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Mazat JP. The metabolic control theory: Its development and its application to mitochondrial oxidative phosphorylation. Biosystems 2023; 234:105038. [PMID: 37838015 DOI: 10.1016/j.biosystems.2023.105038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 09/08/2023] [Accepted: 09/21/2023] [Indexed: 10/16/2023]
Abstract
Metabolic Control Theory (MCT) and Metabolic Control Analysis (MCA) are the two sides, theoretical and experimental, of the measurement of the sensitivity of metabolic networks in the vicinity of a steady state. We will describe the birth and the development of this theory from the first analyses of linear pathways up to a global mathematical theory applicable to any metabolic network. We will describe how the theory, given the global nature of mitochondrial oxidative phosphorylation, solved the problem of what controls mitochondrial ATP synthesis and then how it led to a better understanding of the differential tissue expression of human mitochondrial pathologies and of the heteroplasmy of mitochondrial DNA, leading to the concept of the threshold effect.
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Affiliation(s)
- Jean-Pierre Mazat
- IBGC CNRS UMR 5095 & Université de Bordeaux, 1, rue Camille Saint-Saëns, 33077, BORDEAUX Cedex, France.
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Harada N, Nagasaki H, Yamamoto H, Matsubara K, Suzuki T, Gomori A, Yokogawa T, Matsuo K, Miyadera K. Depletion of plasma thymidine results in growth retardation and mitochondrial myopathy in mice overexpressing human thymidine phosphorylase. J Biol Chem 2023; 299:103002. [PMID: 36773803 PMCID: PMC10020661 DOI: 10.1016/j.jbc.2023.103002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
Plasma thymidine levels in rodents are higher than in other mammals including humans, possibly due to a different pattern and lower level of thymidine phosphorylase expression. Here, we generated a novel knock-in (KI) mouse line with high systemic expression of human thymidine phosphorylase to investigate this difference in nucleotide metabolism in rodents. The KI mice showed growth retardation around weaning and died by 4 weeks of age with a decrease in plasma thymidine level compared with the litter-control WT mice. These phenotypes were completely or partially rescued by administration of the thymidine phosphorylase inhibitor 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4(1H,3H)-pyrimidinedione hydrochloride or thymidine, respectively. Interestingly, when thymidine phosphorylase inhibitor administration was discontinued in adult animals, KI mice showed deteriorated grip strength and locomotor activity, decreased bodyweight, and subsequent hind-limb paralysis. Upon histological analyses, we observed axonal degeneration in the spinal cord, muscular atrophy with morphologically abnormal mitochondria in quadriceps, retinal degeneration, and abnormality in the exocrine pancreas. Moreover, we detected mitochondrial DNA depletion in multiple tissues of KI mice. These results indicate that the KI mouse represents a new animal model for mitochondrial diseases and should be applicable for the study of differences in nucleotide metabolism between humans and mice.
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Affiliation(s)
- Naomoto Harada
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan.
| | - Haruka Nagasaki
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan
| | - Hiromi Yamamoto
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan
| | - Kenji Matsubara
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan
| | - Takamasa Suzuki
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan
| | - Akira Gomori
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan
| | - Tatsushi Yokogawa
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan
| | - Kenichi Matsuo
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan
| | - Kazutaka Miyadera
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co Ltd, Tsukuba, Ibaraki, Japan
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3
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Gautheron J, Lima L, Akinci B, Zammouri J, Auclair M, Ucar SK, Ozen S, Altay C, Bax BE, Nemazanyy I, Lenoir V, Prip-Buus C, Acquaviva-Bourdain C, Lascols O, Fève B, Vigouroux C, Noel E, Jéru I. Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes. BMC Med 2022; 20:95. [PMID: 35341481 PMCID: PMC8958798 DOI: 10.1186/s12916-022-02296-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/10/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2'-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. METHODS Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. RESULTS All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. CONCLUSIONS The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.
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Affiliation(s)
- Jérémie Gautheron
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France.
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France.
| | - Lara Lima
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
| | - Baris Akinci
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Dokuz Eylul University, 35330, Izmir, Turkey
| | - Jamila Zammouri
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
| | - Martine Auclair
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
| | - Sema Kalkan Ucar
- Department of Pediatrics, Division of Metabolic Diseases, Ege University, 35100, Izmir, Turkey
| | - Samim Ozen
- Department of Pediatrics, Division of Pediatric Endocrinology, Ege University, 35100, Izmir, Turkey
| | - Canan Altay
- Department of Radiology, Dokuz Eylul University, 35100, Izmir, Turkey
| | - Bridget E Bax
- Institute of Molecular and Clinical Sciences, St George's University of London, London, SW17 0RE, UK
| | - Ivan Nemazanyy
- Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, Inserm, US24/CNRS UMS 3633, 75015, Paris, France
| | - Véronique Lenoir
- Institut Cochin, Université Paris Descartes-CNRS UMR8104, Paris, France
| | - Carina Prip-Buus
- Institut Cochin, Université Paris Descartes-CNRS UMR8104, Paris, France
| | - Cécile Acquaviva-Bourdain
- Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils, UM Pathologies Héréditaires du Métabolisme et du Globule Rouge, CHU de Lyon, 69500, Bron, France
| | - Olivier Lascols
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France
| | - Bruno Fève
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
- Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France
| | - Corinne Vigouroux
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France
- Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France
| | - Esther Noel
- Département de Médecine Interne, Centre Hospitalier Universitaire, 67000, Strasbourg, France
| | - Isabelle Jéru
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France.
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France.
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France.
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van de Wal M, Adjobo-Hermans M, Keijer J, Schirris T, Homberg J, Wieckowski MR, Grefte S, van Schothorst EM, van Karnebeek C, Quintana A, Koopman WJH. Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention. Brain 2021; 145:45-63. [PMID: 34849584 PMCID: PMC8967107 DOI: 10.1093/brain/awab426] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/25/2021] [Accepted: 11/11/2021] [Indexed: 11/14/2022] Open
Abstract
Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases. With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (complex I) induce isolated complex I deficiency and Leigh syndrome. This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA-encoded NDUFS4 gene, encoding the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) of complex I, induce ‘mitochondrial complex I deficiency, nuclear type 1’ (MC1DN1) and Leigh syndrome in paediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the Leigh syndrome pathomechanism and intervention testing. Here, we review and discuss the role of complex I and NDUFS4 mutations in human mitochondrial disease, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/Leigh syndrome pathomechanism and its therapeutic targeting.
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Affiliation(s)
- Melissa van de Wal
- Department of Pediatrics, Amalia Children's Hospital, RIMLS, RCMM, Radboudumc, Nijmegen, The Netherlands
| | - Merel Adjobo-Hermans
- Department of Biochemistry (286), RIMLS, RCMM, Radboudumc, Nijmegen, The Netherlands
| | - Jaap Keijer
- Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
| | - Tom Schirris
- Department of Pharmacology and Toxicology, RIMLS, RCMM, Radboudumc, Nijmegen, The Netherlands
| | - Judith Homberg
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands
| | - Mariusz R Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Sander Grefte
- Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
| | | | - Clara van Karnebeek
- Department of Pediatrics, Amalia Children's Hospital, RIMLS, RCMM, Radboudumc, Nijmegen, The Netherlands.,Department of Pediatrics, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Albert Quintana
- Mitochondrial Neuropathology Laboratory, Institut de Neurociències and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Werner J H Koopman
- Department of Pediatrics, Amalia Children's Hospital, RIMLS, RCMM, Radboudumc, Nijmegen, The Netherlands.,Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
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5
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Mas R, Magy L, Jésus P, Ly K, Archambeaud F, Gondran G. [Muscular weakness and weight loss in à 44 year-old man]. Rev Med Interne 2021; 42:887-890. [PMID: 34776277 DOI: 10.1016/j.revmed.2021.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/09/2021] [Indexed: 11/17/2022]
Affiliation(s)
- R Mas
- Service d'Endocrinologie Diabétologie Nutrition, CHU Dupuytren 2, 16, rue Bernard Descottes, 87042 Limoges.
| | - L Magy
- Service de Neurologie, CHU Dupuytren 1, 2, avenue Martin Luther King, 87042 Limoges
| | - P Jésus
- Service d'Hépatogastroentérologie, Unité de nutrition, CHU Dupuytren 1, 2, avenue Martin Luther King, 87042 Limoges
| | - K Ly
- Service de Médecine interne, CHU Dupuytren 2, 16, rue Bernard Descottes, 87042 Limoges
| | - F Archambeaud
- Service d'Endocrinologie Diabétologie Nutrition, CHU Dupuytren 2, 16, rue Bernard Descottes, 87042 Limoges
| | - G Gondran
- Service de Médecine interne, CHU Dupuytren 2, 16, rue Bernard Descottes, 87042 Limoges
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6
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Abstract
Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes a historic record of past drug treatments (mitochondrial memory) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of doxorubicin-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation, and permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes and increased apoptosis. We also suggest some possible pharmacological and nonpharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in doxorubicin-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.
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Affiliation(s)
- Kendall B Wallace
- From the Department of Biomedical Sciences, University of Minnesota Medical School, Duluth (K.B.W.)
| | - Vilma A Sardão
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal (V.A.S., P.J.O.)
| | - Paulo J Oliveira
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal (V.A.S., P.J.O.)
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7
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OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation. Nat Commun 2020; 11:1487. [PMID: 32198407 PMCID: PMC7083862 DOI: 10.1038/s41467-020-15237-5] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 02/25/2020] [Indexed: 02/07/2023] Open
Abstract
Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. Here, we report on mitochondrial respiration, DNA mutations and gene expression in paired benign/malignant human prostate tissue samples. Results reveal reduced respiratory capacities with NADH-pathway substrates glutamate and malate in malignant tissue and a significant metabolic shift towards higher succinate oxidation, particularly in high-grade tumors. The load of potentially deleterious mitochondrial-DNA mutations is higher in tumors and associated with unfavorable risk factors. High levels of potentially deleterious mutations in mitochondrial Complex I-encoding genes are associated with a 70% reduction in NADH-pathway capacity and compensation by increased succinate-pathway capacity. Structural analyses of these mutations reveal amino acid alterations leading to potentially deleterious effects on Complex I, supporting a causal relationship. A metagene signature extracted from the transcriptome of tumor samples exhibiting a severe mitochondrial phenotype enables identification of tumors with shorter survival times.
