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Mitochondrial dysfunction is prevalent in the aging gastrointestinal tract. We investigated whether mitochondrial function in aging colonic crypts and exercise influences microbial gut communities in mice. Twelve PolgAmut/mut mice were randomly divided into a sedentary and exercise group at 4 months. Seven-aged matched PolgA+/+ mice remained sedentary throughout. Stool samples were collected at 4, 7, and 11 months, and bacterial profiling was achieved through 16S rRNA sequencing profiling. Mitochondrial enzyme activity was assessed in colonic epithelial crypts at 11 months for PolgAmut/mut and PolgA+/+ mice. Sedentary and exercised PolgAmut/mut mice had significantly higher levels of mitochondrial dysfunction than PolgA+/+ mice (78%, 77%, and 1% of crypts, respectively). Bacterial profiles of sedentary PolgAmut/mut mice were significantly different from the sedentary PolgA+/+ mice, with increases in Lactobacillus and Mycoplasma, and decreases in Alistipes, Odoribacter, Anaeroplasma, Rikenella, Parabacteroides, and Allobaculum in the PolgAmut/mut mice. Exercise did not have any impact upon gut mitochondrial dysfunction; however, exercise did increase gut microbiota diversity and significantly increased bacterial genera Mucispirillum and Desulfovibrio. Mitochondrial dysfunction is associated with changes in the gut microbiota. Endurance exercise moderated some of these changes, establishing that environmental factors can influence gut microbiota, despite mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

The major progress made in the identification of the molecular bases of mitochondrial disease has revealed the huge diversity of their origin. Today up to 300 mutations were identified in the mitochondrial genome and about 200 nuclear genes are possibly mutated. In this review, we highlight a number of features specific to mitochondria which possibly participate in the complexity of these diseases. These features include both the complexity of mitochondrial genetics and the multiplicity of the roles ensured by the organelles in numerous aspects of cell life and death. This spectacular complexity presumably accounts for the present lack of an efficient therapy in the vast majority of cases. [ABSTRACT FROM AUTHOR]

Objective: The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease.Methods: We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7-year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke-like episode, and death.Results: Overall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke-like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83).Interpretation: Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke-like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. [ABSTRACT FROM AUTHOR]

Background: Chronic progressive external ophthalmoplegia (CPEO) is a classical mitochondrial ocular disorder characterised by bilateral progressive ptosis and ophthalmoplegia. These ocular features can develop either in isolation or in association with other prominent neurological deficits (CPEO+). Molecularly, CPEO can be classified into two distinct genetic subgroups depending on whether patients harbour single, large-scale mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions secondary to a nuclear mutation disrupting mtDNA replication or repair. The aim of this magnetic resonance imaging (MRI) study was to investigate whether the ophthalmoplegia in CPEO is primarily myopathic in origin or whether there is evidence of contributory supranuclear pathway dysfunction. Methods: Ten age-matched normal controls and twenty patients with CPEO were recruited nine patients with single, large-scale mtDNA deletions and eleven patients with multiple mtDNA deletions secondary to mutations in POLG, PEO1, OPA1, and RRM2B. All subjects underwent a standardised brain and orbital MRI protocol, together with proton magnetic resonance spectroscopy in two voxels located within the parietal white matter and the brainstem. Results: There was evidence of significant extraocular muscle atrophy in patients with single or multiple mtDNA deletions compared with controls. There was no significant difference in metabolite concentrations between the patient and control groups in both the parietal white matter and brainstem voxels. Volumetric brain measurements revealed marked cortical and cerebellar atrophy among patients with CPEO+ phenotypes. Conclusion: The results of this study support a primary myopathic aetiology for the progressive limitation of eye movements that develops in CPEO. [ABSTRACT FROM AUTHOR]

