion and a measure of obesity. Overall, there was a significant negative relationship between the proportion of type I fibers and body mass index (BMI) and a significant positive relationship between the proportion of type IIX fibers and BMI. Moreover, between‐group comparisons indicated a greater prevalence...
Uncoupling protein 3 (UCP3) is an inner mitochondrial protein responsible for proton leak and may... more Uncoupling protein 3 (UCP3) is an inner mitochondrial protein responsible for proton leak and may play a key role in facilitating complete fatty acid oxidation. Acylcarnitines are the byproducts of incomplete fatty acid oxidation and have been shown to increase oxidative stress and have been linked to the development of insulin resistance in this tissue. The Harper Laboratory has investigated the effects of acylcarnitines on mitochondrial respiration in UCP3 knockout and wild type mice. Preliminary research has demonstrated that mitochondrial respiration in white gastrocnemius is decreased in the presence of long-chained acylcarnitines compared to short-chained acylcarnitines and UCP3 may play a role in this (Koves et al, 2007).
SUMMARYWe recently hypothesized that parkin plays a role in redox homeostasis and provided eviden... more SUMMARYWe recently hypothesized that parkin plays a role in redox homeostasis and provided evidence that it directly reduces hydrogen peroxide (H2O2) in vitro. Here, we examined this anti-oxidant activity in vivo. Informed by findings in human brain, we demonstrate that elevated oxidative stress promotes parkin insolubility in mice. In normal mouse brain parkin was partially oxidized, e.g., at cysteines 195 and 252, which was augmented by oxidative stress. Although under basal conditions H2O2 levels were unchanged in adult prkn-/- brain, a parkin-dependent reduction of cytosolic H2O2 was observed when mitochondria were impaired, either due to neurotoxicant exposure (MPTP) or Sod2 haploinsufficiency. In accordance, markers of oxidative stress, e.g., protein carbonylation and nitrotyrosination, were elevated in the cytosol but not in mitochondria from prkn-/- mice. Nevertheless, this rise in oxidative stress led to changes in mitochondrial enzyme activities and the metabolism of gluta...
Weight loss in response to energy restriction is highly variable, and identification of genetic c... more Weight loss in response to energy restriction is highly variable, and identification of genetic contributors can provide insights into underlying biology. Leveraging 1000 Genomes imputed genotypes, we carried out genome-wide association study (GWAS) analysis in 551 unrelated obese subjects of European ancestry who participated in an intensively supervised weight loss program with replication of promising signals in an independent sample of 1,331 obese subjects who completed the program at a later date. By single nucleotide polymorphism–based and sib-pair analysis, we show that that weight loss is a heritable trait, with estimated heritability (h2 = 0.49) within the range reported for obesity. We find rs679482, intronic to SGCG (sarcoglycan γ), highly expressed in skeletal muscle, to concordantly associate with weight loss in discovery and replication samples reaching GWAS significance in the combined meta-analysis (β = −0.35, P = 1.7 × 10−12). Located in a region of open chromatin, ...
Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide ... more Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention remains unknown. We perform a GWAS in two large low-caloric diet intervention cohorts of obese participants. Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort (n = 1166) and replicated in the DiOGenes cohort (n = 789). Modulation of HGTX (NKX6.3 ortholog) levels in Drosophila melanogaster leads to significantly altered triglyceride levels. Additional tissue-specific experiments demonstrate an action through the oenocytes, fly hepatocyte-like cells that regulate lipid metabolism. Our results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control.
