Axonal response of mitochondria to demyelination and complex IV activity within demyelinated axons in experimental models of multiple sclerosis.

Aims: Axonal injury in multiple sclerosis (MS) and experimental models is most frequently detected in acutely demyelinating lesions. We recently reported a compensatory neuronal response, where mitochondria move to the acutely demyelinated axon and increase the mitochondrial content following lysolecithin-induced demyelination. We termed this homeostatic phenomenon, which is also evident in MS, the axonal response of mitochondria to demyelination (ARMD).

Exercise-induced changes in gait kinematics in multiple sclerosis with minimal neurological disability.

Background: Exercise-induced gait deterioration is a frequently encountered symptom that limits ambulation throughout the clinical course, becoming more prominent with increasing neurological disability in people with MS (pwMS).

Objective: We attempted to objectively document exercise-induced gait changes in pwMS with minimal neurological disability and stable disease.

Methods: Gait kinematics and spatio-temporal parameters were recorded using 3D motion analysis before and after a 20-minute treadmill walk (Group A, n=15)/run (Group B, n=15) at a self-selected speed in pwMS and compared with healthy controls (n=15).

Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis.

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination.

Test-retest reliability and minimal detectable change of ankle kinematics and spatiotemporal parameters in MS population.

Background: Many people with multiple sclerosis (pwMS) experience walking impairments often including foot drop, evident as either reduced dorsiflexion at initial contact and/or at the swing phase of the gait cycle. To measure even subtle differences in ankle kinematics, 3D gait analysis is considered a 'gold' standard. However, the psychometric properties of ankle kinematics in the MS population have not yet been examined.

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects.

Interference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS).

A Method to Detect Cytochrome c Oxidase Activity and Mitochondrial Proteins in Oligodendrocytes.

Cytochrome c oxidase or mitochondrial respiratory chain complex IV is where over 90% of oxygen is consumed. The relationship between complex IV activity and mitochondrial proteins, which provides a guide to understanding the mechanisms in primary mitochondrial disorders, has been determined by histochemistry (complex IV activity) and immunohistochemistry in serial sections. In the central nervous system (CNS), mitochondrial activity and immunoreactivity have been determined in populations of cells in serial sections as capturing cells in more than one section is difficult.

Mitochondrial dysfunction and axon degeneration in progressive multiple sclerosis.

The neuron is the target of inflammatory demyelinating processes in multiple sclerosis (MS). In progressive MS, however, there is a gathering body of evidence indicating that molecular changes converge on mitochondria within neuronal cell bodies. The most reproducible change relates to mitochondrial respiratory chain complex deficiency, which compromises the capacity of neurons to generate ATP.

Oxidative Injury and Iron Redistribution Are Pathological Hallmarks of Marmoset Experimental Autoimmune Encephalomyelitis.

Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as redistribution of iron are hallmarks of the MS-like pathology in the EAE model in the common marmoset. Active lesions in the marmoset EAE brain display increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p22phox, p47phox, and gp91phox) and inducible nitric oxide synthase immunoreactivity within lesions with active inflammation and demyelination, coinciding with enhanced expression of mitochondrial heat-shock protein 70 and superoxide dismutase 1 and 2.

Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.

Key Points: Neurodegenerative disorders can exhibit dysfunctional mitochondrial respiratory chain complex IV activity. Conditional deletion of cytochrome c oxidase, the terminal enzyme in the respiratory electron transport chain of mitochondria, from hippocampal dentate granule cells in mice does not affect low-frequency dentate to CA3 glutamatergic synaptic transmission. High-frequency dentate to CA3 glutamatergic synaptic transmission and feedforward inhibition are significantly attenuated in cytochrome c oxidase-deficient mice.

Mitochondrial fission augments capsaicin-induced axonal degeneration.

Capsaicin, an agonist of transient receptor potential vanilloid receptor 1, induces axonal degeneration of peripheral sensory nerves and is commonly used to treat painful sensory neuropathies. In this study, we investigated the role of mitochondrial dynamics in capsaicin-induced axonal degeneration. In capsaicin-treated rodent sensory axons, axonal swellings, decreased mitochondrial stationary site length and reduced mitochondrial transport preceded axonal degeneration.

The central role of mitochondria in axonal degeneration in multiple sclerosis.