Aims Hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Screening strategies for cardiac disease are unclear. We investigated whether myocardial abnormalities could be identified in mitochondrial DNA mutation carriers without clinical cardiac involvement. Methods and results Cardiac magnetic resonance imaging was performed in 22 adult patients with mitochondrial disease due to the m.3243A>G mutation, but no known cardiac involvement, and 22 age- and gender-matched control subjects: (i) Phosphorus-31- magnetic resonance spectroscopy, (ii) cine imaging (iii), cardiac tagging and (iv) late gadolinium enhancement (LGE) imaging. Disease burden was determined using the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and urinary mutation load. Compared with control subjects, patients had an increased left ventricular mass index (LVMI), LV mass to end-diastolic volume (M/V) ratio, wall thicknesses (all P < 0.01), torsion and torsion to endocardial strain ratio (both P < 0.05). Longitudinal shortening was decreased in patients (P < 0.0001) and correlated with an increased LVMI (r = −0.52, P < 0.03), but there were no differences in the diastolic function. Among patients there was no correlation of LVMI or the M/V ratio with diabetic or hypertensive status, but the mutation load and NMDAS correlated with the LVMI (r = 0.71 and r = 0.79, respectively, both P < 0.001). The phosphocreatine/adenosine triphosphate ratio was decreased in patients (P < 0.001) but did not correlate with other parameters. No patients displayed focal LGE. Conclusion Concentric remodelling and subendocardial dysfunction occur in patients carrying m.3243A>G mutation without clinical cardiac disease. Patients with higher mutation loads and disease burden may be at increased risk of cardiac involvement. [ABSTRACT FROM PUBLISHER]

Abstract: The spectrum of genetic disorders associated with primary mitochondrial dysfunction ranges from isolated hearing loss to lethal neonatal syndromes. Mitochondrial biogenesis and function relies on the enigmatic interplay of the mitochondrial and nuclear genome and allows for adjustment of energy consumption to substrate availability and adaption to genetic and toxic stressors. Whole transcriptome studies permit a global perspective on these events and promise deeper insight into mitochondrial physiology and dysfunction. Data coming from microarray studies has revealed the activation of an intricate signaling network that promotes bioenergetic adaption through autophagy and enhanced mitochondrial biogenesis. The effectors of this network are currently under much investigation for their therapeutic potential. Microarray data also implicate a profound impact of mitochondrial dysfunction on global nuclear transcription activity through alteration of genomic stability, cell cycle progression and epigenetic regulation. In this review, results of gene expression studies performed on human and animal tissue as well as cell culture models with mitochondrial dysfunction are summarized and discussed. [Copyright &y& Elsevier]

Mitochondrial disease can be attributed to both mitochondrial and nuclear gene mutations. It has a heterogeneous clinical and biochemical profile, which is compounded by the diversity of the genetic background. Disease-based epidemiological information has expanded significantly in recent decades, but little information is known that clarifies the aetiology in African patients. The aim of this study was to investigate mitochondrial DNA variation and pathogenic mutations in the muscle of diagnosed paediatric patients from South Africa. A cohort of 71 South African paediatric patients was included and a high-throughput nucleotide sequencing approach was used to sequence full-length muscle mtDNA. The average coverage of the mtDNA genome was 81±26 per position. After assigning haplogroups, it was determined that although the nature of non-haplogroup-defining variants was similar in African and non-African haplogroup patients, the number of substitutions were significantly higher in African patients. We describe previously reported disease-associated and novel variants in this cohort. We observed a general lack of commonly reported syndrome-associated mutations, which supports clinical observations and confirms general observations in African patients when using single mutation screening strategies based on (predominantly non-African) mtDNA disease-based information. It is finally concluded that this first extensive report on muscle mtDNA sequences in African paediatric patients highlights the need for a full-length mtDNA sequencing strategy, which applies to all populations where specific mutations is not present. This, in addition to nuclear DNA gene mutation and pathogenicity evaluations, will be required to better unravel the aetiology of these disorders in African patients. [ABSTRACT FROM AUTHOR]

