Journal of Clinical Medicine

Editorial

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3 pages, 172 KiB

Open AccessEditorial

Biochemical Assessment and Monitoring of Mitochondrial Disease

by Iain P. Hargreaves

J. Clin. Med. 2018, 7(4), 66; https://doi.org/10.3390/jcm7040066 - 29 Mar 2018

Cited by 6 | Viewed by 3967

Abstract

Mitochondrial respiratory chain (MRC) disorders have a multifaceted clinical presentation and genetic origin[...] Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

Research

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6 pages, 530 KiB

Open AccessArticle

Blood Mononuclear Cell Mitochondrial Respiratory Chain Complex IV Activity is Decreased in Multiple Sclerosis Patients: Effects of β-Interferon Treatment

by Iain Hargreaves, Nimesh Mody, John Land and Simon Heales

J. Clin. Med. 2018, 7(2), 36; https://doi.org/10.3390/jcm7020036 - 20 Feb 2018

Cited by 22 | Viewed by 4148

Abstract

Objectives: Evidence of mitochondrial respiratory chain (MRC) dysfunction and oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS). However, at present, there is no reliable low invasive surrogate available to evaluate mitochondrial function in these patients. In view of the [...] Read more.

Objectives: Evidence of mitochondrial respiratory chain (MRC) dysfunction and oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS). However, at present, there is no reliable low invasive surrogate available to evaluate mitochondrial function in these patients. In view of the particular sensitivity of MRC complex IV to oxidative stress, the aim of this study was to assess blood mononuclear cell (BMNC) MRC complex IV activity in MS patients and compare these results to age matched controls and MS patients on β-interferon treatment. Methods: Spectrophotometric enzyme assay was employed to measure MRC complex IV activity in blood mononuclear cell obtained multiple sclerosis patients and aged matched controls. Results: MRC Complex IV activity was found to be significantly decreased (p < 0.05) in MS patients (2.1 ± 0.8 k/nmol × 10⁻³; mean ± SD] when compared to the controls (7.2 ± 2.3 k/nmol × 10⁻³). Complex IV activity in MS patients on β-interferon (4.9 ± 1.5 k/nmol × 10⁻³) was not found to be significantly different from that of the controls. Conclusions: This study has indicated evidence of peripheral MRC complex IV deficiency in MS patients and has highlighted the potential utility of BMNCs as a potential means to evaluate mitochondrial function in this disorder. Furthermore, the reported improvement of complex IV activity may provide novel insights into the mode(s) of action of β-interferon. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessFeature PaperArticle

Measurement of Respiratory Chain Enzyme Activity in Human Renal Biopsy Specimens

by Arun Ghose, Christopher M. Taylor, Alexander J. Howie, Anapurna Chalasani, Iain Hargreaves and David V. Milford

J. Clin. Med. 2017, 6(9), 90; https://doi.org/10.3390/jcm6090090 - 19 Sep 2017

Cited by 3 | Viewed by 4625

Abstract

Background: Mitochondrial disorders can present as kidney disease in children and be difficult to diagnose. Measurement of mitochondrial function in kidney tissue may help diagnosis. This study was to assess the feasibility of obtaining renal samples and analysing them for respiratory chain [...] Read more.

Background: Mitochondrial disorders can present as kidney disease in children and be difficult to diagnose. Measurement of mitochondrial function in kidney tissue may help diagnosis. This study was to assess the feasibility of obtaining renal samples and analysing them for respiratory chain enzyme activity. Methods: The subjects were children undergoing a routine diagnostic renal biopsy, in whom a clinical condition of renal inflammation, scarring and primary metabolic disorder was unlikely. A fresh sample of kidney was snap frozen and later assayed for the activities of respiratory chain enzyme complexes I, II/III, and IV using spectrophotometric enzyme assay, and expressed as a ratio of citrate synthase activity. Results: The range of respiratory chain enzyme activity for complex I was 0.161 to 0.866 (mean 0.404, SD 0.2), for complex II/III was 0.021 to 0.318 (mean 0.177, SD 0.095) and for complex IV was 0.001 to 0.025 (mean 0.015, SD 0.006). There were correlations between the different activities but not between them and the age of the children or a measure of the amount of chronic damage in the kidneys. Conclusion: It is feasible to measure respiratory chain enzyme activity in routine renal biopsy specimens. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessFeature PaperArticle

Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice

by Alireza Morovat, Gayani Weerasinghe, Victoria Nesbitt, Monika Hofer, Thomas Agnew, Geralrine Quaghebeur, Kate Sergeant, Carl Fratter, Nishan Guha, Mehdi Mirzazadeh and Joanna Poulton

J. Clin. Med. 2017, 6(8), 80; https://doi.org/10.3390/jcm6080080 - 21 Aug 2017

Cited by 59 | Viewed by 7107

Abstract

Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other [...] Read more.

Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other laboratory findings. Patients’ FGF-21 results were assessed by the use of age-adjusted z-scores based on normalised FGF-21 values from a healthy population. One hundred and fifty five patients were investigated. One hundred and four of these patients had molecular evidence for MD, 27 were deemed to have disorders other than MD (non-MD), and 24 had possible MD. Patients with defects in mitochondrial DNA (mtDNA) maintenance (n = 32) and mtDNA rearrangements (n = 17) had the highest median FGF-21 among the MD group. Other MD patients harbouring mtDNA point mutations (n = 40) or mutations in other autosomal genes (n = 7) and those with partially characterised MD had lower FGF-21 levels. The area under the receiver operating characteristic curve for distinguishing MD from non-MD patients was 0.69. No correlation between FGF-21 and creatinine, creatine kinase, or cardio-skeletal myopathy score was found. FGF-21 was significantly associated with plasma lactate and ocular myopathy. Although FGF-21 was found to have a low sensitivity for detecting MD, at a z-score of 2.8, its specificity was above 90%. We suggest that a high serum concentration of FGF-21 would be clinically useful in MD, especially in adult patients with chronic progressive external ophthalmoplegia, and may enable bypassing muscle biopsy and directly opting for genetic analysis. Availability of its assay has thus modified our diagnostic pathway. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessArticle

An Effective, Versatile, and Inexpensive Device for Oxygen Uptake Measurement

by Paule Bénit, Dominique Chrétien, Mathieu Porceddu, Constantin Yanicostas, Malgorzata Rak and Pierre Rustin

J. Clin. Med. 2017, 6(6), 58; https://doi.org/10.3390/jcm6060058 - 8 Jun 2017

Cited by 8 | Viewed by 6665

Abstract

In the last ten years, the use of fluorescent probes developed to measure oxygen has resulted in several marketed devices, some unreasonably expensive and with little flexibility. We have explored the use of the effective, versatile, and inexpensive Redflash technology to determine oxygen [...] Read more.

In the last ten years, the use of fluorescent probes developed to measure oxygen has resulted in several marketed devices, some unreasonably expensive and with little flexibility. We have explored the use of the effective, versatile, and inexpensive Redflash technology to determine oxygen uptake by a number of different biological samples using various layouts. This technology relies on the use of an optic fiber equipped at its tip with a membrane coated with a fluorescent dye (www.pyro-science.com). This oxygen-sensitive dye uses red light excitation and lifetime detection in the near infrared. So far, the use of this technology has mostly been used to determine oxygen concentration in open spaces for environmental studies, especially in aquatic media. The oxygen uptake determined by the device can be easily assessed in small volumes of respiration medium and combined with the measurement of additional parameters, such as lactate excretion by intact cells or the membrane potential of purified mitochondria. We conclude that the performance of by this technology should make it a first choice in the context of both fundamental studies and investigations for respiratory chain deficiencies in human samples. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessArticle

The Relationship between Mitochondrial Respiratory Chain Activities in Muscle and Metabolites in Plasma and Urine: A Retrospective Study

by Corinne Alban, Elena Fatale, Abed Joulani, Polina Ilin and Ann Saada

J. Clin. Med. 2017, 6(3), 31; https://doi.org/10.3390/jcm6030031 - 10 Mar 2017

Cited by 13 | Viewed by 5470

Abstract

The relationship between 114 cases with decreased enzymatic activities of mitochondrial respiratory chain (MRC) complexes I-V (C I-V) in muscle and metabolites in urine and plasma was retrospectively examined. Less than 35% disclosed abnormal plasma amino acids and acylcarnitines, with elevated alanine and [...] Read more.

