Mitochondrial Pathology Research Articles

Mitochondrial disease: current understanding and future directions.

Mitochondrial disease was chosen as the topic for the 13th Neurobiology of Disease in Children Symposium, held on October 31, 2013, in Austin, Texas. Program codirectors Drs Bruce Cohen and William Copeland prepared an engaging agenda that included individual presentations as well as a panel discussion from leaders working to advance the field of mitochondrial medicine. The symposium covered a variety of topics such as clinical features, recent advances in understanding the pathogenesis of mitochondrial disease, and new investigations of characteristic symptoms of the broad class of mitochondrial dysfunction. This was followed by a session on controversial topics and unanswered questions. The symposium concluded with a panel discussion led by scientific leaders in the field of mitochondrial medicine. Dr Eric Schon initiated the symposium, giving an overview of mitochondrial biology, including the genetic and molecular components that contribute to the vast array of clinical representations associated with mitochondrial disease. After the introduction, Dr Bruce Cohen presented common issues involved with properly classifying various mitochondrial diseases, in addition to providing potential diagnostic tools for clinicians to properly diagnose disease. Dr Patrick Chinnery discussed the genetic theory of heteroplasmy in which individual patients contain varying levels of mutated copies of genes, creating a wide spectrum of disease severity. Dr Chinnery went on to detail a study conducted with his group that analyzed more than 100 primary oocytes after surgical hysterectomy. The group assessed the level and distribution of mutated genetic information within the evaluated oocytes. To conclude the first session, Dr Robert Naviaux described the etiology of primary and secondary polymerase gamma disorders. Dr Naviaux defined how changes in biological pathways related to polymerase gamma can increase the mutation load in individual patients. Depending on the genetic loci where the replication error occurs, mutated polymerase gamma can produce various mitochondrial syndromes. The next session of the symposium focused on progress in understanding the molecular mechanisms behind various mitochondrial dysfunctions. Dr William Copeland detailed his work in understanding the basic function involved in polymerase gamma, and how variation from the enzymatic machinery can promote disease pathology. Dr Copeland reviewed various accessory proteins and subunits, such as polymerase gamma exonuclease and twinkle helicase, which ensure proper replication of the mitochondrial genome. Dr Copeland also elaborated on the contributions of the gene POLG2, responsible for producing the p55 subunit, to the fidelity of mitochondrial genome replication. Dr Richard Youle shared interesting findings about the association of mitochondrial dysfunction and disease pathology in Parkinson patients, as a model for understanding pediatric disorders. Dr Youle described disease progression in Parkinson patients caused by an inhibition of the mitochondrial quality control pathway, which leads to cellular accumulation of damaged or inefficient mitochondria. Dr Vamsi Mootha concluded the session with his presentation on a computational biology approach to mitochondrial research. Dr Mootha specifically detailed the effects genetic sequencing methods such as mito exome sequencing have had on the advancement of mitochondrial research. The third session of the symposium focused on translational and clinical advances in mitochondrial disease research. Dr Michio Hirano gave an overview of current gene and enzyme replacement therapies that target the nuclear DNA defect associated with mitochondrial disease symptoms. This discussion focused on current advances in these treatment options within animal models, which shift heteroplasmy under a threshold level to alleviate the effects of disease progression. Dr Mark Tarnopolsky introduced contemporary studies on exercise therapies for treating moderate pediatric myopathies. In addition, he described a therapeutic agent called myokines, which can be given to patients with mitochondrial disease via muscular injection to mimic the beneficial effects of physical exercise. Dr Gregory Enns discussed the results of various clinical trials involving patients with mitochondrial disease who were treated with EPI-743, also

Expanding the clinical phenotypes of MT-ATP6 mutations.