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8
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Pacitti D, Levene M, Garone C, Nirmalananthan N, Bax BE. Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far. Front Genet 2018; 9:669. [PMID: 30627136 PMCID: PMC6309918 DOI: 10.3389/fgene.2018.00669] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 12/04/2018] [Indexed: 02/05/2023] Open
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterized by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.
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Affiliation(s)
- Dario Pacitti
- Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom
| | - Michelle Levene
- Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom
| | - Caterina Garone
- MRC Mitochondrial Biology Unit, Cambridge Biomedical, Cambridge, United Kingdom
| | | | - Bridget E. Bax
- Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom
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9
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Radzvilavicius AL. Evolutionary dynamics of cytoplasmic segregation and fusion: Mitochondrial mixing facilitated the evolution of sex at the origin of eukaryotes. J Theor Biol 2016; 404:160-168. [DOI: 10.1016/j.jtbi.2016.05.037] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 05/05/2016] [Accepted: 05/31/2016] [Indexed: 11/30/2022]
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Rak M, Bénit P, Chrétien D, Bouchereau J, Schiff M, El-Khoury R, Tzagoloff A, Rustin P. Mitochondrial cytochrome c oxidase deficiency. Clin Sci (Lond) 2016; 130:393-407. [PMID: 26846578 PMCID: PMC4948581 DOI: 10.1042/cs20150707] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
As with other mitochondrial respiratory chain components, marked clinical and genetic heterogeneity is observed in patients with a cytochrome c oxidase deficiency. This constitutes a considerable diagnostic challenge and raises a number of puzzling questions. So far, pathological mutations have been reported in more than 30 genes, in both mitochondrial and nuclear DNA, affecting either structural subunits of the enzyme or proteins involved in its biogenesis. In this review, we discuss the possible causes of the discrepancy between the spectacular advances made in the identification of the molecular bases of cytochrome oxidase deficiency and the lack of any efficient treatment in diseases resulting from such deficiencies. This brings back many unsolved questions related to the frequent delay of clinical manifestation, variable course and severity, and tissue-involvement often associated with these diseases. In this context, we stress the importance of studying different models of these diseases, but also discuss the limitations encountered in most available disease models. In the future, with the possible exception of replacement therapy using genes, cells or organs, a better understanding of underlying mechanism(s) of these mitochondrial diseases is presumably required to develop efficient therapy.
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Affiliation(s)
- Malgorzata Rak
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1141, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France Faculté de Médecine Denis Diderot, Université Paris Diderot-Paris 7, Site Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France
| | - Paule Bénit
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1141, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France Faculté de Médecine Denis Diderot, Université Paris Diderot-Paris 7, Site Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France
| | - Dominique Chrétien
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1141, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France Faculté de Médecine Denis Diderot, Université Paris Diderot-Paris 7, Site Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France
| | - Juliette Bouchereau
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1141, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France Faculté de Médecine Denis Diderot, Université Paris Diderot-Paris 7, Site Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France
| | - Manuel Schiff
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1141, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France Faculté de Médecine Denis Diderot, Université Paris Diderot-Paris 7, Site Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France Reference Center for Inherited Metabolic Diseases, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, 48 Boulevard Sérurier, 75019 Paris, France
| | - Riyad El-Khoury
- American University of Beirut Medical Center, Department of Pathology and Laboratory Medicine, Cairo Street, Hamra, Beirut, Lebanon
| | - Alexander Tzagoloff
- Biological Sciences Department, Columbia University, New York, NY 10027, U.S.A
| | - Pierre Rustin
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1141, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France Faculté de Médecine Denis Diderot, Université Paris Diderot-Paris 7, Site Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France
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11
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Blein-Nicolas M, Albertin W, da Silva T, Valot B, Balliau T, Masneuf-Pomarède I, Bely M, Marullo P, Sicard D, Dillmann C, de Vienne D, Zivy M. A Systems Approach to Elucidate Heterosis of Protein Abundances in Yeast. Mol Cell Proteomics 2015; 14:2056-71. [PMID: 25971257 DOI: 10.1074/mcp.m115.048058] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Indexed: 11/06/2022] Open
Abstract
Heterosis is a universal phenomenon that has major implications in evolution and is of tremendous agro-economic value. To study the molecular manifestations of heterosis and to find factors that maximize its strength, we implemented a large-scale proteomic experiment in yeast. We analyzed the inheritance of 1,396 proteins in 55 inter- and intraspecific hybrids obtained from Saccharomyces cerevisiae and S. uvarum that were grown in grape juice at two temperatures. We showed that the proportion of heterotic proteins was highly variable depending on the parental strain and on the temperature considered. For intraspecific hybrids, this proportion was higher at nonoptimal temperature. Unexpectedly, heterosis for protein abundance was strongly biased toward positive values in interspecific hybrids but not in intraspecific hybrids. Computer modeling showed that this observation could be accounted for by assuming concave relationships between protein abundances and their controlling factors, in line with the metabolic model of heterosis. These results point to nonlinear processes that could play a central role in heterosis.
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Affiliation(s)
- Mélisande Blein-Nicolas
- From the INRA, PAPPSO, UMR 0320/UMR 8120 Génétique Végétale, F-91190, Gif-sur-Yvette, France
| | - Warren Albertin
- CNRS, UMR 0320/UMR 8120, Génétique Végétale, F-91190 Gif-sur-Yvette, France; Université Bordeaux, Unité de Recherche Œnologie, EA 4577, ISVV, 210 chemin de Leysotte, 33140 Villenave d'Ornon, France
| | - Telma da Silva
- From the INRA, PAPPSO, UMR 0320/UMR 8120 Génétique Végétale, F-91190, Gif-sur-Yvette, France; Ariana Pharmaceuticals, 28 rue du Docteur Finlay, 75015 Paris, France
| | - Benoît Valot
- CNRS, Université de Franche-Comté, UMR 6249 Chrono-Environnement, F-25000, Besançon, France
| | - Thierry Balliau
- From the INRA, PAPPSO, UMR 0320/UMR 8120 Génétique Végétale, F-91190, Gif-sur-Yvette, France
| | - Isabelle Masneuf-Pomarède
- Université Bordeaux, Unité de Recherche Œnologie, EA 4577, ISVV, 210 chemin de Leysotte, 33140 Villenave d'Ornon, France; Bordeaux Sciences Agro, Gradignan, France
| | - Marina Bely
- Université Bordeaux, Unité de Recherche Œnologie, EA 4577, ISVV, 210 chemin de Leysotte, 33140 Villenave d'Ornon, France
| | - Philippe Marullo
- Université Bordeaux, Unité de Recherche Œnologie, EA 4577, ISVV, 210 chemin de Leysotte, 33140 Villenave d'Ornon, France; BIOLAFFORT, F-33034 Bordeaux, France
| | - Delphine Sicard
- Univ Paris-Sud, UMR 0320/UMR 8120 Génétique Végétale, F-91190, Gif-sur-Yvette, France; INRA, UMR1083, 2 Place Viala, F-34060 Montpellier, France
| | - Christine Dillmann
- Univ Paris-Sud, UMR 0320/UMR 8120 Génétique Végétale, F-91190, Gif-sur-Yvette, France
| | - Dominique de Vienne
- Univ Paris-Sud, UMR 0320/UMR 8120 Génétique Végétale, F-91190, Gif-sur-Yvette, France
| | - Michel Zivy
- CNRS, PAPPSO, UMR 0320/UMR 8120 Génétique Végétale, F-91190, Gif-sur-Yvette, France
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12
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Alam MT, Manjeri GR, Rodenburg RJ, Smeitink JAM, Notebaart RA, Huynen M, Willems PHGM, Koopman WJH. Skeletal muscle mitochondria of NDUFS4-/- mice display normal maximal pyruvate oxidation and ATP production. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2015; 1847:526-33. [PMID: 25687896 DOI: 10.1016/j.bbabio.2015.02.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 02/03/2015] [Accepted: 02/07/2015] [Indexed: 10/24/2022]
Abstract
Mitochondrial ATP production is mediated by the oxidative phosphorylation (OXPHOS) system, which consists of four multi-subunit complexes (CI-CIV) and the FoF1-ATP synthase (CV). Mitochondrial disorders including Leigh Syndrome often involve CI dysfunction, the pathophysiological consequences of which still remain incompletely understood. Here we combined experimental and computational strategies to gain mechanistic insight into the energy metabolism of isolated skeletal muscle mitochondria from 5-week-old wild-type (WT) and CI-deficient NDUFS4-/- (KO) mice. Enzyme activity measurements in KO mitochondria revealed a reduction of 79% in maximal CI activity (Vmax), which was paralleled by 45-72% increase in Vmax of CII, CIII, CIV and citrate synthase. Mathematical modeling of mitochondrial metabolism predicted that these Vmax changes do not affect the maximal rates of pyruvate (PYR) oxidation and ATP production in KO mitochondria. This prediction was empirically confirmed by flux measurements. In silico analysis further predicted that CI deficiency altered the concentration of intermediate metabolites, modestly increased mitochondrial NADH/NAD+ ratio and stimulated the lower half of the TCA cycle, including CII. Several of the predicted changes were previously observed in experimental models of CI-deficiency. Interestingly, model predictions further suggested that CI deficiency only has major metabolic consequences when its activity decreases below 90% of normal levels, compatible with a biochemical threshold effect. Taken together, our results suggest that mouse skeletal muscle mitochondria possess a substantial CI overcapacity, which minimizes the effects of CI dysfunction on mitochondrial metabolism in this otherwise early fatal mouse model.
