Investigating complex <scp>I</scp> deficiency in <scp>P</scp>urkinje cells and synapses in patients with mitochondrial disease

Chrysostomou, Alexia; Grady, John P.; Laude, Alex; Taylor, Robert W.; Turnbull, Doug M.; Lax, Nichola Z.

doi:10.1111/nan.12282

Cited by 26 publications

(41 citation statements)

References 44 publications

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“…It is not understood if neurons that harbour such a severe complex I defect are capable of normal neurotransmission and why they do not undergo cell death. While cell loss and synaptic changes are detected in patients harbouring a single large‐scale mtDNA deletion associated with KSS , the major neurohistopathological hallmark is that of a myelinopathy in the deep white matter of the cerebellum, which is widespread throughout the CNS, and this is attributed to specific changes to the oligodendrocyte populations .…”

Section: Neurological Symptoms and Neuropathologymentioning

confidence: 99%

Review: Central nervous system involvement in mitochondrial disease

Lax

Gorman

Turnbull

2016

Neuropathology Appl Neurobio

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Mitochondrial respiratory chain defects are an important cause of inherited disorders affecting approximately 1 in 5000 people in the UK population. Collectively these disorders are termed ‘mitochondrial diseases’ and they result from either mitochondrial DNA mutations or defects in nuclear DNA. Although they are frequently multisystem disorders, neurological deficits are particularly common, wide‐ranging and disabling for patients. This review details the manifold neurological impairments associated with mitochondrial disease, and describes the efforts to understand how they arise and progressively worsen in patients with mitochondrial disease. We describe advances in our understanding of disease pathogenesis through detailed neuropathological studies and how this has spurred the development of cellular and animal models of disease. We underscore the importance of continued clinical, molecular genetic, neuropathological and animal model studies to fully characterize mitochondrial diseases and understand mechanisms of neurodegeneration. These studies are instrumental for the next phase of mitochondrial research that has a particular emphasis on finding novel ways to treat mitochondrial disease to improve patient care and quality of life.

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Section: Neurological Symptoms and Neuropathologymentioning

confidence: 99%

Review: Central nervous system involvement in mitochondrial disease

Lax

Gorman

Turnbull

2016

Neuropathology Appl Neurobio

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“…In contrast, NDUFB8 was low with 50% deficiency in the post‐mitotic smooth muscle of the colon from patients compared with age‐matched controls (Figure ). We found higher levels of nuclear encoded mitochondrial proteins, SDHA and COX4, both of which are reported to be preserved in tissues with mtDNA defects , in the epithelium of the patients' oesophagus (47.62% and 40.91%, respectively), stomach (14.29% for SDHA), and SI (10% in patient 2 for SDHA; 8.57% in patient 1 and 14.29% in patient 2 for COX4) (supplementary material, Figure S1). SDHA also increased in the colonic muscle of the patient (27.27% (supplementary material, Figure S1)).…”

Section: Resultsmentioning

confidence: 82%

Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations

Grady

Afshar

et al. 2018

The Journal of Pathology

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Inherited mitochondrial DNA (mtDNA) mutations cause mitochondrial disease, but mtDNA mutations also occur somatically and accumulate during ageing. Studies have shown that the mutation load of some inherited mtDNA mutations decreases over time in blood, suggesting selection against the mutation. However, it is unknown whether such selection occurs in other mitotic tissues, and where it occurs within the tissue. Gastrointestinal epithelium is a canonical mitotic tissue rapidly renewed by stem cells. Intestinal crypts (epithelium) undergo monoclonal conversion with a single stem cell taking over the niche and producing progeny. We show: (1) that there is a significantly lower mtDNA mutation load in the mitotic epithelium of the gastrointestinal tract when compared to the smooth muscle in the same tissue in patients with the pathogenic m.3243A>G and m.8344A>G mutations; (2) that there is considerable variation seen in individual crypts, suggesting changes in the stem cell population; (3) that this lower mutation load is reflected in the absence of a defect in oxidative phosphorylation in the epithelium. This suggests that there is selection against inherited mtDNA mutations in the gastrointestinal stem cells that is in marked contrast to the somatic mtDNA mutations that accumulate with age in epithelial stem cells leading to a biochemical defect. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…40 In non-mitochondrial migraine patients increased oxidative stress markers like malondialdehyde, total antioxidant activity, GSH/GSSG concentrations were observed as were decreased concentrations of plasma GSH, glutathionine-S-transferase (GST), and total antioxidant capacity compared to controls. 40,80 PET imaging with 56 Cu-ATSM and 18 FDG demonstrated increased oxidative stress and increased glucose metabolism following hyperemia in a MELAS syndrome patient with stroke-like episodes. 41 Importantly, to our best knowledge, so far none of these imaging studies have been done in migraine m.3243A>G patients without stroke-like episodes.…”

Section: Mitochondria: Structure Function and Pathologymentioning

confidence: 93%

Mitochondrial Migraine: Disentangling the angiopathy paradigm in m.3243A>G patients

Smeitink¹,

Koene²,

Saris³

et al. 2019

JIMD Reports

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Migraine, characterized by recurrent attacks of predominantly unilateral throbbing headache, affects approximately 15% of the adult population and is an important cause of disability worldwide. Knowledge required for the development of new classes of antimigraine drugs might come from studying rare metabolic diseases associated with migraine. An illustrative example of a monogenetic disorder associated with migraine is the spectrum of disorders caused by the m.3243A>G mutation in the mitochondrial transfer RNA Leucine. Reported migraine prevalence figures in patients with this particular mutation vary considerably, but compared to the general population, m.3243A>G patients have a higher migraine prevalence. This burdensome symptom might sometimes even be the only clinical feature in maternal relatives carrying the m.3243A>G mutation. Although the exact sequence of events and the relative importance of factors underlying migraine in m.3243A>G MELAS spectrum disorders are still enigmatic, substantial evidence in man exist that dysfunctional mitochondria in both the vascular, the smooth muscle cells and the neuronal system and the interaction between these are at the starting point of the migraine developing pathophysiological cascade. Exclusively based on results of studies performed in patients harboring the m.3243A>G mutation, either in vivo or ex vivo, we here summarize our current understanding of mitochondrial angiopathy associated migraine in m.3243A>G patients which knowledge might lead to potential new avenues for migraine drug development.

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Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease

Cited by 26 publications

References 44 publications

Review: Central nervous system involvement in mitochondrial disease

Review: Central nervous system involvement in mitochondrial disease

Inherited pathogenic mitochondrial DNA mutations and gastrointestinal stem cell populations

Mitochondrial Migraine: Disentangling the angiopathy paradigm in m.3243A>G patients

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