Mitochondrial DNA mutations at MT-ATP6 gene are relatively common in individuals suffering from striatal necrosis syndromes. These patients usually do not show apparent histochemical and/or biochemical signs of oxidative phosphorylation dysfunction. Because of this, MT-ATP6 is not typically analyzed in many other mitochondrial disorders that have not been previously associated to mutations in this gene. To correct this bias, we have performed a screening of the MT-ATP6 gene in a large collection of patients suspected of suffering different mitochondrial DNA (mtDNA) disorders. In three cases, biochemical, molecular-genetics and other analyses in patient tissues and cybrids were also carried out. We found three new pathologic mutations. Two of them in patients showing phenotypes that have not been commonly associated to mutations in the MT-ATP6 gene. These results remark the importance of sequencing the MT-ATP6 gene in patients with striatal necrosis syndromes, but also within other mitochondrial pathologies. This gene should be sequenced at least in all those patients suspected of suffering an mtDNA disorder disclosing normal results for histochemical and biochemical analyses of respiratory chain.

Assessment of cytochrome C oxidase dysfunction in the substantia nigra/ventral tegmental area in schizophrenia.

Perturbations in metabolism are a well-documented but complex facet of schizophrenia pathology. Optimal cellular performance requires the proper functioning of the electron transport chain, which is constituted by four enzymes located within the inner membrane of mitochondria. These enzymes create a proton gradient that is used to power the enzyme ATP synthase, producing ATP, which is crucial for the maintenance of cellular functioning. Anomalies in a single enzyme of the electron transport chain are sufficient to cause disruption of cellular metabolism. The last of these complexes is the cytochrome c oxidase (COX) enzyme, which is composed of thirteen different subunits. COX is a major site for oxidative phosphorylation, and anomalies in this enzyme are one of the most frequent causes of mitochondrial pathology. The objective of the present report was to assess if metabolic anomalies linked to COX dysfunction may contribute to substantia nigra/ventral tegmental area (SN/VTA) pathology in schizophrenia. We tested COX activity in postmortem SN/VTA from schizophrenia and non-psychiatric controls. We also tested the protein expression of key subunits for the assembly and activity of the enzyme, and the effect of antipsychotic medication on subunit expression. COX activity was not significantly different between schizophrenia and non-psychiatric controls. However, we found significant decreases in the expression of subunits II and IV-I of COX in schizophrenia. Interestingly, these decreases were observed in samples containing the entire rostro-caudal extent of the SN/VTA, while no significant differences were observed for samples containing only mid-caudal regions of the SN/VTA. Finally, rats chronically treated with antipsychotic drugs did not show significant changes in COX subunit expression. These findings suggest that COX subunit expression may be compromised in specific sub-regions of the SN/VTA (i.e. rostral regions), which may lead to a faulty assembly of the enzyme and a greater vulnerability to metabolic insult.

Mitochondrial pathology in osteoarthritic chondrocytes.

Osteoarthritis (OA) is a chronic degenerative disease leading to aberrance of cartilage structures with unclear or multifactorial mechanisms. Recently, a great portion of research endeavor to explore the molecular mechanisms of OA in focusing on the mitochondrial pathology. Mitochondrial respiratory chain (MRC) produces reactive oxygen species (ROS), which in turn impair mtDNA integrity and link to cartilage degradation in OA. The fine-tuning between ROS and antioxidant within chondrocytes ensures cartilage homeostasis. With disturbance from pro-inflammatory cytokines, oxidative stress synergistically instigates cellular signaling and exacerbates mitochondrial pathology, which may affect several pathways implicated in OA cartilage degradation, including oxidative stress, increase of cytokine-induced chondrocytes inflammation and matrix catabolism, aging and senescence, obesity-related pathology, and cartilage matrix calcification. Unveiling the molecular mechanisms of mitochondrial function in OA pathogenesis and progression is essential for providing relevant therapeutic targets. These suggest that efficient protection and improvement of mitochondrial activity can be a therapeutic alternative for OA patients.

Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases.

Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.