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Affiliation(s)
- Mohammad T Alam
- Department of Biochemistry, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
| | - Ganesh R Manjeri
- Department of Biochemistry, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
| | - Richard J Rodenburg
- Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Pediatrics, NCMD, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Jan A M Smeitink
- Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Pediatrics, NCMD, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Richard A Notebaart
- Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Centre for Molecular and Biomolecular Informatics, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Martijn Huynen
- Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Centre for Molecular and Biomolecular Informatics, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Peter H G M Willems
- Department of Biochemistry, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
| | - Werner J H Koopman
- Department of Biochemistry, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; Centre for Systems Biology and Bioenergetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
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13
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D'Erchia AM, Atlante A, Gadaleta G, Pavesi G, Chiara M, De Virgilio C, Manzari C, Mastropasqua F, Prazzoli GM, Picardi E, Gissi C, Horner D, Reyes A, Sbisà E, Tullo A, Pesole G. Tissue-specific mtDNA abundance from exome data and its correlation with mitochondrial transcription, mass and respiratory activity. Mitochondrion 2014; 20:13-21. [PMID: 25446395 DOI: 10.1016/j.mito.2014.10.005] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 09/23/2014] [Accepted: 10/29/2014] [Indexed: 01/12/2023]
Abstract
Eukaryotic cells contain a population of mitochondria, variable in number and shape, which in turn contain multiple copies of a tiny compact genome (mtDNA) whose expression and function is strictly coordinated with the nuclear one. mtDNA copy number varies between different cell or tissues types, both in response to overall metabolic and bioenergetics demands and as a consequence or cause of specific pathological conditions. Here we present a novel and reliable methodology to assess the effective mtDNA copy number per diploid genome by investigating off-target reads obtained by whole-exome sequencing (WES) experiments. We also investigate whether and how mtDNA copy number correlates with mitochondrial mass, respiratory activity and expression levels. Analyzing six different tissues from three age- and sex-matched human individuals, we found a highly significant linear correlation between mtDNA copy number estimated by qPCR and the frequency of mtDNA off target WES reads. Furthermore, mtDNA copy number showed highly significant correlation with mitochondrial gene expression levels as measured by RNA-Seq as well as with mitochondrial mass and respiratory activity. Our methodology makes thus feasible, at a large scale, the investigation of mtDNA copy number in diverse cell-types, tissues and pathological conditions or in response to specific treatments.
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Affiliation(s)
- Anna Maria D'Erchia
- Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, Bari 70126, Italy
| | - Anna Atlante
- Istituto di Biomembrane e Bioenergetica, CNR, via Amendola 165/A, Bari 70126, Italy
| | - Gemma Gadaleta
- Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, Bari 70126, Italy
| | - Giulio Pavesi
- Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, Milano 20133, Italy
| | - Matteo Chiara
- Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, Milano 20133, Italy
| | - Caterina De Virgilio
- Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, Bari 70126, Italy
| | - Caterina Manzari
- Istituto di Biomembrane e Bioenergetica, CNR, via Amendola 165/A, Bari 70126, Italy
| | - Francesca Mastropasqua
- Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, Bari 70126, Italy
| | - Gian Marco Prazzoli
- Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, Milano 20133, Italy
| | - Ernesto Picardi
- Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, Bari 70126, Italy
| | - Carmela Gissi
- Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, Milano 20133, Italy
| | - David Horner
- Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, Milano 20133, Italy
| | - Aurelio Reyes
- Mitochondrial Biology Unit, Medical Research Council, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, United Kingdom
| | - Elisabetta Sbisà
- Istituto di Tecnologie Biomediche- Sede di Bari, CNR, Via Amendola 122/D, Bari 70126, Italy
| | - Apollonia Tullo
- Istituto di Tecnologie Biomediche- Sede di Bari, CNR, Via Amendola 122/D, Bari 70126, Italy
| | - Graziano Pesole
- Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, Bari 70126, Italy; Istituto di Biomembrane e Bioenergetica, CNR, via Amendola 165/A, Bari 70126, Italy.
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14
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Nuñez-Figueredo Y, Pardo-Andreu GL, Ramírez-Sánchez J, Delgado-Hernández R, Ochoa-Rodríguez E, Verdecia-Reyes Y, Naal Z, Muller AP, Portela LV, Souza DO. Antioxidant effects of JM-20 on rat brain mitochondria and synaptosomes: mitoprotection against Ca²⁺-induced mitochondrial impairment. Brain Res Bull 2014; 109:68-76. [PMID: 25305343 DOI: 10.1016/j.brainresbull.2014.10.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 09/25/2014] [Accepted: 10/01/2014] [Indexed: 12/31/2022]
Abstract
Because mitochondrial oxidative stress and impairment are important mediators of neuronal damage in neurodegenerative diseases and in brain ischemia/reperfusion, in the present study, we evaluated the antioxidant and mitoprotective effect of a new promising neuroprotective molecule, JM-20, in mitochondria and synaptosomes isolated from rat brains. JM-20 inhibited succinate-mediated H₂O₂ generation in both mitochondria and synaptosomes incubated in depolarized (high K(+)) medium at extremely low micromolar concentration and with identical IC₅₀ values of 0.91 μM. JM-20 also repressed glucose-induced H₂O₂ generation stimulated by rotenone or by antimycin A in synaptosomes incubated in high sodium-polarized medium at extremely low IC₅₀ values of 0.395 μM and 2.452 μM, respectively. JM-20 was unable to react directly with H₂O₂ or with superoxide anion radicals but displayed a cathodic reduction peak at -0.71V, which is close to that of oxygen (-0.8V), indicating high electron affinity. JM-20 also inhibited uncoupled respiration in mitochondria or synaptosomes and was a more effective inhibitor in the presence of the respiratory substrates glutamate/malate than in the presence of succinate. JM-20 also prevented Ca(2+)-induced mitochondrial permeability transition pore opening, membrane potential dissipation and cytochrome c release, which are key pathogenic events during stroke. This molecule also prevented Ca(2+) influx into synaptosomes and mitochondria; the former effect was a consequence of the latter because JM-20 inhibition followed the patterns of carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP), which is a classic mitochondrial uncoupler. Because the mitochondrion is considered an important source and target of neuronal cell death signaling after an ischemic insult, the antioxidant and protective effects of JM-20 against the deleterious effects of Ca(2+) observed at the mitochondrial level in this study may endow this molecule with the ability to succeed in mitochondrion-targeted strategies to combat ischemic brain damage.
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Affiliation(s)
- Yanier Nuñez-Figueredo
- Centro de Investigación y Desarrollo de Medicamentos, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600, La Habana, Cuba
| | - Gilberto L Pardo-Andreu
- Centro de Estudio para las Investigaciones y Evaluaciones Biológicas, Instituto de Farmacia y Alimentos, Universidad de La Habana, Ave 23, No. 21425 e/214 y 222, La Coronela, La Lisa, CP 13600, La Habana, Cuba.
| | - Jeney Ramírez-Sánchez
- Centro de Investigación y Desarrollo de Medicamentos, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600, La Habana, Cuba
| | - René Delgado-Hernández
- Centro de Investigación y Desarrollo de Medicamentos, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600, La Habana, Cuba
| | - Estael Ochoa-Rodríguez
- Laboratorio de Síntesis Orgánica de La Facultad de Química de La Universidad de La Habana, Zapata s/n entre G y Carlitos Aguirre, Vedado Plaza de la Revolución, CP 10400, La Habana, Cuba
| | - Yamila Verdecia-Reyes
- Laboratorio de Síntesis Orgánica de La Facultad de Química de La Universidad de La Habana, Zapata s/n entre G y Carlitos Aguirre, Vedado Plaza de la Revolución, CP 10400, La Habana, Cuba
| | - Zeki Naal
- Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ave. Café s/n, 14040-903 Ribeirão Preto, SP, Brazil
| | - Alexandre Pastoris Muller
- Departamento de Bioquímica, PPG em Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 anexo, Porto Alegre 90035-003, RS, Brazil
| | - Luis Valmor Portela
- Departamento de Bioquímica, PPG em Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 anexo, Porto Alegre 90035-003, RS, Brazil
| | - Diogo O Souza
- Departamento de Bioquímica, PPG em Bioquímica, PPG em Educação em Ciência, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 anexo, Porto Alegre 90035-003, RS, Brazil
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15
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Noninvasive diagnostics of mitochondrial disorders in isolated lymphocytes with high resolution respirometry. BBA CLINICAL 2014; 2:62-71. [PMID: 26675066 PMCID: PMC4633944 DOI: 10.1016/j.bbacli.2014.09.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/19/2014] [Accepted: 09/19/2014] [Indexed: 12/17/2022]
Abstract
Background Mitochondrial diseases belong to the most severe inherited metabolic disorders affecting pediatric population. Despite detailed knowledge of mtDNA mutations and progress in identification of affected nuclear genes, diagnostics of a substantial part of mitochondrial diseases relies on clinical symptoms and biochemical data from muscle biopsies and cultured fibroblasts. Methods To investigate manifestation of oxidative phosphorylation defects in isolated lymphocytes, digitonin-permeabilized cells from 48 children were analyzed by high resolution respirometry, cytofluorometric detection of mitochondrial membrane potential and immunodetection of respiratory chain proteins with SDS and Blue Native electrophoreses. Results Evaluation of individual respiratory complex activities, ATP synthesis, kinetic parameters of mitochondrial respiratory chain and the content and subunit composition of respiratory chain complexes enabled detection of inborn defects of respiratory complexes I, IV and V within 2 days. Low respiration with NADH-dependent substrates and increased respiration with glycerol-3-phosphate revealed complex I defects; changes in p50 for oxygen and elevated uncoupling control ratio pointed to complex IV deficiency due to SURF1 or SCO2 mutation; high oligomycin sensitivity of state 3-ADP respiration, upregulated mitochondrial membrane potential and low content of complex V were found in lymphocytes with ATP synthase deficiency due to TMEM70 mutations. Conclusion Based on our results, we propose the best biochemical parameters predictive for defects of respiratory complexes I, IV and V manifesting in peripheral blood lymphocytes. General significance The noninvasiveness, reliability and speed of an approach utilizing novel biochemical criteria demonstrate the high potential of isolated lymphocytes for diagnostics of oxidative phosphorylation disorders in pediatric patients.