Purpose: Mitochondrial disease is the most common neuromuscular disease and has a profound impact upon daily life, disease and longevity. Exercise therapy has been shown to improve mitochondrial function in patients with mitochondrial disease. However, no information exists about the level of habitual physical activity of people with mitochondrial disease and its relationship with clinical phenotype. Methods: Habitual physical activity, genotype and clinical presentations were assessed in 100 patients with mitochondrial disease. Comparisons were made with a control group individually matched by age, gender and BMI. Results: Patients with mitochondrial disease had significantly lower levels of physical activity in comparison to matched people without mitochondrial disease (steps/day; 6883±3944 vs. 9924±4088, p = 0.001). 78% of the mitochondrial disease cohort did not achieve 10,000 steps per day and 48%were classified as overweight or obese. Mitochondrial disease was associated with less breaks in sedentary activity (Sedentary to Active Transitions, % per day; 13±0.03 vs. 14±0.03, p = 0.001) and an increase in sedentary bout duration (bout lengths / fraction of total sedentary time; 0.206±0.044 vs. 0.187±0.026, p = 0.001). After adjusting for covariates, higher physical activity was moderately associated with lower clinical disease burden (steps / day; rs =20.49; 95% CI -0.33, -0.63, P<0.01). There were no systematic differences in physical activity between different genotypes mitochondrial disease. Conclusions: These results demonstrate for the first time that low levels of physical activity are prominent in mitochondrial disease. Combined with a high prevalence of obesity, physical activity may constitute a significant and potentially modifiable risk factor in mitochondrial disease. [ABSTRACT FROM AUTHOR]

The molecular aetiology of many patients with motor neuron disease (MND) remains unknown. Recent evidence of mitochondrial dysfunction, in particular the finding of histochemical abnormalities and pathogenic mitochondrial DNA (mtDNA) mutations, has prompted us to investigate further the role of mtDNA abnormalities in a cohort of thirteen patients with atypical MND presentations by whole mitochondrial genome sequencing. No pathogenic mutations were detected suggesting that inherited mtDNA mutations are not a common cause of atypical MND presentations. [ABSTRACT FROM AUTHOR]

Pathogenic point mutations in the mitochondrial MTND1 gene have previously been described in association with two distinct clinical phenotypes-Leber hereditary optic neuropathy (LHON) and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Here we report the first heteroplasmic mitochondrial DNA (mtDNA) point mutation (3376G>A) in the MTND1 gene associated with an overlap syndrome comprising the clinical features of both LHON and MELAS. Muscle histochemistry revealed subtle mitochondrial abnormalities, while biochemical analysis showed an isolated complex I deficiency. Our findings serve to highlight the growing importance of mutations in mitochondrial complex I structural genes in MELAS and its associated overlap syndromes.European Journal of Human Genetics (2005) 13, 623-627. doi:10.1038/sj.ejhg.5201363 Published online 12 January 2005 [ABSTRACT FROM AUTHOR]

Symmetrical polyneuropathy is a common feature of mitochondrial disease. Both axonal and demyelinating types are described, with Schwann cell abnormalities demonstrated on nerve biopsy. Some authors have also suggested an increased incidence of entrapment neuropathy. We identified 738 adult patients with proven mitochondrial disease seen in our centre in the past 25 years. One-hundred sixty seven of these patients had undergone nerve conduction studies as part of their routine clinical care, and the results of these studies were reviewed. We found an incidence rate of carpal tunnel syndrome ( CTS) of 50.7 per 100,000 person-years; 32.5 per 100,000 person-years for men and 65.3 per 100,000 person-years for women. One other patient had evidence of ulnar neuropathy at the elbow. The incidence of CTS in mitochondrial disease is similar to published rates for the UK general population. We found no evidence that mitochondrial disease per se increases the risk of entrapment neuropathy. We suggest that the pathophysiological mechanisms for the development of polyneuropathy in mitochondrial disease are quite distinct from the pathophysiology of CTS. Furthermore, it is essential that patients with mitochondrial disease who present with upper limb paraesthesia be referred for neurophysiological testing, so that treatable CTS is not missed. [ABSTRACT FROM AUTHOR]

Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% ± 9.3%; individuals with Parkinson disease, 52.3% ± 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease. [ABSTRACT FROM AUTHOR]

The author discusses the difficulties of mitochondrial replacement. Mitochondrial DNA diseases are both ordinary and, in their worst forms, devastating. There are limited therapeutics available for these patients, and those that are successful are concentrated on treating complications such as epilepsy and heart disease.