The relationship between 114 cases with decreased enzymatic activities of mitochondrial respiratory chain (MRC) complexes I-V (C I-V) in muscle and metabolites in urine and plasma was retrospectively examined. Less than 35% disclosed abnormal plasma amino acids and acylcarnitines, with elevated alanine and low free carnitine or elevated C4-OH-carnitine as the most common findings, respectively. Abnormal urine organic acids (OA) were detected in 82% of all cases. In CI and CII defects, lactic acid (LA) in combination with other metabolites was the most common finding. 3-Methylglutaconic (3MGA) acid was more frequent in CIV and CV, while Tyrosine metabolites, mainly 4-hydroxyphenyllactate, were common in CI and IV defects. Ketones were present in all groups but more prominent in combined deficiencies. There was a significant strong correlation between elevated urinary LA and plasma lactate but none between urine Tyrosine metabolites and plasma Tyrosine or urinary LA and plasma Alanine. All except one of 14 cases showed elevated FGF21, but correlation with urine OA was weak. Although this study is limited, we conclude that urine organic acid test in combination with plasma FGF21 determination are valuable tools in the diagnosis of mitochondrial diseases. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessArticle

Mitochondrial Modification Techniques and Ethical Issues

by Lucía Gómez-Tatay, José M. Hernández-Andreu and Justo Aznar

J. Clin. Med. 2017, 6(3), 25; https://doi.org/10.3390/jcm6030025 - 24 Feb 2017

Cited by 39 | Viewed by 11259

Abstract

Current strategies for preventing the transmission of mitochondrial disease to offspring include techniques known as mitochondrial replacement and mitochondrial gene editing. This technology has already been applied in humans on several occasions, and the first baby with donor mitochondria has already been born. [...] Read more.

Current strategies for preventing the transmission of mitochondrial disease to offspring include techniques known as mitochondrial replacement and mitochondrial gene editing. This technology has already been applied in humans on several occasions, and the first baby with donor mitochondria has already been born. However, these techniques raise several ethical concerns, among which is the fact that they entail genetic modification of the germline, as well as presenting safety problems in relation to a possible mismatch between the nuclear and mitochondrial DNA, maternal mitochondrial DNA carryover, and the “reversion” phenomenon. In this essay, we discuss these questions, highlighting the advantages of some techniques over others from an ethical point of view, and we conclude that none of these are ready to be safely applied in humans. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessArticle

The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder

by Leanna M. Delhey, Ekim Nur Kilinc, Li Yin, John C. Slattery, Marie L. Tippett, Shannon Rose, Sirish C. Bennuri, Stephen G. Kahler, Shirish Damle, Agustin Legido, Michael J. Goldenthal and Richard E. Frye

J. Clin. Med. 2017, 6(2), 18; https://doi.org/10.3390/jcm6020018 - 13 Feb 2017

Cited by 34 | Viewed by 13514

Abstract

Treatment for mitochondrial dysfunction is typically guided by expert opinion with a paucity of empirical evidence of the effect of treatment on mitochondrial activity. We examined citrate synthase and Complex I and IV activities using a validated buccal swab method in 127 children [...] Read more.

Treatment for mitochondrial dysfunction is typically guided by expert opinion with a paucity of empirical evidence of the effect of treatment on mitochondrial activity. We examined citrate synthase and Complex I and IV activities using a validated buccal swab method in 127 children with autism spectrum disorder with and without mitochondrial disease, a portion of which were on common mitochondrial supplements. Mixed-model linear regression determined whether specific supplements altered the absolute mitochondrial activity as well as the relationship between the activities of mitochondrial components. Complex I activity was increased by fatty acid and folate supplementation, but folate only effected those with mitochondrial disease. Citrate synthase activity was increased by antioxidant supplementation but only for the mitochondrial disease subgroup. The relationship between Complex I and IV was modulated by folate while the relationship between Complex I and Citrate Synthase was modulated by both folate and B12. This study provides empirical support for common mitochondrial treatments and demonstrates that the relationship between activities of mitochondrial components might be a marker to follow in addition to absolute activities. Measurements of mitochondrial activity that can be practically repeated over time may be very useful to monitor the biochemical effects of treatments. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Review

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9 pages, 211 KiB

Open AccessFeature PaperReview

Biomarkers for Detecting Mitochondrial Disorders

by Josef Finsterer and Sinda Zarrouk-Mahjoub

J. Clin. Med. 2018, 7(2), 16; https://doi.org/10.3390/jcm7020016 - 30 Jan 2018

Cited by 31 | Viewed by 7354

Abstract

(1) Objectives: Mitochondrial disorders (MIDs) are a genetically and phenotypically heterogeneous group of slowly or rapidly progressive disorders with onset from birth to senescence. Because of their variegated clinical presentation, MIDs are difficult to diagnose and are frequently missed in their early and [...] Read more.