Development of pharmacological strategies for mitochondrial disorders

Mitochondrial diseases are an unusually genetically and phenotypically heterogeneous group of disorders, which are extremely challenging to treat. Currently, apart from supportive therapy, there are no effective treatments for the vast majority of mitochondrial diseases. Huge scientific effort, however, is being put into understanding the mechanisms underlying mitochondrial disease pathology and developing potential treatments. To date, a variety of treatments have been evaluated by randomized clinical trials, but unfortunately, none of these has delivered breakthrough results. Increased understanding of mitochondrial pathways and the development of many animal models, some of which are accurate phenocopies of human diseases, are facilitating the discovery and evaluation of novel prospective treatments. Targeting reactive oxygen species has been a treatment of interest for many years; however, only in recent years has it been possible to direct antioxidant delivery specifically into the mitochondria. Increasing mitochondrial biogenesis, whether by pharmacological approaches, dietary manipulation or exercise therapy, is also currently an active area of research. Modulating mitochondrial dynamics and mitophagy and the mitochondrial membrane lipid milieu have also emerged as possible treatment strategies. Recent technological advances in gene therapy, including allotopic and transkingdom gene expression and mitochondrially targeted transcription activator-like nucleases, have led to promising results in cell and animal models of mitochondrial diseases, but most of these techniques are still far from clinical application.Linked ArticlesThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8

Inhibition of ATPIF1 Ameliorates Severe Mitochondrial Respiratory Chain Dysfunction in Mammalian Cells

Mitochondrial respiratory chain disorders are characterized by loss of electron transport chain (ETC) activity. Although the causes of many such diseases are known, there is a lack of effective therapies. To identify genes that confer resistance to severe ETC dysfunction when inactivated, we performed a genome-wide genetic screen in haploid human cells with the mitochondrial complex III inhibitor antimycin. This screen revealed that loss of ATPIF1 strongly protects against antimycin-induced ETC dysfunction and cell death by allowing for the maintenance of mitochondrial membrane potential. ATPIF1 loss protects against other forms of ETC dysfunction and is even essential for the viability of human ρ° cells lacking mitochondrial DNA, a system commonly used for studying ETC dysfunction. Importantly, inhibition of ATPIF1 ameliorates complex III blockade in primary hepatocytes, a cell type afflicted in severe mitochondrial disease. Altogether, these results suggest that inhibition of ATPIF1 can ameliorate severe ETC dysfunction in mitochondrial pathology.

Tempol Protects Cardiomyocytes from Nucleoside Reverse Transcriptase Inhibitor-Induced Mitochondrial Toxicity

Nucleoside reverse transcriptase inhibitors (NRTIs), essential components of combinational therapies used for treatment of human immunodeficiency virus-1, damage heart mitochondria. Here, we have shown mitochondrial compromise in H9c2 rat cardiomyocytes exposed for 16 passages (P) to the NRTIs zidovudine (AZT, 50μM) and didanosine (ddI, 50μM), and we have demonstrated protection from mitochondrial compromise in cells treated with 200μM 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine (Tempol) or 200μM 1-hydroxy-4-[2-triphenylphosphonio)-acetamido]-2,2,6,6-tetramethylpiperidine (Tempol-H), along with AZT/ddI, for 16P. Exposure to AZT/ddI caused a moderate growth inhibition at P3, P5, P7, and P13, which was not altered by addition of Tempol or Tempol-H. Mitochondrial oxidative phosphorylation capacity was determined as uncoupled oxygen consumption rate (OCR) by Seahorse XF24 Analyzer. At P5, P7, and P13, AZT/ddI-exposed cells showed an OCR reduction of 8.8-57.2% in AZT/ddI-exposed cells, compared with unexposed cells. Addition of Tempol or Tempol-H, along with AZT/ddI, resulted in OCR levels increased by about 300% above the values seen with AZT/ddI alone. The Seahorse data were further supported by electron microscopy (EM) studies in which P16 cells exposed to AZT/ddI/Tempol had less mitochondrial pathology than P16 cells exposed to AZT/ddI. Western blots of P5 cells showed that Tempol and Tempol-H upregulated expression of mitochondrial uncoupling protein-2 (UCP-2). However, Complex I activity that was reduced by AZT/ddI, was not restored in the presence of AZT/ddI/Tempol. Superoxide levels were increased in the presence of AZT/ddI and significantly decreased in cells exposed to AZT/3TC/Tempol at P3, P7, and P10. In conclusion, Tempol protects against NRTI-induced mitochondrial compromise, and UCP-2 plays a role through mild uncoupling.