Analysis of inborn mitochondrial disorders in peripheral blood lymphocytes Detection of specific defects of respiratory chain complexes I, IV and V Manifestation of cytochrome c oxidase deficiency due to SCO2 mutations Rapid and noninvasive diagnostics/screening appropriate for pediatric patients
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Key Words
- AA, antimycin A
- BNE, Blue Native PAGE
- COX, cytochrome c oxidase
- Diagnostics
- FCCP, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone
- GP, glycerol-3-phosphate
- GPDH, mitochondrial FAD-dependent glycerophosphate dehydrogenase
- Lymphocytes
- Mitochondrial diseases
- OXPHOS, oxidative phosphorylation
- Oxidative phosphorylation
- PAGE, polyacrylamide gel electrophoresis
- Respirometry
- TMPD, tetramethylphenylenediamine
- TMRM, tetramethylrhodamine methyl ester
- cI–cV, respiratory chain complexes I–V
- s3, state 3-ADP
- s3u, state 3-uncoupled
- s4o, state 4-oligomycin
- ΔΨm, mitochondrial membrane potential
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16
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Scandroglio F, Tórtora V, Radi R, Castro L. Metabolic control analysis of mitochondrial aconitase: influence over respiration and mitochondrial superoxide and hydrogen peroxide production. Free Radic Res 2014; 48:684-93. [PMID: 24601712 DOI: 10.3109/10715762.2014.900175] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The Fe-S cluster of mitochondrial aconitase is rapidly and selectively inactivated by oxidants, yielding an inactive enzyme that can be reactivated by reductants and iron in vivo. In order to elucidate the metabolic impact of oxidant-dependent aconitase inhibition over the citric acid cycle, the respiratory chain reactions, and reactive species formation, we performed a metabolic analysis using isolated mitochondria from different rat tissues. Titrations with fluorocitrate showed IC50 for aconitase inhibition ranging from 7 to 24 μM. The aconitase inhibition threshold in mitochondrial oxygen consumption was determined to range from 63 to 98%. Of the tissues examined, brain and heart exhibited the highest values in the flux control coefficient (> 0.95). Aconitase-specific activity varied widely among tissues examined from ~60 mU/mg in liver to 321 mU/mg in kidney at 21% O2. In brain and heart, aconitase-specific activity increased by 42 and 12%, respectively, at 2% O2 reflecting aconitase inactivation by oxygen-derived oxidants at 21% O2. Both mitochondrial membrane potential and hydrogen peroxide production significantly decreased upon aconitase inhibition in heart and brain mitochondria. These results indicate that aconitase can exert control over respiration (with tissue specificity) and support the hypothesis that inactivation of aconitase may provide a control mechanism to prevent O2(●-) and H2O2 formation by the respiratory chain.
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Affiliation(s)
- F Scandroglio
- Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República , Montevideo , Uruguay
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17
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Walker UA, Lebrecht D, Reichard W, Kirschner J, Bissé E, Iversen L, Venhoff AC, Venhoff N. Zidovudine induces visceral mitochondrial toxicity and intra-abdominal fat gain in a rodent model of lipodystrophy. Antivir Ther 2014; 19:783-92. [PMID: 24584039 DOI: 10.3851/imp2758] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND The use of zidovudine is associated with a loss of subcutaneous adipose tissue (SAT). We assessed if zidovudine treatment also affects visceral adipose tissue (VAT) and if uridine supplementation abrogates the adverse effects of zidovudine on VAT. METHODS Rats were fed zidovudine for 21 weeks with or without simultaneous uridine supplementation. Control animals did not receive zidovudine, or were treated with uridine alone. Changes in SAT and VAT were monitored by magnetic resonance imaging. Adipose tissue was examined for structural and molecular signs of mitochondrial toxicity. RESULTS Zidovudine induced lipoatrophy in SAT and fat hypertrophy in VAT. Compared with controls zidovudine-exposed VAT adipocytes had increased diameters, microvesicular steatosis and enlarged mitochondria with disrupted crystal architecture on electron microscopy. VAT adipocyte mitochondrial DNA (mtDNA) copy numbers were diminished, as were mtDNA-encoded respiratory chain proteins. The 'common' mtDNA deletion was detected in high frequencies in zidovudine treated animals, but not in the controls. Although mtDNA depletion was more profound in SAT compared with VAT, the 'common' deletion tended to be more frequent in the VAT than in the SAT. Uridine coadministration abrogated all effects of zidovudine on VAT and SAT pathology. CONCLUSIONS Zidovudine induces a gain of intra-abdominal fat in association with quantitative and qualitative alterations of the mitochondrial genome and impaired expression of mtDNA-encoded respiratory chain components, indicating that zidovudine may contribute to abdominal fat hypertrophy in HIV-infected patients. In this rodent model, uridine supplementation abrogates both SAT and VAT pathology induced by zidovudine.
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Affiliation(s)
- Ulrich A Walker
- Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany
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18
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Amadoro G, Corsetti V, Florenzano F, Atlante A, Ciotti MT, Mongiardi MP, Bussani R, Nicolin V, Nori SL, Campanella M, Calissano P. AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons. Neurobiol Dis 2013; 62:489-507. [PMID: 24411077 DOI: 10.1016/j.nbd.2013.10.018] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 09/10/2013] [Accepted: 10/16/2013] [Indexed: 12/01/2022] Open
Abstract
Functional as well as structural alterations in mitochondria size, shape and distribution are precipitating, early events in progression of Alzheimer's Disease (AD). We reported that a 20-22kDa NH2-tau fragment (aka NH2htau), mapping between 26 and 230 amino acids of the longest human tau isoform, is detected in cellular and animal AD models and is neurotoxic in hippocampal neurons. The NH2htau -but not the physiological full-length protein- interacts with Aβ at human AD synapses and cooperates with it in inhibiting the mitochondrial ANT-1-dependent ADP/ATP exchange. Here we show that the NH2htau also adversely affects the interplay between the mitochondria dynamics and their selective autophagic clearance. Fragmentation and perinuclear mislocalization of mitochondria with smaller size and density are early found in dying NH2htau-expressing neurons. The specific effect of NH2htau on quality control of mitochondria is accompanied by (i) net reduction in their mass in correlation with a general Parkin-mediated remodeling of membrane proteome; (ii) their extensive association with LC3 and LAMP1 autophagic markers; (iii) bioenergetic deficits and (iv) in vitro synaptic pathology. These results suggest that NH2htau can compromise the mitochondrial biology thereby contributing to AD synaptic deficits not only by ANT-1 inactivation but also, indirectly, by impairing the quality control mechanism of these organelles.
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Affiliation(s)
- G Amadoro
- Institute of Translational Pharmacology (IFT), CNR, Via Fosso del Cavaliere 100-00133, Rome, Italy; European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy.
| | - V Corsetti
- European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy
| | - F Florenzano
- European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy; Institute of Cellular Biology and Neurobiology (IBCN), CNR, IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano 64-65-00143, Rome, Italy
| | - A Atlante
- Insitute of Biomembrane and Bioenergetic (IBBE), CNR, Via Amendola 165/A-70126, Bari, Italy
| | - M T Ciotti
- Institute of Cellular Biology and Neurobiology (IBCN), CNR, IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano 64-65-00143, Rome, Italy
| | - M P Mongiardi
- Institute of Cellular Biology and Neurobiology (IBCN), CNR, IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano 64-65-00143, Rome, Italy
| | - R Bussani
- UCO Anatomy and Pathological Histology, Hospital of Cattinara, Strada di Fiume 447-34149, Trieste Italy
| | - V Nicolin
- University of Trieste, Clinical Department of Medical, Surgical and Health Science-section of Human Morphology, Via Manzoni 16-34138, Trieste, Italy
| | - S L Nori
- University of Salerno, Department of Pharmaceutical and Biomedical Sciences (FARMABIOMED), NANOMATES, Via Ponte don Melillo 1-85084, Fisciano (SA), Italy
| | - M Campanella
- European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy; Department of Comparative Biomedical Sciences, The Royal Veterinary College, and Consortium for Mitochondrial Research, University College London, Royal College Street, NW1 0TU, United Kingdom
| | - P Calissano
- European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy
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19
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Murakoshi Y, Sueoka K, Takahashi K, Sato S, Sakurai T, Tajima H, Yoshimura Y. Embryo developmental capability and pregnancy outcome are related to the mitochondrial DNA copy number and ooplasmic volume. J Assist Reprod Genet 2013; 30:1367-75. [PMID: 23897005 DOI: 10.1007/s10815-013-0062-6] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 07/16/2013] [Indexed: 10/26/2022] Open
Abstract
PURPOSE To investigate the correlation between the ooplasmic volume and the number of mitochondrial DNA (mtDNA) copies in embryos and how they may affect fecundity. METHOD Using real-time PCR, mtDNA quantification was analyzed in unfertilized oocytes and uncleaved embryos. The size of the ovum was also assessed by calculating the ooplasmic volume at the time of granulosa cell removal for IVF or ICSI. Quantification analysis of the mtDNA in blastomeres was performed by real-time PCR at the 7-8 cell stage of the cleaved embryos at 72 h after oocyte retrieval. We calculated the cytoplasmic volume of the blastomeres. RESULT Our studies showed a significantly lower mtDNA copy number in unfertilized oocytes and uncleaved embryos in women who were older than 40 years of age (p < 0.05). The larger ooplasmic volume was also associated with earlier and more rapid cleavage (p < 0.05). The ooplasmic volume was also significantly larger in the group achieving pregnancy. We found a significant positive correlation between blastomere volume and the number of mtDNA copies (r = 0.76, p < 0.01, from Pearson product-moment correlation coefficient). CONCLUSIONS We have shown that blastomere volume is directly proportional to the number of mtDNA copies. Therefore, larger cytoplasmic volume, with earlier cleavage speed, implies more mtDNA copies. Evaluation of mtDNA quantification and the measurement of ooplasmic and blastomere volume may be useful for selection of high quality embryo and pregnancy outcome.
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Affiliation(s)
- Yukitaka Murakoshi
- Department of Obstetrics and Gynecology, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan,
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Jose C, Melser S, Benard G, Rossignol R. Mitoplasticity: adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis. Antioxid Redox Signal 2013; 18:808-49. [PMID: 22989324 DOI: 10.1089/ars.2011.4357] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Adaptation and transformation biology of the mitochondrion to redox status is an emerging domain of physiology and pathophysiology. Mitochondrial adaptations occur in response to accidental changes in cellular energy demand or supply while mitochondrial transformations are a part of greater program of cell metamorphosis. The possible role of mitochondrial adaptations and transformations in pathogenesis remains unexplored, and it has become critical to decipher the stimuli and the underlying molecular pathways. Immediate activation of mitochondrial function was described during acute exercise, respiratory chain injury, Endoplasmic Reticulum stress, genotoxic stress, or environmental toxic insults. Delayed adaptations of mitochondrial form, composition, and functions were evidenced for persistent changes in redox status as observed in endurance training, in fibroblasts grown in presence of respiratory chain inhibitors or in absence of glucose, in the smooth muscle of patients with severe asthma, or in the skeletal muscle of patients with a mitochondrial disease. Besides, mitochondrial transformations were observed in the course of human cell differentiation, during immune response activation, or in cells undergoing carcinogenesis. Little is known on the signals and downstream pathways that govern mitochondrial adaptations and transformations. Few adaptative loops, including redox sensors, kinases, and transcription factors were deciphered, but their implication in physiology and pathology remains elusive. Mitoplasticity could play a protective role against aging, diabetes, cancer, or neurodegenerative diseases. Research on adaptation and transformation could allow the design of innovative therapies, notably in cancer.