Aims To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs)... more Aims To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs) and to connect genetic risk to blood traits/biomarkers through the circulating miRNAs. Methods and results Leveraging miRNA-Seq data and the 1000 Genomes imputed genotypes, we carried out genome-wide association analysis for SNPs that regulate the expression of circulating miRNAs in a sample of 710 unrelated subjects of European ancestry. Wherever possible, we used data from the Framingham and the Geuvadis studies to replicate our findings. We found at least one genome-wide significant (P < 5e−8) miRNA-eQTL (mirQTL) for 143 circulating miRNAs. Overall each mirQTL explained a small portion (<1%) of variation in miRNA levels; however, we identified a few mirQTLs that explained 4% to 20% of variation in miRNA levels in plasma. Unlike trans-mirQTLs (P = 0.7), cis-mirQTLs tend to be also associated with their counterpart mature miRNAs (P < 0.0001), this suggests trans-mirQTLs exert ...
Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic... more Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which > 80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synt...
Holistic human proteome maps are expected to complement comprehensive profile assessment of healt... more Holistic human proteome maps are expected to complement comprehensive profile assessment of health and disease phenotypes. However, methodologies to analyze proteomes in human tissue or body fluid samples at relevant scale and performance are still limited in clinical research. Their deployment and demonstration in large enough human populations are even sparser. In the present study, we have characterized and compared the plasma proteomes of two large independent cohorts of obese and overweight individuals using shotgun mass spectrometry (MS)-based proteomics. Herein, we showed, in both populations from different continents of about 500 individuals each, the concordance of plasma protein MS measurements in terms of variability, gender-specificity, and age-relationship. Additionally, we replicated several known and new associations between proteins, clinical and molecular variables, such as insulin and glucose concentrations. In conclusion, our MS-based analyses of plasma samples fr...
Acyl-CoA Synthetase Long Chain 5 (ACSL5) gene's rs2419621 T/C polymorphism was associated wit... more Acyl-CoA Synthetase Long Chain 5 (ACSL5) gene's rs2419621 T/C polymorphism was associated with ACSL5 mRNA expression and response to lifestyle interventions. However, the mechanistic understanding of the increased response in T allele carriers is lacking. Study objectives were to investigate the effect of rs2419621 genotype and ACSL5 human protein isoforms on fatty acid oxidation and respiration. Human ACSL5 overexpression in C2C12 mouse myoblasts was conducted to measure C palmitic acid oxidation and protein isoform localization in vitro. C palmitic acid oxidation studies and Western blot analysis of ACSL5 proteins were carried out in rectus abdominis primary myotubes from 5 rs2419621 T allele carriers and 4 non-carriers. In addition, mitochondrial high-resolution respirometry was conducted on vastus lateralis muscle biopsies from 4 rs2419621 T allele carriers and 4 non-carriers. Multiple linear regression analysis was conducted to test the association between rs2419621 genotyp...
a Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ot... more a Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada b Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, Ontario, Canada c Atherogenomics Laboratory, and Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada d Ottawa Hospital Weight Management Clinic, Ottawa, Ontario, Canada
<p>Locations of the human R225W and the porcine R225Q mutations in the γ<sub>3</su... more <p>Locations of the human R225W and the porcine R225Q mutations in the γ<sub>3</sub> subunit as well as the R302Q and R61Q mutations in the γ<sub>2</sub> long and short forms, respectively, are indicated. Figure adapted from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000903#pone.0000903-Carling1" target="_blank">[12]</a>.</p
<p>Muscle sections were prepared and stained with OsO<sub>4</sub>, as described... more <p>Muscle sections were prepared and stained with OsO<sub>4</sub>, as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000903#s2" target="_blank">methods</a> section (A: control, B: R225W). C: quantification of IMTG via imaging software. Means +/− SD. n = 4, Student's <i>t</i>-test, *p = 0.032.</p
As the metabolism community has grown and diversified with scientists from multidisciplinary back... more As the metabolism community has grown and diversified with scientists from multidisciplinary backgrounds, metabolic terminology has evolved and expanded. In this Comment, we reflect on this new vernacular and how established terminology can guide future discussions of metabolic research.