(1) Objectives: Mitochondrial disorders (MIDs) are a genetically and phenotypically heterogeneous group of slowly or rapidly progressive disorders with onset from birth to senescence. Because of their variegated clinical presentation, MIDs are difficult to diagnose and are frequently missed in their early and late stages. This is why there is a need to provide biomarkers, which can be easily obtained in the case of suspecting a MID to initiate the further diagnostic work-up. (2) Methods: Literature review. (3) Results: Biomarkers for diagnostic purposes are used to confirm a suspected diagnosis and to facilitate and speed up the diagnostic work-up. For diagnosing MIDs, a number of dry and wet biomarkers have been proposed. Dry biomarkers for MIDs include the history and clinical neurological exam and structural and functional imaging studies of the brain, muscle, or myocardium by ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), MR-spectroscopy (MRS), positron emission tomography (PET), or functional MRI. Wet biomarkers from blood, urine, saliva, or cerebrospinal fluid (CSF) for diagnosing MIDs include lactate, creatine-kinase, pyruvate, organic acids, amino acids, carnitines, oxidative stress markers, and circulating cytokines. The role of microRNAs, cutaneous respirometry, biopsy, exercise tests, and small molecule reporters as possible biomarkers is unsolved. (4) Conclusions: The disadvantages of most putative biomarkers for MIDs are that they hardly meet the criteria for being acceptable as a biomarker (missing longitudinal studies, not validated, not easily feasible, not cheap, not ubiquitously available) and that not all MIDs manifest in the brain, muscle, or myocardium. There is currently a lack of validated biomarkers for diagnosing MIDs. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessFeature PaperReview

Oxidative Stress: Mechanistic Insights into Inherited Mitochondrial Disorders and Parkinson’s Disease

by Mesfer Al Shahrani, Simon Heales, Iain Hargreaves and Michael Orford

J. Clin. Med. 2017, 6(11), 100; https://doi.org/10.3390/jcm6110100 - 27 Oct 2017

Cited by 57 | Viewed by 10115

Abstract

Oxidative stress arises when cellular antioxidant defences become overwhelmed by a surplus generation of reactive oxygen species (ROS). Once this occurs, many cellular biomolecules such as DNA, lipids, and proteins become susceptible to free radical-induced oxidative damage, and this may consequently lead to [...] Read more.

Oxidative stress arises when cellular antioxidant defences become overwhelmed by a surplus generation of reactive oxygen species (ROS). Once this occurs, many cellular biomolecules such as DNA, lipids, and proteins become susceptible to free radical-induced oxidative damage, and this may consequently lead to cellular and ultimately tissue and organ dysfunction. Mitochondria, as well as being a source of ROS, are vulnerable to oxidative stress-induced damage with a number of key biomolecules being the target of oxidative damage by free radicals, including membrane phospholipids, respiratory chain complexes, proteins, and mitochondrial DNA (mt DNA). As a result, a deficit in cellular energy status may occur along with increased electron leakage and partial reduction of oxygen. This in turn may lead to a further increase in ROS production. Oxidative damage to certain mitochondrial biomolecules has been associated with, and implicated in the pathophysiology of a number of diseases. It is the purpose of this review to discuss the impact of such oxidative stress and subsequent damage by reviewing our current knowledge of the pathophysiology of several inherited mitochondrial disorders together with our understanding of perturbations observed in the more commonly acquired neurodegenerative disorders such as Parkinson’s disease (PD). Furthermore, the potential use and feasibility of antioxidant therapies as an adjunct to lower the accumulation of damaging oxidative species and hence slow disease progression will also be discussed. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessFeature PaperReview

Statins, Muscle Disease and Mitochondria

by Radha Ramachandran and Anthony S. Wierzbicki

J. Clin. Med. 2017, 6(8), 75; https://doi.org/10.3390/jcm6080075 - 25 Jul 2017

Cited by 71 | Viewed by 8049

Abstract

Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030. Numerous studies have explored the relationship between cholesterol and CVD and there is now consensus that dyslipidaemia is a causal [...] Read more.

Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030. Numerous studies have explored the relationship between cholesterol and CVD and there is now consensus that dyslipidaemia is a causal factor in the pathogenesis of atherosclerosis. Statins have become the cornerstone of the management of dyslipidaemia. Statins have proved to have a very good safety profile. The risk of adverse events is small compared to the benefits. Nevertheless, the potential risk of an adverse event occurring must be considered when prescribing and monitoring statin therapy to individual patients. Statin-associated muscle disease (SAMS) is by far the most studied and the most common reason for discontinuation of therapy. The reported incidence varies greatly, ranging between 5% and 29%. Milder disease is common and the more serious form, rhabdomyolysis is far rarer with an incidence of approximately 1 in 10,000. The pathophysiology of, and mechanisms leading to SAMS, are yet to be fully understood. Literature points towards statin-induced mitochondrial dysfunction as the most likely cause of SAMS. However, the exact processes leading to mitochondrial dysfunction are not yet fully understood. This paper details some of the different aetiological hypotheses put forward, focussing particularly on those related to mitochondrial dysfunction. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessFeature PaperReview

Evidence of Oxidative Stress and Secondary Mitochondrial Dysfunction in Metabolic and Non-Metabolic Disorders

by Karolina M. Stepien, Robert Heaton, Scott Rankin, Alex Murphy, James Bentley, Darren Sexton and Iain P. Hargreaves

J. Clin. Med. 2017, 6(7), 71; https://doi.org/10.3390/jcm6070071 - 19 Jul 2017

Cited by 101 | Viewed by 12763

Abstract

Mitochondrial dysfunction and oxidative stress have been implicated in the pathogenesis of a number of diseases and conditions. Oxidative stress occurs once the antioxidant defenses of the body become overwhelmed and are no longer able to detoxify reactive oxygen species (ROS). The ROS [...] Read more.

Mitochondrial dysfunction and oxidative stress have been implicated in the pathogenesis of a number of diseases and conditions. Oxidative stress occurs once the antioxidant defenses of the body become overwhelmed and are no longer able to detoxify reactive oxygen species (ROS). The ROS can then go unchallenged and are able to cause oxidative damage to cellular lipids, DNA and proteins, which will eventually result in cellular and organ dysfunction. Although not always the primary cause of disease, mitochondrial dysfunction as a secondary consequence disease of pathophysiology can result in increased ROS generation together with an impairment in cellular energy status. Mitochondrial dysfunction may result from either free radical-induced oxidative damage or direct impairment by the toxic metabolites which accumulate in certain metabolic diseases. In view of the importance of cellular antioxidant status, a number of therapeutic strategies have been employed in disorders associated with oxidative stress with a view to neutralising the ROS and reactive nitrogen species implicated in disease pathophysiology. Although successful in some cases, these adjunct therapies have yet to be incorporated into the clinical management of patients. The purpose of this review is to highlight the emerging evidence of oxidative stress, secondary mitochondrial dysfunction and antioxidant treatment efficacy in metabolic and non-metabolic diseases in which there is a current interest in these parameters. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessFeature PaperReview

Myopathology of Adult and Paediatric Mitochondrial Diseases

by Rahul Phadke

J. Clin. Med. 2017, 6(7), 64; https://doi.org/10.3390/jcm6070064 - 4 Jul 2017

Cited by 32 | Viewed by 8360

Abstract

Mitochondria are dynamic organelles ubiquitously present in nucleated eukaryotic cells, subserving multiple metabolic functions, including cellular ATP generation by oxidative phosphorylation (OXPHOS). The OXPHOS machinery comprises five transmembrane respiratory chain enzyme complexes (RC). Defective OXPHOS gives rise to mitochondrial diseases (mtD). The incredible [...] Read more.