Mitochondrial Dynamics in Peripheral Neuropathies

Mitochondrial dynamics describes the continuous change in the position, size, and shape of mitochondria within cells. The morphological and functional complexity of neurons, the remarkable length of their processes, and the rapid changes in metabolic requirements arising from their intrinsic excitability render these cells particularly dependent on effective mitochondrial function and positioning. The rules that govern these changes and their functional significance are not fully understood, yet the dysfunction of mitochondrial dynamics has been implicated as a pathogenetic factor in a number of diseases, including disorders of the central and peripheral nervous systems. In recent years, a number of mutations of genes encoding proteins that play important roles in mitochondrial dynamics and function have been discovered in patients with Charcot-Marie-Tooth (CMT) disease, a hereditary peripheral neuropathy. These findings have directly linked mitochondrial pathology to the pathology of peripheral nerve and have identified certain aspects of mitochondrial dynamics as potential early events in the pathogenesis of CMT. In addition, mitochondrial dysfunction has now been implicated in the pathogenesis of noninherited neuropathies, including diabetic and inflammatory neuropathies. The role of mitochondria in peripheral nerve diseases has been mostly examined in vitro, and less so in animal models. This review examines available evidence for the role of mitochondrial dynamics in the pathogenesis of peripheral neuropathies, their relevance in human diseases, and future challenges for research in this field.

Gene therapy for mitochondrial diseases: Leber Hereditary Optic Neuropathy as the first candidate for a clinical trial

Mitochondrial disorders cannot be ignored anymore in most medical disciplines; indeed their minimum estimated prevalence is superior to 1 in 5000 births. Despite the progress made in the last 25 years on the identification of gene mutations causing mitochondrial pathologies, only slow progress was made towards their effective treatments. Ocular involvement is a frequent feature in mitochondrial diseases and corresponds to severe and irreversible visual handicap due to retinal neuron loss and optic atrophy. Interestingly, three clinical trials for Leber Congenital Amaurosis due to RPE65 mutations are ongoing since 2007. Overall, the feasibility and safety of ocular Adeno-Associated Virus delivery in adult and younger patients and consistent visual function improvements have been demonstrated. The success of gene-replacement therapy for RPE65 opens the way for the development of similar approaches for a broad range of eye disorders, including those with mitochondrial etiology such as Leber Hereditary Optic Neuropathy (LHON).

Two novel compound heterozygous mutations in OPA3 in two siblings with OPA3-related 3-methylglutaconic aciduria

OPA3-related 3-methylglutaconic aciduria, or Costeff Optic Atrophy syndrome, is a neuro-ophthalmologic syndrome of early-onset bilateral optic atrophy and later-onset spasticity, and extrapyramidal dysfunction. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is markedly increased. OPA3-related 3-methylglutaconic aciduria is due to mutations in the OPA3 gene located at 19q13.2–13.3. Here we describe two siblings with novel compound heterozygous variants in OPA3: c.1A>G (p.1M>V) in the translation initiation codon in exon 1 and a second variant, c.142+5G>C in intron 1. On cDNA sequencing the c.1A>G appeared homozygous, indicating that the allele without the c.1A>G variant is degraded. This is likely due to an intronic variant; possibly the IVS1+5 splice site variant. The older female sibling initially presented with motor developmental delay and vertical nystagmus during her first year of life and was diagnosed subsequently with optic atrophy. Her brother presented with mildly increased hip muscle tone followed by vertical nystagmus within the first 6months of life, and was found to have elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid, and optic atrophy by 1.5years of age. Currently, ages 16 and 7, both children exhibit ataxic gaits and dysarthric speech. Immunofluorescence studies on patient's cells showed fragmented mitochondrial morphology. Thus, though the exact function of OPA3 remains unknown, our experimental results and clinical summary provide evidence for the pathogenicity of the identified OPA3 variants and provide further evidence for a mitochondrial pathology in this disease.