To meet its exceptionally high energy demands, the heart relies largely on fatty acid oxidation, ... more To meet its exceptionally high energy demands, the heart relies largely on fatty acid oxidation, which then drives the oxidative phosphorylation system in mitochondria. Each day, this system produces about 6kg of ATP to sustain heart function. Fatty acid oxidation is sometimes associated with high rates of mitochondrial reactive oxygen species (ROS) production. By definition, ROS are singlet electron intermediates formed during the partial reduction of oxygen to water and they include radical and non-radical intermediates like superoxide, hydrogen peroxide and hydroxyl radical. Superoxide can also interact with nitric oxide to produce peroxynitrite that in turn can give rise to other radical or non-radical reactive nitrogen species (RNS) like nitrogen dioxide, dinitrogen trioxide and others. While mitochondrial and cellular functions can be impaired by ROS if they accumulate, under normal physiological conditions ROS are important signaling molecules in the cardiovascular system. A ...
Biochimica et biophysica acta. Molecular cell research, 2021
Mitochondria are highly dynamic organelles. Alterations in mitochondrial dynamics are causal or a... more Mitochondria are highly dynamic organelles. Alterations in mitochondrial dynamics are causal or are linked to numerous neurodegenerative, neuromuscular, and metabolic diseases. It is generally thought that cells with altered mitochondrial structure are prone to mitochondrial dysfunction, increased reactive oxygen species generation and widespread oxidative damage. The objective of the current study was to investigate the relationship between mitochondrial dynamics and the master cellular antioxidant, glutathione (GSH). We reveal that mouse embryonic fibroblasts (MEFs) lacking the mitochondrial fusion machinery display elevated levels of GSH, which limits oxidative damage. Moreover, targeted metabolomics and 13C isotopic labeling experiments demonstrate that cells lacking the inner membrane fusion GTPase OPA1 undergo widespread metabolic remodeling altering the balance of citric acid cycle intermediates and ultimately favoring GSH synthesis. Interestingly, the GSH precursor and antioxidant n-acetylcysteine did not increase GSH levels in OPA1 KO cells, suggesting that cysteine is not limiting for GSH production in this context. Post-mitotic neurons were unable to increase GSH production in the absence of OPA1. Finally, the ability to use glycolysis for ATP production was a requirement for GSH accumulation following OPA1 deletion. Thus, our results demonstrate a novel role for mitochondrial fusion in the regulation of GSH synthesis, and suggest that cysteine availability is not limiting for GSH synthesis in conditions of mitochondrial fragmentation. These findings provide a possible explanation for the heightened sensitivity of certain cell types to alterations in mitochondrial dynamics.
SummaryObesity derives from an extended period of positive energy imbalance due to a complex inte... more SummaryObesity derives from an extended period of positive energy imbalance due to a complex interplay of environmental and biological factors. Muscle fiber type and physiology have been hypothesized to affect metabolism and energy expenditure and thus to affect an individual's propensity to gain weight. However, there have been conflicting reports regarding a relationship between muscle fiber type and obesity. Here, we systematically reviewed literature investigating this topic from PubMed, Web of Science, and EMBASE. Of these, 32 articles were included in our final review and analysis. Most studies (22/32) reported a significant relationship between muscle fiber‐type proportion and a measure of obesity. Overall, there was a significant negative relationship between the proportion of type I fibers and body mass index (BMI) and a significant positive relationship between the proportion of type IIX fibers and BMI. Moreover, between‐group comparisons indicated a greater prevalence...
Uncoupling protein 3 (UCP3) is an inner mitochondrial protein responsible for proton leak and may... more Uncoupling protein 3 (UCP3) is an inner mitochondrial protein responsible for proton leak and may play a key role in facilitating complete fatty acid oxidation. Acylcarnitines are the byproducts of incomplete fatty acid oxidation and have been shown to increase oxidative stress and have been linked to the development of insulin resistance in this tissue. The Harper Laboratory has investigated the effects of acylcarnitines on mitochondrial respiration in UCP3 knockout and wild type mice. Preliminary research has demonstrated that mitochondrial respiration in white gastrocnemius is decreased in the presence of long-chained acylcarnitines compared to short-chained acylcarnitines and UCP3 may play a role in this (Koves et al, 2007).