Mitochondria are dynamic organelles ubiquitously present in nucleated eukaryotic cells, subserving multiple metabolic functions, including cellular ATP generation by oxidative phosphorylation (OXPHOS). The OXPHOS machinery comprises five transmembrane respiratory chain enzyme complexes (RC). Defective OXPHOS gives rise to mitochondrial diseases (mtD). The incredible phenotypic and genetic diversity of mtD can be attributed at least in part to the RC dual genetic control (nuclear DNA (nDNA) and mitochondrial DNA (mtDNA)) and the complex interaction between the two genomes. Despite the increasing use of next-generation-sequencing (NGS) and various omics platforms in unravelling novel mtD genes and pathomechanisms, current clinical practice for investigating mtD essentially involves a multipronged approach including clinical assessment, metabolic screening, imaging, pathological, biochemical and functional testing to guide molecular genetic analysis. This review addresses the broad muscle pathology landscape including genotype–phenotype correlations in adult and paediatric mtD, the role of immunodiagnostics in understanding some of the pathomechanisms underpinning the canonical features of mtD, and recent diagnostic advances in the field. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessFeature PaperReview

Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders

by Eleni Paleologou, Naila Ismayilova and Maria Kinali

J. Clin. Med. 2017, 6(6), 56; https://doi.org/10.3390/jcm6060056 - 26 May 2017

Cited by 30 | Viewed by 10673

Abstract

Mitochondrial disorders are a clinically heterogeneous group of disorders that are caused by defects in the respiratory chain, the metabolic pathway of the adenosine tri-phosphate (ATP) production system. Epilepsy is a common and important feature of these disorders and its management can be [...] Read more.

Mitochondrial disorders are a clinically heterogeneous group of disorders that are caused by defects in the respiratory chain, the metabolic pathway of the adenosine tri-phosphate (ATP) production system. Epilepsy is a common and important feature of these disorders and its management can be challenging. Epileptic seizures in the context of mitochondrial disease are usually treated with conventional anti-epileptic medication, apart from valproic acid. However, in accordance with the treatment of intractable epilepsy where there are limited treatment options, the ketogenic diet (KD) has been considered as an alternative therapy. The use of the KD and its more palatable formulations has shown promising results. It is especially indicated and effective in the treatment of mitochondrial disorders due to complex I deficiency. Further research into the mechanism of action and the neuroprotective properties of the KD will allow more targeted therapeutic strategies and thus optimize the treatment of both epilepsy in the context of mitochondrial disorders but also in other neurodegenerative disorders. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessFeature PaperReview

Riboflavin Responsive Mitochondrial Dysfunction in Neurodegenerative Diseases

by Tamilarasan Udhayabanu, Andreea Manole, Mohan Rajeshwari, Perumal Varalakshmi, Henry Houlden and Balasubramaniem Ashokkumar

J. Clin. Med. 2017, 6(5), 52; https://doi.org/10.3390/jcm6050052 - 5 May 2017

Cited by 84 | Viewed by 16294

Abstract

Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on [...] Read more.

Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on biologically active flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN), which are derived from the dietary component riboflavin, a water soluble vitamin. Riboflavin regulates the structure and function of flavoenzymes through its cofactors FMN and FAD and, thus, protects the cells from oxidative stress and apoptosis. Hence, it is not surprising that any disturbance in riboflavin metabolism and absorption of this vitamin may have consequences on cellular FAD and FMN levels, resulting in mitochondrial dysfunction by reduced energy levels, leading to riboflavin associated disorders, like cataracts, neurodegenerative and cardiovascular diseases, etc. Furthermore, mutations in either nuclear or mitochondrial DNA encoding for flavoenzymes and flavin transporters significantly contribute to the development of various neurological disorders. Moreover, recent studies have evidenced that riboflavin supplementation remarkably improved the clinical symptoms, as well as the biochemical abnormalities, in patients with neuronopathies, like Brown-Vialetto-Van-Laere syndrome (BVVLS) and Fazio-Londe disease. This review presents an updated outlook on the cellular and molecular mechanisms of neurodegenerative disorders in which riboflavin deficiency leads to dysfunction in mitochondrial energy metabolism, and also highlights the significance of riboflavin supplementation in aforementioned disease conditions. Thus, the outcome of this critical assessment may exemplify a new avenue to enhance the understanding of possible mechanisms in the progression of neurodegenerative diseases and may provide new rational approaches of disease surveillance and treatment. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessReview

Glutathione as a Redox Biomarker in Mitochondrial Disease—Implications for Therapy

by Gregory M. Enns and Tina M. Cowan

J. Clin. Med. 2017, 6(5), 50; https://doi.org/10.3390/jcm6050050 - 3 May 2017

Cited by 67 | Viewed by 9300

Abstract

Technical advances in the ability to measure mitochondrial dysfunction are providing new insights into mitochondrial disease pathogenesis, along with new tools to objectively evaluate the clinical status of mitochondrial disease patients. Glutathione (l-ϒ-glutamyl-l-cysteinylglycine) is the most abundant intracellular thiol, [...] Read more.