Diabetes Mellitus And The Brain: Special Emphasis To Cognitive Function

Diabetes mellitus (DM) is a major public health problem. Cognitive deficits are common with DM which range from subclinical or subtle to severe deficits as dementia. Both hypoglycemia and hyperglycemia are causes of cognitive impairment with DM. In patients with DM, not only severe hypoglycemia but also recurrent mild or moderate hypoglycemia have deleterious effect on the brain. Recurrent mild/moderate hypoglycemia is associated with intellectual decline, reduced attention, impaired mental abilities and memory deficits. Hypoglycemia may result in abnormalities of neuronal plasticity, synaptic weakening and scattered neuronal death in the cerebral cortex and the hippocampus. Chronic hyperglycemia in type 1 and type 2 DM is associated with low IQ (verbal, performance and total) and abnormalities in testing for different domains of cognitive function as verbal relations, comprehension, visual reasoning, pattern analysis, quantitation, memory, learning, mental control, psychomotor efficiency, mental and motor processing speed and executive function. The suggested mechanisms incriminated in the pathogenesis of hyperglycemia related cognitive dysfunction include, macro- and micro-vascular disease or vasculopathy, hyperlipidemia, hypertension, insulin resistance and hyperinsulinemia, stress response, direct toxic effect of chronic hyperglycemia on the brain, advanced glycation end products, inflammatory cytokines and oxidative stress. Hyperglycemia causes oxidative stress, amyloidosis, angiopathy, abnormal lipid peroxidation, accumulation of β-amyloid and tau phosphorylation, neuroinflammation, mitochondrial pathology, apoptosis and neuronal degeneration in the cortex and hippocampus. Depression has been identified as a risk for accelerated cognitive decline with DM. The knowledge that diagnosis at early age, frequency of hypoglycemia, poor glycemic control and presence of risk factors which negatively affect cognitive functions in DM, will have important implications for treatment and for research purposes.

Does the study of genetic interactions help predict the function of mitochondrial proteins in Saccharomyces cerevisiae?

Mitochondria are complex organelles of eukaryotic cells that contain their own genome, encoding key subunits of the respiratory complexes. The successive steps of mitochondrial gene expression are intimately linked, and are under the control of a large number of nuclear genes encoding factors that are imported into mitochondria. Investigating the relationships between these genes and their interaction networks, and whether they reveal direct or indirect partners, can shed light on their role in mitochondrial biogenesis, as well as identify new actors in this process. These studies, mainly developed in yeasts, are significant because mammalian equivalents of such yeast genes are candidate genes in mitochondrial pathologies. In practice, studies of physical, chemical and genetic interactions can be undertaken. The search for genetic interactions, either aggravating or alleviating the phenotype of the starting mutants, has proved to be particularly powerful in yeast since even subtle changes in respiratory phenotypes can be screened in a very efficient way. In addition, several high throughput genetic approaches have recently been developed. In this review we analyze the genetic network of three genes involved in different steps of mitochondrial gene expression, from the transcription and translation of mitochondrial RNAs to the insertion of newly synthesized proteins into the inner mitochondrial membrane, and we examine their relevance to our understanding of mitochondrial biogenesis. We find that these genetic interactions are seldom redundant with physical interactions, and thus bring a considerable amount of original and significant information as well as open new areas of research.

HIV Treatment and Associated Mitochondrial Pathology

Antiretroviral therapy has dramatically reduced mortality in human immunodeficiency virus (HIV) infection. In 1988, the suggestion that the first antiretroviral drug, zidovudine, was the potential cause of muscle pathology in HIV-infected persons resulted in structural and biochemical patient studies demonstrating acquired mitochondrial dysfunction. Assessment of subsequent nucleoside analog reverse transcriptase inhibitor (NRTI) antiretroviral drugs has indicated that mitochondria are a common target of NRTI toxicity in multiple tissues, leading to a wide variety of pathology ranging from lipodystrophy to neuropathy. Overwhelmingly, these complications have emerged during post-licensing human studies. Subsequent animal and in vitro studies have then elucidated the potential pathological mechanisms, suggesting that NRTI-associated mitochondrial toxicity arises principally from inhibition of the sole mitochondrial DNA (mtDNA) polymerase gamma, leading to a reduction in mtDNA content (depletion). Millions of patients have been treated with mitochondrially toxic NRTIs and these drugs remain the backbone of antiretroviral rollout in much of sub-Saharan Africa. Here we describe the 25-year history of antiretroviral associated mitochondrial pathology and critically review the strength of evidence linking clinical, histopathological, and molecular data. We discuss recently described novel mechanisms of NRTI-associated mitochondrial damage and whether or not recently licensed NRTIs may be considered free from mitochondrial toxicity.