The uniqueness of the mitochondrial genome presents a number of obstacles to the successful use of gene therapy for the treatment of mitochondrial DNA disease. A new study shows that the effects of a pathogenic mutation in a human mitochondrial gene can be rectified by expressing an engineered wildtype copy of the gene in the nucleus. [ABSTRACT FROM AUTHOR]

Highlights: [•] Mitochondrial disorders are common, genetically-heterogeneous diseases characterised by multisystem involvement. [•] Endocrine dysfunction in mitochondrial disease is not uncommon. [•] This is predominantly restricted to disease of the endocrine pancreas leading to diabetes mellitus. [•] We review the common endocrine disorders associated with mitochondrial dysfunction. [•] Optimal strategies for supporting and managing patients are discussed. [ABSTRACT FROM AUTHOR]

Summary: Disruption of the most fundamental cellular energy process, the mitochondrial respiratory chain, results in a diverse and variable group of multisystem disorders known collectively as mitochondrial disease. The frequent involvement of the brain, nerves, and muscles, often in the same patient, places neurologists at the forefront of the interesting and challenging process of diagnosing and caring for these patients. Mitochondrial diseases are among the most frequently inherited neurological disorders, and can be caused by mutations in mitochondrial or nuclear DNA. Substantial progress has been made over the past decade in understanding the genetic basis of these disorders, with important implications for the general neurologist in terms of the diagnosis, investigation, and multidisciplinary management of these patients. [Copyright &y& Elsevier]

Abstract: Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by a lack of cellular energy due to oxidative phosphorylation (OXPHOS) defects. Since the identification of the first human pathological mitochondrial DNA (mtDNA) mutations in 1988, significant efforts have been spent in cataloguing the vast array of causative genetic defects of these disorders. Currently, more than 250 pathogenic mtDNA mutations have been identified. An ever-increasing number of nuclear DNA mutations are also being reported as the majority of proteins involved in mitochondrial metabolism and maintenance are nuclear-encoded. Understanding the phenotypic diversity and elucidating the molecular mechanisms at the basis of these diseases has however proved challenging. Progress has been hampered by the peculiar features of mitochondrial genetics, an inability to manipulate the mitochondrial genome, and difficulties in obtaining suitable models of disease. In this review, we will first outline the unique features of mitochondrial genetics before detailing the diseases and their genetic causes, focusing specifically on primary mtDNA genetic defects. The functional consequences of mtDNA mutations that have been characterised to date will also be discussed, along with current and potential future diagnostic and therapeutic advances. [Copyright &y& Elsevier]

Abstract: A number of epidemiological studies of mitochondrial disease have been carried out over the last decade, clearly demonstrating that mitochondrial disorders are far more common than was previously accepted. This review summarizes current knowledge of the prevalence of human mitochondrial disorders—data that has important implications for the provision of health care and adequate resources for research into the pathogenesis and treatment of these disorders. [Copyright &y& Elsevier]

In this era of “the gene and the genome”, communication of complex genetic information to individuals and their families is becoming an increasingly common but difficult task for the clinician. This problem is particularly evident in the rapidly evolving field of mitochondrial disease: the clinician is faced with a diversity of clinical presentations and myriad mutations with, for many, only a loose relation between genotype and phenotype. The aim of this review is to familiarise the clinician with the main clinical syndromes encountered in practice, and to provide an overview of current concepts of mitochondrial genetics, including recent advances in molecular aetiology. In addition, we have included clinical guidance on the investigation and management of patients with suspected or proven mitochondrial disease based on our own experience over the past decade. [Copyright &y& Elsevier]