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Affiliation(s)
- Caroline Jose
- University Bordeaux, Maladies Rares: Génétique et Métabolisme, France
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21
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The Chemical Interplay between Nitric Oxide and Mitochondrial Cytochrome c Oxidase: Reactions, Effectors and Pathophysiology. Int J Cell Biol 2012; 2012:571067. [PMID: 22811713 PMCID: PMC3395247 DOI: 10.1155/2012/571067] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 03/23/2012] [Indexed: 01/20/2023] Open
Abstract
Nitric oxide (NO) reacts with Complex I and cytochrome c oxidase (CcOX, Complex IV), inducing detrimental or cytoprotective effects. Two alternative reaction pathways (PWs) have been described whereby NO reacts with CcOX, producing either a relatively labile nitrite-bound derivative (CcOX-NO2
−, PW1) or a more stable nitrosyl-derivative (CcOX-NO, PW2). The two derivatives are both inhibited, displaying different persistency and O2 competitiveness. In the mitochondrion, during turnover with O2, one pathway prevails over the other one depending on NO, cytochrome c2+ and O2 concentration. High cytochrome c2+, and low O2 proved to be crucial in favoring CcOX nitrosylation, whereas under-standard cell-culture conditions formation of the nitrite derivative prevails. All together, these findings suggest that NO can modulate physiologically the mitochondrial respiratory/OXPHOS efficiency, eventually being converted to nitrite by CcOX, without cell detrimental effects. It is worthy to point out that nitrite, far from being a simple oxidation byproduct, represents a source of NO particularly important in view of the NO cell homeostasis, the NO production depends on the NO synthases whose activity is controlled by different stimuli/effectors; relevant to its bioavailability, NO is also produced by recycling cell/body nitrite. Bioenergetic parameters, such as mitochondrial ΔΨ, lactate, and ATP production, have been assayed in several cell lines, in the presence of endogenous or exogenous NO and the evidence collected suggests a crucial interplay between CcOX and NO with important energetic implications.
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Chistiakov DA, Sobenin IA, Bobryshev YV, Orekhov AN. Mitochondrial dysfunction and mitochondrial DNA mutations in atherosclerotic complications in diabetes. World J Cardiol 2012; 4:148-56. [PMID: 22655163 PMCID: PMC3364501 DOI: 10.4330/wjc.v4.i5.148] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 04/30/2012] [Accepted: 05/07/2012] [Indexed: 02/06/2023] Open
Abstract
Mitochondrial DNA (mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system. This explains an increased mutation rate of mtDNA that results in heteroplasmy, e.g., the coexistence of the mutant and wild-type mtDNA molecules within the same mitochondrion. In diabetes mellitus, glycotoxicity, advanced oxidative stress, collagen cross-linking, and accumulation of lipid peroxides in foam macrophage cells and arterial wall cells may significantly decrease the mutation threshold required for mitochondrial dysfunction, which in turn further contributes to the oxidative damage of the diabetic vascular wall, endothelial dysfunction, and atherosclerosis.
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Affiliation(s)
- Dimitry A Chistiakov
- Dimitry A Chistiakov, Igor A Sobenin, Department of Medical Nanobiotechnology, Pirogov Russian State Medical University, 117997 Moscow, Russia
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Strategies for reducing or preventing the generation of oxidative stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2011; 2011:194586. [PMID: 22191011 PMCID: PMC3236599 DOI: 10.1155/2011/194586] [Citation(s) in RCA: 143] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/20/2011] [Revised: 10/20/2011] [Accepted: 10/21/2011] [Indexed: 12/14/2022]
Abstract
The reduction of oxidative stress could be achieved in three levels: by lowering exposure to environmental pollutants with oxidizing properties, by increasing levels of endogenous and exogenous antioxidants, or by lowering the generation of oxidative stress by stabilizing mitochondrial energy production and efficiency. Endogenous oxidative stress could be influenced in two ways: by prevention of ROS formation or by quenching of ROS with antioxidants. However, the results of epidemiological studies where people were treated with synthetic antioxidants are inconclusive and contradictory. Recent evidence suggests that antioxidant supplements (although highly recommended by the pharmaceutical industry and taken by many individuals) do not offer sufficient protection against oxidative stress, oxidative damage or increase the lifespan. The key to the future success of decreasing oxidative-stress-induced damage should thus be the suppression of oxidative damage without disrupting the wellintegrated antioxidant defense network. Approach to neutralize free radicals with antioxidants should be changed into prevention of free radical formation. Thus, this paper addresses oxidative stress and strategies to reduce it with the focus on nutritional and psychosocial interventions of oxidative stress prevention, that is, methods to stabilize mitochondria structure and energy efficiency, or approaches which would increase endogenous antioxidative protection and repair systems.
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Metabolic and molecular action of Trigonella foenum-graecum (fenugreek) and trace metals in experimental diabetic tissues. J Biosci 2011; 36:383-96. [PMID: 21654091 DOI: 10.1007/s12038-011-9042-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycaemia resulting in defective insulin secretion, resistance to insulin action or both. The use of biguanides, sulphonylurea and other drugs are valuable in the treatment of diabetes mellitus; their use, however, is restricted by their limited action, pharmacokinetic properties, secondary failure rates and side effects. Trigonella foenum-graecum, commonly known as fenugreek, is a plant that has been extensively used as a source of antidiabetic compounds from its seeds and leaf extracts. Preliminary human trials and animal experiments suggest possible hypoglycaemic and antihyperlipedemic properties of fenugreek seed powder taken orally. Our results show that the action of fenugreek in lowering blood glucose levels is almost comparable to the effect of insulin. Combination with trace metal showed that vanadium had additive effects and manganese had additive effects with insulin on in vitro system in control and diabetic animals of young and old ages using adipose tissue. The Trigonella and vanadium effects were studied in a number of tissues including liver, kidney, brain peripheral nerve, heart, red blood cells and skeletal muscle. Addition of Trigonella to vanadium significantly removed the toxicity of vanadium when used to reduce blood glucose levels. Administration of the various combinations of the antidiabetic compounds to diabetic animals was found to reverse most of the diabetic effects studied at physiological, biochemical, histochemical and molecular levels. Results of the key enzymes of metabolic pathways have been summarized together with glucose transporter, Glut-4 and insulin levels. Our findings illustrate and elucidate the antidiabetic/insulin mimetic effects of Trigonella, manganese and vanadium.
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Kilbride SM, Gluchowska SA, Telford JE, O'Sullivan C, Davey GP. High-level inhibition of mitochondrial complexes III and IV is required to increase glutamate release from the nerve terminal. Mol Neurodegener 2011; 6:53. [PMID: 21791084 PMCID: PMC3169489 DOI: 10.1186/1750-1326-6-53] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Accepted: 07/26/2011] [Indexed: 11/10/2022] Open
Abstract
Background The activities of mitochondrial complex III (ubiquinol-cytochrome c reductase, EC 1.10.2.2) and complex IV (cytochrome c oxidase EC 1.9.3.1) are reduced by 30-70% in Huntington's disease and Alzheimer's disease, respectively, and are associated with excitotoxic cell death in these disorders. In this study, we investigated the control that complexes III and complex IV exert on glutamate release from the isolated nerve terminal. Results Inhibition of complex III activity by 60-90% was necessary for a major increase in the rate of Ca2+-independent glutamate release to occur from isolated nerve terminals (synaptosomes) depolarized with 4-aminopyridine or KCl. Similarly, an 85-90% inhibition of complex IV activity was required before a major increase in the rate of Ca2+-independent glutamate release from depolarized synaptosomes was observed. Inhibition of complex III and IV activities by ~ 60% and above was required before rates of glutamate efflux from polarized synaptosomes were increased. Conclusions These results suggest that nerve terminal mitochondria possess high reserves of complex III and IV activity and that high inhibition thresholds must be reached before excess glutamate is released from the nerve terminal. The implications of the results in the context of the relationship between electron transport chain enzyme deficiencies and excitotoxicity in neurodegenerative disorders are discussed.
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Affiliation(s)
- Seán M Kilbride
- School of Biochemistry and Immunology & Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
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Lustgarten MS, Jang YC, Liu Y, Qi W, Qin Y, Dahia PL, Shi Y, Bhattacharya A, Muller FL, Shimizu T, Shirasawa T, Richardson A, Van Remmen H. MnSOD deficiency results in elevated oxidative stress and decreased mitochondrial function but does not lead to muscle atrophy during aging. Aging Cell 2011; 10:493-505. [PMID: 21385310 DOI: 10.1111/j.1474-9726.2011.00695.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
In a previous study, we reported that a deficiency in MnSOD activity (approximately 80% reduction) targeted to type IIB skeletal muscle fibers was sufficient to elevate oxidative stress and to reduce muscle function in young adult mice (TnIFastCreSod2(fl/fl) mice). In this study, we used TnIFastCreSod2(fl/fl) mice to examine the effect of elevated oxidative stress on mitochondrial function and to test the hypothesis that elevated oxidative stress and decreased mitochondrial function over the lifespan of the TnIFastCreSod2(fl/fl) mice would be sufficient to accelerate muscle atrophy associated with aging. We found that mitochondrial function is reduced in both young and old TnIFastCreSod2(fl/fl) mice, when compared with control mice. Complex II activity is reduced by 47% in young and by approximately 90% in old TnIFastCreSod2(fl/fl) mice, and was found to be associated with reduced levels of the catalytic subunits for complex II, SDHA and SDHB. Complex II-linked mitochondrial respiration is reduced by approximately 70% in young TnIFastCreSod2(fl/fl) mice. Complex II-linked mitochondrial Adenosine-Tri-Phosphate (ATP) production is reduced by 39% in young and was found to be almost completely absent in old TnIFastCreSod2(fl/fl) mice. Furthermore, in old TnIFastCreSod2(fl/fl) mice, aconitase activity is almost completely abolished; mitochondrial superoxide release remains > 2-fold elevated; and oxidative damage (measured as F(2) - isoprostanes) is increased by 30% relative to age-matched controls. These data show that despite elevated skeletal muscle-specific mitochondrial oxidative stress, oxidative damage, and complex II-linked mitochondrial dysfunction, age-related muscle atrophy was not accelerated in old TnIFastCreSod2(fl/fl) mice, suggesting mitochondrial oxidative stress may not be causal for age-related muscle atrophy.