Introduction:Focus on mitochondria

This is a series of papers (three reviews and five regular papers) focused on Mitochondria from authors contributing to two FEBS courses on Mitochondria held in 2012. These papers focus on: (i) mitochondrial biogenesis (regulation by phosphorylation, import of SOD1 and Mia40, mitophagy and tRNA variants) or (ii) mitochondrial pathology (ischaemia, obesity and Parkinson's disease).

Perspectives of mitochondrial medicine

Mitochondrial medicine was established more than 50 years ago after discovery of the very first pathology caused by impaired mitochondria. Since then, more than 100 mitochondrial pathologies have been discovered. However, the number may be significantly higher if we interpret the term "mitochondrial medicine" more widely and include in these pathologies not only those determined by the genetic apparatus of the nucleus and mitochondria, but also acquired mitochondrial defects of non-genetic nature. Now the main problems of mitochondriology arise from methodology, this being due to studies of mitochondrial activities under different models and conditions that are far from the functioning of mitochondria in a cell, organ, or organism. Controversial behavior of mitochondria ("friends and foes") to some extent might be explained by their bacterial origin with possible preservation of "egoistic" features peculiar to bacteria. Apparently, for normal mitochondrial functioning it is essential to maintain homeostasis of a number of mitochondrial elements such as mitochondrial DNA structure, membrane potential, and the system of mitochondrial quality control. Abrogation of these elements can cause a number of pathologies that have become subjects of mitochondrial medicine. Some approaches to therapy of mitochondrial pathologies are discussed.

I.I.1 Myopathologic classification of acquired immune and inflammatory myopathies

It is now difficult to classify acquired immune and inflammatory myopathies (IIMs) into traditional groups: dermatomyositis, polymyositis, and inclusion body myositis (IBM). Myopathologic classification of IIM provides more specific and inclusive diagnostic information. Pathologic features used to define IIM subtypes include: Muscle fiber changes; Immune abnormalities (cellular, humoral); and Tissue types involved (connective tissue, vessels, muscle fibers). Some features, like B-cell foci and alkaline phosphatase positive vessels or perimysium, occur more generally with treatable IIM. Myopathologic subtypes of IIM include: (1) Immune myopathies with perimysial pathology (IMPP) have perimysial connective tissue with fragmentation and histiocytic cellularity. Jo-1 antibody associated IIM often have IMPP pathology; (2) Myovasculopathies have damaged perimysial or endomysial vessels. Muscle damage may be due to ischemia rather than direct immune attack. Childhood dermatomyositis syndromes are often myovasculopathies. (3). Immune polymyopathies are active myopathies with necrosis but little inflammation. Serum CK is very high. Myopathies with signal recognition particle antibodies are an example. (4) Immune myopathies with endomysial pathology (IM-EP) often have C5b-9 complement deposition on endomysial connective tissue, and mononuclear cell foci. Brachio-cervical inflammatory myopathies illustrate IM-EP. (5) Histiocytic inflammatory myopathies have granulomas and focal invasion of muscle fibers by mononuclear cells. They include sarcoid myopathy. (6) Inflammatory myopathies with vacuoles, aggregates and mitochondrial pathology (IM-VAMP) in myofibers can also have diffusely upregulated myofiber MHC I, CD4 and CD8 cell foci and NT5C1A antibodies. IBM is a subgroup. IM-VAMP are poorly treatable. Myopathologic classification of IIM adds diagnostic and prognostic accuracy, and focuses testing, treatment, and pathogenic investigations.