Perceived fatigue is a prominent symptom in patients with mitochondrial disease but to date its prevalence, impact and aetiology are poorly understood. Our aim was to determine the prevalence and assess for comorbidities associated with clinically relevant fatigue in patients with mitochondrial disease. A cross-sectional postal survey of patients with mitochondrial disease was undertaken using a validated self-completion, patient-reported outcome measures (response rate: 60%; n = 132). The prevalence and perceived functional impact of experienced fatigue were assessed using the Fatigue Impact Scale. Other putative biological mechanisms were evaluated using the Hospital Anxiety Depression scale and Epworth sleepiness scale. Data were compared with those for healthy control subjects and patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome matched for age and gender. Sixty-two per cent of patients with mitochondrial disease reported excessive symptomatic fatigue (Fatigue Impact Scale ≥ 40); whilst 32% reported severe, functionally limiting fatigue symptoms (Fatigue Impact Scale ≥ 80) comparable to perceived fatigue in patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome. Fatigue is common and often severe in patients with mitochondrial disease irrespective of age, gender or genotype. Future evaluation of causal factors in mitochondrial disease-associated fatigue is warranted with the potential to guide future treatment modalities. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown. Methods and results: Before and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.3243A>G-related mitochondrial disease, and compared to age- and gender-matched sedentary control subjects. At baseline, patients had increased left ventricular mass index (LVMI, p <0.05) and LV mass to end-diastolic volume ratio, and decreased longitudinal shortening and myocardial phosphocreatine/adenosine triphosphate ratio (all p <0.01). Peak arterial–venous oxygen difference (p <0.05), oxygen uptake (VO2) and power were decreased in patients (both p <0.01) with no significant difference in cardiac power output. All patients remained stable and completed ≥80% sessions. With training, there were similar proportional increases in peak VO2, anaerobic threshold and work capacity in patients and controls. LVMI increased in both groups (p <0.01), with no significant effect on myocardial function or bioenergetics. Pre- and post-exercise training, HRV and BPV demonstrated increased low frequency and decreased high frequency components in patients compared to controls (all p <0.05). Conclusion: Patients with mitochondrial disease and controls achieved similar proportional benefits of exercise training, without evidence of disease progression, or deleterious effects on cardiac function. Reduced exercise capacity is largely mediated through skeletal muscle dysfunction at baseline and sympathetic over-activation may be important in pathogenesis. [Copyright &y& Elsevier]

Abstract: Mitochondrial tRNA point mutations are important causes of human disease, and have been associated with a diverse range of clinical phenotypes. Definitively proving the pathogenicity of any given mt-tRNA mutation requires combined molecular, genetic and functional studies. Subsequent evaluation of the mutation using a pathogenicity scoring system is often very helpful in concluding whether or not the mutation is causing disease. Despite several independent reports linking the m.3291T>C mutation to disease in humans, albeit in association with several different phenotypes, its pathogenicity remains controversial. A lack of conclusive functional evidence and an over-emphasis on the poor evolutionary conservation of the affected nucleotide have contributed to this controversy. Here we describe an adult patient who presented with deafness and lipomas and evidence of mitochondrial abnormalities in his muscle biopsy, who harbours the m.3291T>C mutation, providing conclusive evidence of pathogenicity through analysis of mutation segregation with cytochrome c oxidase (COX) deficiency in single muscle fibres, underlining the importance of performing functional studies when assessing pathogenicity. [Copyright &y& Elsevier]

The article describes the case of a 47-year-old man who complained of a short history of severe muscle ache and dark-brown urine. Physical examination on the patient led to an initial diagnosis of rhabdomyolysis. However, the patient revealed that he always develop muscle pain and brown urine every time he walked on the fells since he was 30 years old. Further laboratory tests on the patient led to a diagnosis of mitochondrial myopathy.

Abstract: Mutations of the BCS1L gene are a recognised cause of isolated respiratory chain complex III deficiency and underlie several fatal, neonatal mitochondrial diseases. Here we describe a 20-year-old Kenyan woman who initially presented as a floppy infant but whose condition progressed during childhood and adolescence with increasing muscle weakness, focal motor seizures and optic atrophy. Muscle biopsy demonstrated complex III deficiency and the pathogenicity of a novel, homozygous BCS1L mutation was confirmed by yeast complementation studies. Our data indicate that BCS1L mutations can cause a variable, neurological course which is not always fatal in childhood. [ABSTRACT FROM AUTHOR]

Mitochondrial respiratory chain abnormalities are an important cause of neuromuscular disease and may be due to defects of either the mitochondrial or nuclear genome. On account of the clinical and genetic heterogeneity exhibited by the mitochondrial myopathies, their investigation and diagnosis remains a challenge, requiring a combination of techniques including muscle histochemistry, biochemical assessment of respiratory chain function and molecular genetic studies. Here, we describe a step-by-step approach to the clinical and laboratory diagnosis of mitochondrial muscle disease, highlighting the many potential problems that can hinder reaching the correct diagnosis. [Copyright &y& Elsevier]