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Affiliation(s)
- Michael S Lustgarten
- Department of Physiology, University of Texas Health Science Center at San Antonio, USA
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The power of life--cytochrome c oxidase takes center stage in metabolic control, cell signalling and survival. Mitochondrion 2011; 12:46-56. [PMID: 21640202 DOI: 10.1016/j.mito.2011.05.003] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2010] [Revised: 04/04/2011] [Accepted: 05/18/2011] [Indexed: 11/21/2022]
Abstract
Mitochondrial dysfunction is increasingly recognized as a major factor in the etiology and progression of numerous human diseases, such as (neuro-)degeneration, ischemia reperfusion injury, cancer, and diabetes. Cytochrome c oxidase (COX) represents the rate-limiting enzyme of the mitochondrial respiratory chain and is thus predestined for being a central site of regulation of oxidative phosphorylation, proton pumping efficiency, ATP and reactive oxygen species production, which in turn affect cell signaling and survival. A unique feature of COX is its regulation by various factors and mechanisms interacting with the nucleus-encoded subunits, whose actual functions we are only beginning to understand.
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Bour S, Carmona MC, Galinier A, Caspar-Bauguil S, Van Gaal L, Staels B, Pénicaud L, Casteilla L. Coenzyme Q as an antiadipogenic factor. Antioxid Redox Signal 2011; 14:403-13. [PMID: 21091355 DOI: 10.1089/ars.2010.3350] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Coenzyme Q (CoQ) is not only the single antioxidant synthesized in humans but also an obligatory element of mitochondrial functions. We have previously reported CoQ deficiency in white adipose tissue of ob/ob mice. We sought to determine (i) whether this deficit exists in all species and its relevance in human obesity and (ii) to what extent CoQ could be involved in adipocyte differentiation. Here we identified in rodents as well as in humans a specific very strong nonlinear negative correlation between CoQ content in subcutaneous adipose tissue and obesity indexes. This striking correlation reveals a threshold value similar in both species. This relative deficit in CoQ content in adipose tissue rapidly took place during the time course of high-fat-diet-induced obesity in mice. Adipocyte differentiation was assessed in vitro using the preadipocyte 3T3-F442A cell line. When CoQ synthesis was inhibited by a pharmacological approach using chlorobenzoic acid, this strongly triggered adipose differentiation. In contrast, adipogenesis was strongly inhibited when a long-term increase in CoQ content was obtained by overexpressing human 4-hydroxy benzoate acid polyprenyltransferase gene. Altogether, these data suggest that a strict level of CoQ remains essential for adipocyte differentiation, and its impairment is associated with obesity.
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Affiliation(s)
- Sandy Bour
- UMR 5241 Métabolisme, Plasticité et Mitochondrie, Université de Toulouse, UPS, Toulouse, France
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29
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Virtual mitochondrion: towards an integrated model of oxidative phosphorylation complexes and beyond. Biochem Soc Trans 2011; 38:1215-9. [PMID: 20863287 DOI: 10.1042/bst0381215] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The modelling of OXPHOS (oxidative phosphorylation) in order to integrate all kinetic and thermodynamic aspects of chemiosmotic theory has a long history. We briefly review this history and show how new ways of modelling are required to integrate a local model of the individual respiratory complexes into a global model of OXPHOS and, beyond that, into a reliable overall model of central metabolism.
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30
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McGee KC, Shahmanesh M, Boothby M, Nightingale P, Gathercole LL, Tripathi G, Harte AL, Shojaee-Moradie F, Umpleby AM, Das S, Al-Daghri NM, McTernan PG, Tomlinson JW. Evidence for a shift to anaerobic metabolism in adipose tissue in efavirenz-containing regimens for HIV with different nucleoside backbones. Antivir Ther 2011; 17:495-507. [DOI: 10.3851/imp2017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/27/2011] [Indexed: 10/14/2022]
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31
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Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes. Neurochem Res 2010; 35:1880-915. [DOI: 10.1007/s11064-010-0307-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2010] [Indexed: 02/07/2023]
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32
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Fernández-Vizarra E, Enríquez JA, Pérez-Martos A, Montoya J, Fernández-Silva P. Tissue-specific differences in mitochondrial activity and biogenesis. Mitochondrion 2010; 11:207-13. [PMID: 20933104 DOI: 10.1016/j.mito.2010.09.011] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Revised: 08/03/2010] [Accepted: 09/28/2010] [Indexed: 10/19/2022]
Abstract
Each cell type develops and maintains a specific oxidative phosphorylation (OXPHOS) capacity to satisfy its metabolic and energetic demands. This implies that there are differences between tissues in mitochondrial number, function, protein composition and morphology. The OXPHOS system biogenesis requires the coordinated expression of both mitochondrial and nuclear genomes. Mitochondrial DNA (mtDNA) expression can be regulated at different levels (replication, transcription, translation and post-translational levels) to contribute to the final observed OXPHOS activities. By analyzing five mammalian tissues, we evaluated the differences in the cellular amount of mtDNA and its correlation with the final observed mitochondrial activity.
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Affiliation(s)
- Erika Fernández-Vizarra
- Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Pedro Cerbuna, 12. 50009 Zaragoza, Spain
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Sutinen J, Laaksonen MS, Walker UA, Setzer B, Kemppainen J, Nuutila P, Yki-Jarvinen H. Skeletal muscle mitochondrial DNA content and aerobic metabolism in patients with antiretroviral therapy-associated lipoatrophy. J Antimicrob Chemother 2010; 65:1497-504. [DOI: 10.1093/jac/dkq138] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Rateitschak K, Wolkenhauer O. Thresholds in transient dynamics of signal transduction pathways. J Theor Biol 2010; 264:334-46. [PMID: 20144619 DOI: 10.1016/j.jtbi.2010.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2009] [Revised: 02/01/2010] [Accepted: 02/02/2010] [Indexed: 10/19/2022]
Abstract
Transient dynamics of signal transduction pathways play an important role in many biological processes, including cell differentiation, apoptosis, metabolism and DNA damage response. Recent examples of quantitative methods to characterize transient signals include transient metabolic control coefficients and finite time Lyapunov exponents. In our work we compare these quantitative methods to characterize transient phenomena and specifically discuss their predictive power for three examples. We focus on the identification of thresholds that separate different transient dynamic behaviors. Our investigation leads to the following results: The spectrum of the finite-time Lyapunov exponents unambiguously and reliably identifies putative thresholds in transient dynamics. Metabolic control coefficients do not reliably detect all thresholds and suffer from false positives.
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Affiliation(s)
- Katja Rateitschak
- Systems Biology and Bioinformatics Group, University of Rostock, 18051 Rostock, Germany.
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35
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Dalmonte ME, Forte E, Genova ML, Giuffrè A, Sarti P, Lenaz G. Control of respiration by cytochrome c oxidase in intact cells: role of the membrane potential. J Biol Chem 2009; 284:32331-5. [PMID: 19776013 DOI: 10.1074/jbc.m109.050146] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Metabolic control analysis was applied to intact HepG2 cells. The effect on the control coefficient of cytochrome c oxidase (CcOX) over cell respiration of both the electrical (Delta psi) and chemical (Delta pH) component of the mitochondrial transmembrane proton electrochemical gradient (Delta mu(H(+))) was investigated. The overall O(2) consumption and specific CcOX activity of actively phosphorylating cells were titrated with cyanide under conditions in which Delta psi and Delta pH were selectively modulated by addition of ionophores. In the absence of ionophores, CcOX displayed a high control coefficient (C(IV) = 0.73), thus representing an important site of regulation of mitochondrial oxidative phosphorylation. A high control coefficient value (C(IV) = 0.85) was also measured in the presence of nigericin, i.e. when Delta psi is maximal, and in the presence of nigericin and valinomycin (C(IV) = 0.77), when Delta mu(H(+)) is abolished. In contrast, CcOX displayed a markedly lower control coefficient (C(IV) = 0.30) upon addition of valinomycin, when Delta psi is converted into Delta pH. These results show that Delta psi is responsible for the tight control of CcOX over respiration in actively phosphorylating cells.
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36
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Mallajosyula JK, Chinta SJ, Rajagopalan S, Nicholls DG, Andersen JK. Metabolic control analysis in a cellular model of elevated MAO-B: relevance to Parkinson's disease. Neurotox Res 2009; 16:186-93. [PMID: 19526285 PMCID: PMC2727365 DOI: 10.1007/s12640-009-9032-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Revised: 01/06/2009] [Accepted: 02/06/2009] [Indexed: 11/30/2022]
Abstract
We previously demonstrated that spare respiratory capacity of the TCA cycle enzyme alpha-ketoglutarate dehydrogenase (KGDH) was completely abolished upon increasing levels of MAO-B activity in a dopaminergic cell model system (Kumar et al., J Biol Chem 278:46432–46439, 2003). MAO-B mediated increases in H2O2 also appeared to result in direct oxidative inhibition of both mitochondrial complex I and aconitase. In order to elucidate the contribution that each of these components exerts over metabolic respiratory control as well as the impact of MAO-B elevation on their spare respiratory capacities, we performed metabolic respiratory control analysis. In addition to KGDH, we assessed the activities and substrate-mediated respiration of complex I, pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and mitochondrial aconitase in the absence and presence of complex-specific inhibitors in specific and mixed substrate conditions in mitochondria from our MAO-B elevated cells versus controls. Data from this study indicates that Complex I and KGDH are the most sensitive to inhibition by MAO-B mediated H2O2 generation, and could be instrumental in determining the fate of mitochondrial metabolism in this cellular PD model system.