Increased densities of nitric oxide synthase expressing neurons in the temporal cortex and the hypothalamic paraventricular nucleus of polytoxicomanic heroin overdose victims: Possible implications for heroin neurotoxicity

Heroin is one of the most dangerous drugs of abuse, which may exert various neurotoxic actions on the brain (such as gray matter loss, neuronal apoptosis, mitochondrial dysfunction, synaptic defects, depression of adult neurogenensis, as well as development of spongiform leucoencephalopathy). Some of these toxic effects are probably mediated by the gas nitric oxide (NO). We studied by morphometric analysis the numerical density of neurons expressing neuronal nitric oxide synthase (nNOS) in cortical and hypothalamic areas of eight heroin overdose victims and nine matched controls. Heroin addicts showed significantly increased numerical densities of nNOS immunoreactive cells in the right temporal cortex and the left paraventricular nucleus. Remarkably, in heroin abusers, but not in controls, we observed not only immunostained interneurons, but also cortical pyramidal cells. Given that increased cellular expression of nNOS was accompanied by elevated NO generation in brains of heroin addicts, these elevated levels of NO might have contributed to some of the known toxic effects of heroin (for example, reduced adult neurogenesis, mitochondrial pathology or disturbances in synaptic functioning).

Nicotine increases lifespan and rescues olfactory and motor deficits in a Drosophila model of Parkinson's disease

Drosophila melanogaster is an attractive model of familial Parkinson's disease, as flies with loss-of-function mutations of the parkin gene exhibit many pathologies observed in PD patients. Progressive motor deficits found in homozygous parkin mutants seem to result from mitochondrial pathology that causes indirect flight muscle and dopaminergic neuronal degeneration [1,2]. We have found that heterozygous parkin mutants have decreased lifespan, generally progressive motor dysfunction and olfactory deficits compared to control flies, suggesting that mutation of this gene produces a dominant phenotype. Tobacco smokers are dose-dependently less likely to develop PD [3,4]; subsequent in vitro and in vivo studies show that nicotine is protective in models of sporadic PD [6]. Literature addressing the potential protection by nicotine in Parkin loss-of-function models spans limited concentrations and selected time points in the organism's lifespan. We have found that parkin heterozygotes have late-onset climbing and flying deficits as well as decreased viability and olfactory deficits that precede motor defects. While chronic nicotine exposure decreases lifespan and climbing and flying abilities in control flies, it can improve viability and flying capability as well as rescue climbing and olfactory deficits in parkin heterozygotes. Dopaminergic neurons are spared in the parkin heterozygote, perhaps because this phenotype is less severe than in the homozygous parkin mutants. Nicotine pretreatment may be protective in sporadic PD patients and models; however, timely diagnosis remains to be an obstacle. Our results suggest that nicotine also may be protective in familial PD patients, who can be easily identified before motor symptoms occur.

Alzheimer Disease and Diabetes Mellitus: Do They have Anything in Common?

The prevalence of diabetes mellitus (DM) continues to increase because of sedentary life style and inappropriate diet. DM is one of the most common metabolic diseases, affecting more than 240 million people worldwide. It is projected that the number of people with DM will continue to increase in the next decade. Alzheimer disease (AD) is the most common cause of dementia, and affects over 24 million people globally, mostly senior citizens. The worldwide prevalence of AD is estimated to double in the next 20 years. How are these two chronic and debilitating diseases similar? Do they have common denominators? AD is similar to DM in many ways, in that both are associated with defective insulin release and/or signalling, impaired glucose uptake, amyloidosis, increased oxidative stress, stimulation of the apoptotic pathway, angiopathy, abnormal lipid peroxidation, ageing (in type 2 DM), brain atrophy, increased formation of advanced glycation end products and tau phosphorylation, impaired lipid metabolism and mitochondrial pathology. The pathogenesis of both AD and DM has genetic as well as environmental components. Both can also cause impaired cognition and dementia. All of these common denominators indicate that AD and DM share a lot of factors in terms of pathophysiology, histopathology and clinical outcome. These similarities can be used in the search for and design of effective pharmacotherapy for AD, since potent therapeutic agents such as insulin, incretins, oral hypoglycaemic agents and antioxidants used in the management of DM may play a key role in the treatment of patients with AD.