SUMMARYWe recently hypothesized that parkin plays a role in redox homeostasis and provided eviden... more SUMMARYWe recently hypothesized that parkin plays a role in redox homeostasis and provided evidence that it directly reduces hydrogen peroxide (H2O2) in vitro. Here, we examined this anti-oxidant activity in vivo. Informed by findings in human brain, we demonstrate that elevated oxidative stress promotes parkin insolubility in mice. In normal mouse brain parkin was partially oxidized, e.g., at cysteines 195 and 252, which was augmented by oxidative stress. Although under basal conditions H2O2 levels were unchanged in adult prkn-/- brain, a parkin-dependent reduction of cytosolic H2O2 was observed when mitochondria were impaired, either due to neurotoxicant exposure (MPTP) or Sod2 haploinsufficiency. In accordance, markers of oxidative stress, e.g., protein carbonylation and nitrotyrosination, were elevated in the cytosol but not in mitochondria from prkn-/- mice. Nevertheless, this rise in oxidative stress led to changes in mitochondrial enzyme activities and the metabolism of gluta...
Weight loss in response to energy restriction is highly variable, and identification of genetic c... more Weight loss in response to energy restriction is highly variable, and identification of genetic contributors can provide insights into underlying biology. Leveraging 1000 Genomes imputed genotypes, we carried out genome-wide association study (GWAS) analysis in 551 unrelated obese subjects of European ancestry who participated in an intensively supervised weight loss program with replication of promising signals in an independent sample of 1,331 obese subjects who completed the program at a later date. By single nucleotide polymorphism–based and sib-pair analysis, we show that that weight loss is a heritable trait, with estimated heritability (h2 = 0.49) within the range reported for obesity. We find rs679482, intronic to SGCG (sarcoglycan γ), highly expressed in skeletal muscle, to concordantly associate with weight loss in discovery and replication samples reaching GWAS significance in the combined meta-analysis (β = −0.35, P = 1.7 × 10−12). Located in a region of open chromatin, ...
Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide ... more Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention remains unknown. We perform a GWAS in two large low-caloric diet intervention cohorts of obese participants. Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort (n = 1166) and replicated in the DiOGenes cohort (n = 789). Modulation of HGTX (NKX6.3 ortholog) levels in Drosophila melanogaster leads to significantly altered triglyceride levels. Additional tissue-specific experiments demonstrate an action through the oenocytes, fly hepatocyte-like cells that regulate lipid metabolism. Our results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control.
Aims To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs)... more Aims To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs) and to connect genetic risk to blood traits/biomarkers through the circulating miRNAs. Methods and results Leveraging miRNA-Seq data and the 1000 Genomes imputed genotypes, we carried out genome-wide association analysis for SNPs that regulate the expression of circulating miRNAs in a sample of 710 unrelated subjects of European ancestry. Wherever possible, we used data from the Framingham and the Geuvadis studies to replicate our findings. We found at least one genome-wide significant (P < 5e−8) miRNA-eQTL (mirQTL) for 143 circulating miRNAs. Overall each mirQTL explained a small portion (<1%) of variation in miRNA levels; however, we identified a few mirQTLs that explained 4% to 20% of variation in miRNA levels in plasma. Unlike trans-mirQTLs (P = 0.7), cis-mirQTLs tend to be also associated with their counterpart mature miRNAs (P < 0.0001), this suggests trans-mirQTLs exert ...
Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic... more Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which > 80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synt...