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37
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Schnackenberg LK. Global metabolic profiling and its role in systems biology to advance personalized medicine in the 21st century. Expert Rev Mol Diagn 2009; 7:247-59. [PMID: 17489732 DOI: 10.1586/14737159.7.3.247] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Systems biology attempts to elucidate the complex interaction between genes, proteins and metabolites to provide a mechanistic understanding of cellular function and how this function is affected by disease processes, drug toxicity or drug efficacy effects. Global metabolic profiling is an important component of systems biology that can be applied in both preclinical and clinical settings for drug discovery and development, and to study disease mechanisms. The metabolic profile encodes the phenotype, which is composed of the genotype and environmental factors. The phenotypic profile can be used to make decisions about the best course of treatment for an individual patient. Understanding the combined effects of genetics and environment through a systems biology framework will enable the advancement of personalized medicine.
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Affiliation(s)
- Laura K Schnackenberg
- National Center for Toxicological Research, Division of Systems Toxicology, US Food & Drug Administration, Jefferson, AR 72079-9502, USA.
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38
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Carter CS, Hofer T, Seo AY, Leeuwenburgh C. Molecular mechanisms of life- and health-span extension: role of calorie restriction and exercise intervention. Appl Physiol Nutr Metab 2008; 32:954-66. [PMID: 18059622 DOI: 10.1139/h07-085] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The aging process results in a gradual and progressive structural deterioration of biomolecular and cellular compartments and is associated with many pathological conditions, including cardiovascular disease, stroke, Alzheimer's disease, osteoporosis, sarcopenia, and liver dysfunction. Concomitantly, each of these conditions is associated with progressive functional decline, loss of independence, and ultimately disability. Because disabled individuals require care in outpatient or home care settings, and in light of the social, emotional, and fiscal burden associated with caring for an ever-increasing elderly population, research in geriatric medicine has recently focused on the biological mechanisms that are involved in the progression towards functional decline and disability to better design treatment and intervention strategies. Although not completely understood, the mechanisms underlying the aging process may partly involve inflammatory processes, oxidative damage, mitochondrial dysfunction, and apoptotic tissue degeneration. These hypotheses are based on epidemiological evidence and data from animal models of aging, as well as interventional studies. Findings from these studies have identified possible strategies to decrease the incidence of age-related diseases and delay the aging process. For example, lifelong exercise is known to extend mean life-span, whereas calorie restriction (CR) increases both mean and maximum life-span in a variety of species. Optimal application of these intervention strategies in the elderly may positively affect health-related outcomes and possibly longevity. Therefore, the scope of this article is to (i) provide an interpretation of various theories of aging from a "health-span" perspective; (ii) describe interventional testing in animals (CR and exercise); and (iii) provide a translational interpretation of these data.
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Affiliation(s)
- Christy S Carter
- Department of Aging and Geriatric Research, Division of Biology of Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
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Papa S. Does cAMP play a part in the regulation of the mitochondrial electron transport chain in mammalian cells? IUBMB Life 2007; 58:173-5. [PMID: 16766385 DOI: 10.1080/15216540500494516] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Sergio Papa
- University of Bari, Institute of Biomembrane and Bioenergetics, Italian Research Council (CNR), Bari, Italy.
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40
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Hornberg JJ, Bruggeman FJ, Bakker BM, Westerhoff HV. Metabolic control analysis to identify optimal drug targets. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2007; 64:171, 173-89. [PMID: 17195475 DOI: 10.1007/978-3-7643-7567-6_7] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
This chapter describes the basic principles of Metabolic Control Analysis (MCA) which is a quantitative methodology to evaluate the importance and relative contribution of individual metabolic steps in the overall functioning of a particular system. The control on the flux through a metabolic pathway or subsystem can be quantified by the control coefficients of the individual enzymes or components which reflects the extent to which the component is rate-limiting. The perturbation of an individual step is measured by its elasticity coefficient. The effect of perturbation of a single step on the entire pathway or subsystem is, in turn, measured by the response coefficient. Differential control analysis can be used to compare flux through a single metabolic pathway in a pathogen with the same pathway in its host to identify uniquely vulnerable steps with the greatest potential for specifically inhibiting flux through the pathogen metabolic pathway. The utility of this methodology is illustrated with the glycolysis in Trypanosomes and with oncogenic signaling.
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Affiliation(s)
- Jorrit J Hornberg
- Department of Molecular Cell Physiology, Institute for Molecular Cell Biology, Faculty of Earth and Life Sciences, Vrije Universiteit, Amsterdam, The Netherlands.
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Valla J, Schneider L, Niedzielko T, Coon KD, Caselli R, Sabbagh MN, Ahern GL, Baxter L, Alexander G, Walker DG, Reiman EM. Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment. Mitochondrion 2006; 6:323-30. [PMID: 17123871 PMCID: PMC1864936 DOI: 10.1016/j.mito.2006.10.004] [Citation(s) in RCA: 126] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2006] [Accepted: 10/20/2006] [Indexed: 11/28/2022]
Abstract
Mitochondrial abnormalities are found in Alzheimer's disease (AD), but previous reports have not examined at-risk groups. In subjects with AD, mild cognitive impairment (MCI), and non-demented aged controls, platelet and lymphocyte mitochondria were isolated and analyzed for Complexes I, III, and IV of the electron transport chain. Western blots were used to control for differential enrichment of samples. Results demonstrated significant declines in Complexes III and IV in AD, and a significant decline in Complex IV in MCI. This report confirms mitochondrial deficiencies in AD, extends them to MCI, and suggests they are present at the earliest symptomatic stages of disease.
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Affiliation(s)
- Jon Valla
- Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Arizona Alzheimer's Disease Consortium, 350 W. Thomas Road, Phoenix, AZ 85013, USA.
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Abstract
Brain cells are highly energy dependent for maintaining ion homeostasis during high metabolic activity. During active periods, full mitochondrial function is essential to generate ATP from electrons that originate with the oxidation of NADH. Decreasing brain metabolism is a significant cause of cognitive abnormalities of Alzheimer disease (AD), but it remains uncertain whether this is the cause of further pathology or whether synaptic loss results in a lower energy demand. Synapses are the first to show pathological symptoms in AD before the onset of clinical symptoms. Because synaptic function has high energy demands, interruption in mitochondrial energy supply could be the major factor in synaptic failure in AD. A newly discovered age-related decline in neuronal NADH and redox ratio may jeopardize this function. Mitochondrial dehydrogenases and several mutations affecting energy transfer are frequently altered in aging and AD. Thus, with the accumulation of genetic defects in mitochondria at the level of energy transfer, the issue of neuronal susceptibility to damage as a function of age and age-related disease becomes important. In an aging rat neuron model, mitochondria are both chronically depolarized and produce more reactive oxygen species with age. These concepts suggest that multiple treatment targets may be needed to reverse this multifactorial disease. This review summarizes new insights based on the interaction of mitoenergetic failure, glutamate excitotoxicity, and amyloid toxicity in the exacerbation of AD.
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Affiliation(s)
- Mordhwaj S Parihar
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794-9626, USA
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43
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Piccoli C, Scrima R, Boffoli D, Capitanio N. Control by cytochrome c oxidase of the cellular oxidative phosphorylation system depends on the mitochondrial energy state. Biochem J 2006; 396:573-83. [PMID: 16533168 PMCID: PMC1482809 DOI: 10.1042/bj20060077] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2006] [Revised: 03/08/2006] [Accepted: 03/13/2006] [Indexed: 02/08/2023]
Abstract
Recent measurements of the flux control exerted by cytochrome c oxidase on the respiratory activity in intact cells have led to a re-appraisal of its regulatory function. We have further extended this in vivo study in the framework of the Metabolic Control Analysis and evaluated the impact of the mitochondrial transmembrane electrochemical potential (Deltamu(H+)) on the control strength of the oxidase. The results indicate that, under conditions mimicking the mitochondrial State 4 of respiration, both the flux control coefficient and the threshold value of cytochrome oxidase are modified with respect to the uncoupled condition. The results obtained are consistent with a model based on changes in the assembly state of the oxidative phosphorylation enzyme complexes and possible implications in the understanding of exercise-intolerance of human neuromuscular degenerative diseases are discussed.
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Key Words
- cytochrome c oxidase
- metabolic flux control
- mitochondrial transmembrane electrochemical potential
- oxidative phosphorylation
- respirasome
- cccp, carbonyl cyanide m-chlorophenylhydrazone
- cox, cytochrome c oxidase
- dmem, dulbecco's modified eagle's medium
- dnp, 2,4-dinitrophenol
- m(f)ca, metabolic (flux) control analysis
- mtdna, mitochondrial dna
- oxphos, oxidative phosphorylation
- tmpd, n,n,n′,n′-tetramethyl-p-phenylenediamine
- δph, transmembrane ph gradient
- δμh+, mitochondrial transmembrane electrochemical potential
- δψ, transmembrane electrical potential
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Affiliation(s)
- Claudia Piccoli
- Department of Biomedical Science, University of Foggia, 71100 Foggia, Italy
| | - Rosella Scrima
- Department of Biomedical Science, University of Foggia, 71100 Foggia, Italy
| | - Domenico Boffoli
- Department of Biomedical Science, University of Foggia, 71100 Foggia, Italy
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44
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Calabrese V, Butterfield DA, Scapagnini G, Stella AMG, Maines MD. Redox regulation of heat shock protein expression by signaling involving nitric oxide and carbon monoxide: relevance to brain aging, neurodegenerative disorders, and longevity. Antioxid Redox Signal 2006; 8:444-77. [PMID: 16677090 DOI: 10.1089/ars.2006.8.444] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Increased free radical generation and decreased efficiency of the reparative/degradative mechanisms both primarily contribute to age-related elevation in the level of oxidative stress and brain damage. Excess formation of reactive oxygen and nitrogen species can cause proteasomal dysfunction and protein overloading. The major neurodegenerative diseases are all associated with the presence of abnormal proteins. Different integrated responses exist in the brain to detect oxidative stress which is controlled by several genes termed vitagenes, including the heat shock protein (HSP) system. Of the various HSPs, heme oxygenase-I (HO-1), by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. The HO-1 gene is redox regulated and its expression is modulated by redox active compounds, including nutritional antioxidants. Given the broad cytoprotective properties of the heat shock response, there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. These findings have opened up new neuroprotective strategies, as molecules inducing this defense mechanism can be a therapeutic target to minimize the deleterious consequences associated with accumulation of conformationally aberrant proteins to oxidative stress, such as in neurodegenerative disorders and brain aging, with resulting prolongation of a healthy life span.