Neurodegeneration in multiple sclerosis (MS) is related to inflammation and demyelination. In acute MS lesions and experimental autoimmune encephalomyelitis focal immune attacks damage axons by injuring axonal mitochondria. In progressive MS, however, axonal damage occurs in chronically demyelinated regions, myelinated regions and also at the active edge of slowly expanding chronic lesions.

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons.

Axonal degeneration is a primary cause of permanent neurological disability in individuals with the CNS demyelinating disease multiple sclerosis. Dysfunction of axonal mitochondria and imbalanced energy demand and supply are implicated in degeneration of chronically demyelinated axons. The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination.

Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Current treatments are very effective in reducing the neuroinflammatory attack, but fail to significantly halt disease progression and associated loss of neuronal tissue. In recent years, it has become increasingly clear that dysfunctional mitochondria are important contributors to damage and loss of both axons and neurons.

No excess of mitochondrial DNA deletions within muscle in progressive multiple sclerosis.

Background: Mitochondrial dysfunction is an established feature of multiple sclerosis (MS). We recently described high levels of mitochondrial DNA (mtDNA) deletions within respiratory enzyme-deficient (lacking mitochondrial respiratory chain complex IV with intact complex II) neurons and choroid plexus epithelial cells in progressive MS.

Objectives: The objective of this paper is to determine whether respiratory enzyme deficiency and mtDNA deletions in MS were in excess of age-related changes within muscle, which, like neurons, are post-mitotic cells that frequently harbour mtDNA deletions with ageing and in disease.

Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis.

Mitochondrial DNA deletions (∆-mtDNA) have been implicated in the pathogenesis of Alzheimer's disease (AD), multiple sclerosis (MS) and Parkinson's disease (PD), as well as ageing. Clonal expansion of ∆-mtDNA is the process by which a mutant mtDNA molecule increases to high levels within a single cell containing both wild-type and mutant mtDNA. Unlike in AD and PD, the diffuse inflammatory process in MS involves the choroid plexus, and mitochondria are exposed to reactive oxygen and nitrogen species over a prolonged period.

Clonal expansion of mitochondrial DNA deletions and the progression of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Mechanisms of disease progression in MS are poorly understood but are thought to relate to both focal pathology as well as diffuse inflammation in the white and grey matter. Evidence points to neurodegeneration combined with a loss of cellular function in the remaining tissue as an important factor to the progression of MS.

Mitochondrial changes within axons in multiple sclerosis: an update.

Purpose Of Review: Here, we discuss the recent developments in axonal mitochondrial response to demyelination and remyelination in multiple sclerosis (MS), and following experimental demyelination as well as myelination.

Recent Findings: There is a gathering body of evidence implicating an energy-deficient state in the pathogenesis of MS, and mitochondrial defects have been the subject of a number of previous reviews. In myelinated axons within the central nervous system, over 90% of mitochondria are located within juxtaparanodal and internodal axoplasm.

Loss of myelin-associated glycoprotein in kearns-sayre syndrome.

Objective: To explore myelin components and mitochondrial changes within the central nervous system in patients with well-characterized mitochondrial disorders due to nuclear DNA or mitochondrial DNA (mtDNA) mutations.

Design: Immunohistochemical analysis, histochemical analysis, mtDNA sequencing, and real-time and long-range polymerase chain reaction were used to determine the pathogenicity of mtDNA deletions.

Setting: Department of Clinical Pathology, Columbia University Medical Center, and Newcastle Brain Tissue Resource.

Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis.

Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown.

Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis.

Objective: Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system.

Mitochondrial changes associated with demyelination: consequences for axonal integrity.

The loss of myelin sheath (demyelination) renders axons vulnerable to a variety of insults. Axonal degeneration is well recognised in inflammatory demyelinating disorders of the central nervous system (CNS) such as multiple sclerosis (MS) and also certain neurodegenerative diseases. Energy required for nerve impulse conduction and maintenance of structural integrity of axons is met by mitochondria.

Mitochondria as crucial players in demyelinated axons: lessons from neuropathology and experimental demyelination.

Mitochondria are the most efficient producers of energy in the form of ATP. Energy demands of axons, placed at relatively great distances from the neuronal cell body, are met by mitochondria, which when functionally compromised, produce reactive oxygen species (ROS) in excess. Axons are made metabolically efficient by myelination, which enables saltatory conduction.