Holistic human proteome maps are expected to complement comprehensive profile assessment of healt... more Holistic human proteome maps are expected to complement comprehensive profile assessment of health and disease phenotypes. However, methodologies to analyze proteomes in human tissue or body fluid samples at relevant scale and performance are still limited in clinical research. Their deployment and demonstration in large enough human populations are even sparser. In the present study, we have characterized and compared the plasma proteomes of two large independent cohorts of obese and overweight individuals using shotgun mass spectrometry (MS)-based proteomics. Herein, we showed, in both populations from different continents of about 500 individuals each, the concordance of plasma protein MS measurements in terms of variability, gender-specificity, and age-relationship. Additionally, we replicated several known and new associations between proteins, clinical and molecular variables, such as insulin and glucose concentrations. In conclusion, our MS-based analyses of plasma samples fr...
Acyl-CoA Synthetase Long Chain 5 (ACSL5) gene's rs2419621 T/C polymorphism was associated wit... more Acyl-CoA Synthetase Long Chain 5 (ACSL5) gene's rs2419621 T/C polymorphism was associated with ACSL5 mRNA expression and response to lifestyle interventions. However, the mechanistic understanding of the increased response in T allele carriers is lacking. Study objectives were to investigate the effect of rs2419621 genotype and ACSL5 human protein isoforms on fatty acid oxidation and respiration. Human ACSL5 overexpression in C2C12 mouse myoblasts was conducted to measure C palmitic acid oxidation and protein isoform localization in vitro. C palmitic acid oxidation studies and Western blot analysis of ACSL5 proteins were carried out in rectus abdominis primary myotubes from 5 rs2419621 T allele carriers and 4 non-carriers. In addition, mitochondrial high-resolution respirometry was conducted on vastus lateralis muscle biopsies from 4 rs2419621 T allele carriers and 4 non-carriers. Multiple linear regression analysis was conducted to test the association between rs2419621 genotyp...
a Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ot... more a Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada b Ruddy Canadian Cardiovascular Genetics Centre, Ottawa, Ontario, Canada c Atherogenomics Laboratory, and Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada d Ottawa Hospital Weight Management Clinic, Ottawa, Ontario, Canada
<p>Locations of the human R225W and the porcine R225Q mutations in the γ<sub>3</su... more <p>Locations of the human R225W and the porcine R225Q mutations in the γ<sub>3</sub> subunit as well as the R302Q and R61Q mutations in the γ<sub>2</sub> long and short forms, respectively, are indicated. Figure adapted from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000903#pone.0000903-Carling1" target="_blank">[12]</a>.</p
<p>Muscle sections were prepared and stained with OsO<sub>4</sub>, as described... more <p>Muscle sections were prepared and stained with OsO<sub>4</sub>, as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000903#s2" target="_blank">methods</a> section (A: control, B: R225W). C: quantification of IMTG via imaging software. Means +/− SD. n = 4, Student's <i>t</i>-test, *p = 0.032.</p
As the metabolism community has grown and diversified with scientists from multidisciplinary back... more As the metabolism community has grown and diversified with scientists from multidisciplinary backgrounds, metabolic terminology has evolved and expanded. In this Comment, we reflect on this new vernacular and how established terminology can guide future discussions of metabolic research.
To meet its exceptionally high energy demands, the heart relies largely on fatty acid oxidation, ... more To meet its exceptionally high energy demands, the heart relies largely on fatty acid oxidation, which then drives the oxidative phosphorylation system in mitochondria. Each day, this system produces about 6kg of ATP to sustain heart function. Fatty acid oxidation is sometimes associated with high rates of mitochondrial reactive oxygen species (ROS) production. By definition, ROS are singlet electron intermediates formed during the partial reduction of oxygen to water and they include radical and non-radical intermediates like superoxide, hydrogen peroxide and hydroxyl radical. Superoxide can also interact with nitric oxide to produce peroxynitrite that in turn can give rise to other radical or non-radical reactive nitrogen species (RNS) like nitrogen dioxide, dinitrogen trioxide and others. While mitochondrial and cellular functions can be impaired by ROS if they accumulate, under normal physiological conditions ROS are important signaling molecules in the cardiovascular system. A ...
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Papers by Mary-Ellen Harper