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Affiliation(s)
- Vittorio Calabrese
- Section of Biochemistry and Molecular Biology, Department of Chemistry, Faculty of Medicine, University of Catania, Catania, Italy
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45
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Calabrese V, Lodi R, Tonon C, D'Agata V, Sapienza M, Scapagnini G, Mangiameli A, Pennisi G, Stella AMG, Butterfield DA. Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia. J Neurol Sci 2005; 233:145-62. [PMID: 15896810 DOI: 10.1016/j.jns.2005.03.012] [Citation(s) in RCA: 284] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.
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Affiliation(s)
- Vittorio Calabrese
- Section of Biochemistry and Molecular Biology, Department of Chemistry, Faculty of Medicine, University of Catania, Catania, Viale Andrea Doria 6, 95100 Catania, Italy.
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Chee FC, Mudher A, Cuttle MF, Newman TA, MacKay D, Lovestone S, Shepherd D. Over-expression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Neurobiol Dis 2005; 20:918-28. [PMID: 16023860 DOI: 10.1016/j.nbd.2005.05.029] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2005] [Revised: 05/08/2005] [Accepted: 05/25/2005] [Indexed: 11/22/2022] Open
Abstract
We have shown that over-expression of human tau (0N3R) in Drosophila larval motor neurons causes significant morphological and functional disruption to the neuromuscular junctions (NMJs). Tau-expressing NMJs are reduced in size with irregular and abnormal bouton structure. Immunocytochemical analysis shows that the abnormal NMJs still retain synaptotagmin expression and form active zones. Functionally, the NMJs exhibit abnormal endo/exocytosis as revealed by incorporation of the styryl dye FM1-43. Electrophysiological studies showed that with low frequency stimulation (1 Hz), evoked synaptic potentials produced from tau over-expressing motor neurons were indistinguishable from wild type, however, following high frequency stimulation (50 Hz), evoked synaptic potentials were significantly decreased. Analysis of the number and distribution of mitochondria showed that motor neurons over-expressing tau had a significant reduction in functional mitochondria in the presynaptic terminal. Collapsing the mitochondrial membrane potential in wild type larvae phenocopied the effects of tau over-expression on synaptic transmission. Our results demonstrate that tau over-expression in vivo cause a synaptic dysfunction, which may be caused by a reduced complement of functional mitochondria.
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Affiliation(s)
- Francis C Chee
- School of Biological Sciences, University of Southampton, Bassett Crescent East Southampton, SO16 7PX, UK.
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47
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Bouhours-Nouet N, May-Panloup P, Coutant R, de Casson FB, Descamps P, Douay O, Reynier P, Ritz P, Malthièry Y, Simard G. Maternal smoking is associated with mitochondrial DNA depletion and respiratory chain complex III deficiency in placenta. Am J Physiol Endocrinol Metab 2005; 288:E171-7. [PMID: 15585597 DOI: 10.1152/ajpendo.00260.2003] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Maternal smoking during pregnancy is often associated with a decrease in placental function, which might lead to intrauterine growth retardation. Because tobacco is known to alter the mitochondrial respiratory function in cardiomyocytes and lung tissue, we hypothesized that placental mitochondrial function could be altered by maternal smoking. Placental mitochondria from 9 smoking and 19 nonsmoking mothers were isolated by differential centrifugation. Mitochondrial oxygen consumption was measured by polarography, and the enzymatic activity of each complex of the electron transport chain was assessed by spectrophotometry. In addition, the relative content in mitochondrial DNA (mtDNA) was determined by real-time quantitative PCR in placentas from seven smoking and seven nonsmoking mothers. We observed a 29% reduction in the enzymatic activity of complex III in the placental mitochondria from smokers compared with nonsmokers (P = 0.03). The relative content of mtDNA (with respect to the beta-globin gene) was reduced by 37% in the placental tissue from smokers compared with nonsmokers (P < 0.02). Both the enzymatic activity of complex III and mtDNA content were inversely related with the daily consumption of cigarettes, and mtDNA content was correlated with cord blood insulin-like growth factor-binding protein-3 (r = 0.74, P < 0.01), a marker of fetal growth. These results show that maternal smoking is associated with placental mitochondrial dysfunction, which might contribute to restricted fetal growth by limiting energy availability in cells.
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Affiliation(s)
- Natacha Bouhours-Nouet
- Institut National de la Santé et de la Recherche Médicale EMI-U 00-18, Laboratory of Biochemistry and Molecular Biology, University Hospital of ANgers, Angers, France
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48
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Kannisto K, Sutinen J, Korsheninnikova E, Fisher RM, Ehrenborg E, Gertow K, Virkamäki A, Nyman T, Vidal H, Hamsten A, Yki-Järvinen H. Expression of adipogenic transcription factors, peroxisome proliferator-activated receptor gamma co-activator 1, IL-6 and CD45 in subcutaneous adipose tissue in lipodystrophy associated with highly active antiretroviral therapy. AIDS 2003; 17:1753-62. [PMID: 12891061 DOI: 10.1097/00002030-200308150-00004] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To determine the expressions of multiple genes in the subcutaneous adipose tissue of HIV-positive, highly active antiretroviral therapy (HAART)-treated patients with and without lipodystrophy. DESIGN AND METHODS Real-time polymerase chain reaction was used to measure gene expressions in this cross-sectional study. RESULTS The messenger RNA concentrations of adipose transcription factors (peroxisome proliferator-activated receptor (PPAR) gamma and delta and sterol regulatory element binding protein 1c) were all significantly lower in the lipodystrophic than the non-lipodystrophic group. The mRNA concentration of PPAR-gamma co-activator 1 (PGC-1), which regulates mitochondrial biogenesis, was lower in the lipodystrophic than the non-lipodystrophic group. The mRNA expression of lipoprotein lipase, acyl coenzyme A synthase and glucose transport protein 4 were significantly lower in the lipodystrophic than the non-lipodystrophic group, but the mRNA concentrations of fatty acid transport and binding proteins were similar in both groups. The mRNA concentrations of IL-6 and CD45 (a common leukocyte marker) were significantly higher in the lipodystrophic than the non-lipodystrophic group. CONCLUSION Multiple alterations characterize gene expression in the subcutaneous adipose tissue of patients with HAART-associated lipodystrophy compared with HIV-positive, HAART-treated patients without lipodystrophy. The low expression of transcription factors inhibits adipocyte differentiation. The low expression of PGC-1 may contribute to mitochondrial defects. In addition, IL-6 and CD45 expressions are increased, the latter implying an excessive number of cells of leukocyte origin in lipodystrophic adipose tissue. Mitochondrial injury and an excess of proinflammatory cytokines may lead to increased apoptosis. All these changes may contribute to the loss of subcutaneous fat in HAART-associated lipodystrophy.
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Affiliation(s)
- Katja Kannisto
- Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institutet, Stockholm, Sweden
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Korzeniewski B. Effect of enzyme deficiencies on oxidative phosphorylation: from isolated mitochondria to intact tissues. Theoretical studies. Mol Biol Rep 2003; 29:197-202. [PMID: 12241057 DOI: 10.1023/a:1020329913588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The present article briefly summarizes the theoretical studies made by the authors and co-workers on the effect of inborn enzyme deficiencies on oxidative phosphorylation in intact tissues and on the genesis of mitochondrial diseases. The dynamic computer model of oxidative phosphorylation developed previously allowed to extrapolate experimental data (especially: threshold curves describing the dependence of oxygen consumption and ATP turnover on activities/concentrations of particular oxidative phosphorylation enzymes) obtained for isolated muscle mitochondria in state 3 at saturating oxygen concentrations to more physiological conditions prevailing in intact tissues. In particular, theoretical studies demonstrated that the threshold value of the relative activity/concentration of a given mitochondrial complex, below which a significant decrease in the respiration rate takes place, increases with an increase in energy demand. This fact was proposed as a possible explanation of the tissue specificity of mitochondrial diseases. Additionally, a decreased oxygen concentration was shown to increase the threshold value (and flux control coefficient) for cytochrome oxidase. We subsequently developed a model called 'binary mitochondria heteroplasmy', in which there are only two subpopulations of mitochondria: one 'wild-type' and one containing only defected molecules of a given enzyme. In this model we show that a defect has a pronounced effect on oxidative phosphorylation, significantly increasing the threshold value. It was also proposed that a parallel activation in the ATP supply-demand system during an increased energy demand significantly lessens the effect of enzyme deficiencies on oxidative phosphorylation (decreases the threshold value). Finally, the necessity of substrate activation may lead to an instability in the system and to appearance of a second threshold, below which respiration suddenly drops to zero, which is equivalent to the energetic death of a cell.
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Affiliation(s)
- Bernard Korzeniewski
- Institute of Molecular Biology and Biotechnology, Jagiellonian University, Kraków, Poland.
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50
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Venkatraman A, Shiva S, Davis AJ, Bailey SM, Brookes PS, Darley-Usmar VM. Chronic alcohol consumption increases the sensitivity of rat liver mitochondrial respiration to inhibition by nitric oxide. Hepatology 2003; 38:141-7. [PMID: 12829996 DOI: 10.1053/jhep.2003.50293] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Chronic alcohol consumption is a well-known risk factor for hepatic injury, and mitochondrial damage plays a significant role in this process. Nitric oxide (NO) is an important modulator of mitochondrial function and is known to inhibit mitochondrial respiration. However, the impact of chronic alcohol consumption on NO-dependent control of liver mitochondrial function is unknown. This study examines the effect of alcohol exposure on liver mitochondria in a rat model and explores the interaction of NO and mitochondrial respiration in this context. Mitochondria were isolated from the liver of both control and ethanol-fed rats after 5 to 6 weeks of alcohol consumption. Mitochondria isolated from ethanol-treated rats showed a significant decrease in state 3 respiration and respiratory control ratio that was accompanied by an increased sensitivity to NO-dependent inhibition of respiration. In conclusion, we show that chronic alcohol consumption leads to increased sensitivity to the inhibition of respiration by NO. We propose that this results in a greater vulnerability to hypoxia and the development of alcohol-induced hepatotoxicity.
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Affiliation(s)
- Aparna Venkatraman
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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