Technical advances in the ability to measure mitochondrial dysfunction are providing new insights into mitochondrial disease pathogenesis, along with new tools to objectively evaluate the clinical status of mitochondrial disease patients. Glutathione (l-ϒ-glutamyl-l-cysteinylglycine) is the most abundant intracellular thiol, and the intracellular redox state, as reflected by levels of oxidized (GSSG) and reduced (GSH) glutathione, as well as the GSH/GSSG ratio, is considered to be an important indication of cellular health. The ability to quantify mitochondrial dysfunction in an affected patient will not only help with routine care, but also improve rational clinical trial design aimed at developing new therapies. Indeed, because multiple disorders have been associated with either primary or secondary deficiency of the mitochondrial electron transport chain and redox imbalance, developing mitochondrial therapies that have the potential to improve the intracellular glutathione status has been a focus of several clinical trials over the past few years. This review will also discuss potential therapies to increase intracellular glutathione with a focus on EPI-743 (α-tocotrienol quinone), a compound that appears to have the ability to modulate the activity of oxidoreductases, in particular NAD(P)H:quinone oxidoreductase 1. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessFeature PaperReview

The Value of Coenzyme Q₁₀ Determination in Mitochondrial Patients

by Delia Yubero, George Allen, Rafael Artuch and Raquel Montero

J. Clin. Med. 2017, 6(4), 37; https://doi.org/10.3390/jcm6040037 - 24 Mar 2017

Cited by 23 | Viewed by 5575

Abstract

Coenzyme Q₁₀ (CoQ) is a lipid that is ubiquitously synthesized in tissues and has a key role in mitochondrial oxidative phosphorylation. Its biochemical determination provides insight into the CoQ status of tissues and may detect CoQ deficiency that can result from either [...] Read more.

Coenzyme Q₁₀ (CoQ) is a lipid that is ubiquitously synthesized in tissues and has a key role in mitochondrial oxidative phosphorylation. Its biochemical determination provides insight into the CoQ status of tissues and may detect CoQ deficiency that can result from either an inherited primary deficiency of CoQ metabolism or may be secondary to different genetic and environmental conditions. Rapid identification of CoQ deficiency can also allow potentially beneficial treatment to be initiated as early as possible. CoQ may be measured in different specimens, including plasma, blood mononuclear cells, platelets, urine, muscle, and cultured skin fibroblasts. Blood and urinary CoQ also have good utility for CoQ treatment monitoring. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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Open AccessReview

Biochemical Assessment of Coenzyme Q₁₀ Deficiency

by Juan Carlos Rodríguez-Aguilera, Ana Belén Cortés, Daniel J. M. Fernández-Ayala and Plácido Navas

J. Clin. Med. 2017, 6(3), 27; https://doi.org/10.3390/jcm6030027 - 5 Mar 2017

Cited by 41 | Viewed by 8488

Abstract

Coenzyme Q₁₀ (CoQ₁₀) deficiency syndrome includes clinically heterogeneous mitochondrial diseases that show a variety of severe and debilitating symptoms. A multiprotein complex encoded by nuclear genes carries out CoQ₁₀ biosynthesis. Mutations in any of these genes are responsible for [...] Read more.

Coenzyme Q₁₀ (CoQ₁₀) deficiency syndrome includes clinically heterogeneous mitochondrial diseases that show a variety of severe and debilitating symptoms. A multiprotein complex encoded by nuclear genes carries out CoQ₁₀ biosynthesis. Mutations in any of these genes are responsible for the primary CoQ₁₀ deficiency, but there are also different conditions that induce secondary CoQ₁₀ deficiency including mitochondrial DNA (mtDNA) depletion and mutations in genes involved in the fatty acid β-oxidation pathway. The diagnosis of CoQ₁₀ deficiencies is determined by the decrease of its content in skeletal muscle and/or dermal skin fibroblasts. Dietary CoQ₁₀ supplementation is the only available treatment for these deficiencies that require a rapid and distinct diagnosis. Here we review methods for determining CoQ₁₀ content by HPLC separation and identification using alternative approaches including electrochemical detection and mass spectrometry. Also, we review procedures to determine the CoQ₁₀ biosynthesis rate using labeled precursors. Full article

(This article belongs to the Special Issue Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease)

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