Hepatic mitochondrial dysfunction in manifest and premanifest Huntington disease

Stüwe, Sven H.; Goetze, Oliver; Lukas, Carsten; Klotz, Peter; Hoffmann, Rainer; Banasch, Matthias; Orth, Michael; Schmidt, Wolfgang E.; Gold, Ralf; Saft, Carsten

doi:10.1212/wnl.0b013e318282514e

Cited by 54 publications

(44 citation statements)

References 10 publications

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“…This result is particularly important in the context of the specific metabolic symptoms of HD, albeit these actual data obviously cannot show how the reduced mitochondrial activity observed in the liver could be precisely linked to specific symptoms of HD, for example to the characteristic weight loss. Most importantly, our results support the findings by Stüwe et al [5, 46]. In fact, methionine metabolism in the liver is directly linked to the activity of the mitochondrial respiratory chain, which could be therefore the limiting factor in this case.…”

Section: Discussionsupporting

confidence: 92%

“…Few reports showed in addition mitochondrial alterations in peripheral organs like liver [44] or heart [45]. In the case of the liver, more recent human data presented by Stüwe et al, which measured 13 C exhalation as a marker of methionine metabolism in HD patients, are consistent with a mitochondrial dysfunction in liver of HD patients [5]. All these reports suggest an ubiquitous decrease in mitochondrial function in presence of mHTT, but the experimental approaches applied for the respective investigations differed substantially, thus rendering a conclusive comparison of data from different groups challenging.…”

Section: Discussionmentioning

confidence: 86%

“…In particular, functional changes in metabolically active organs (e.g. liver, pancreas) as well as skeletal muscle atrophy are observed in HD patients [5–7]. These alterations contribute to the characteristic weight loss in HD patients, which occurs despite high or increased food intake.…”

Section: Introductionmentioning

confidence: 99%

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High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington’s disease expansion mutation carriers shows normal mitochondrial respiratory function

et al. 2017

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Alterations in mitochondrial respiration are an important hallmark of Huntington’s disease (HD), one of the most common monogenetic causes of neurodegeneration. The ubiquitous expression of the disease causing mutant huntingtin gene raises the prospect that mitochondrial respiratory deficits can be detected in skeletal muscle. While this tissue is readily accessible in humans, transgenic animal models offer the opportunity to cross-validate findings and allow for comparisons across organs, including the brain. The integrated respiratory chain function of the human vastus lateralis muscle was measured by high-resolution respirometry (HRR) in freshly taken fine-needle biopsies from seven pre-manifest HD expansion mutation carriers and nine controls. The respiratory parameters were unaffected. For comparison skeletal muscle isolated from HD knock-in mice (HdhQ111) as well as a broader spectrum of tissues including cortex, liver and heart muscle were examined by HRR. Significant changes of mitochondrial respiration in the HdhQ knock-in mouse model were restricted to the liver and the cortex. Mitochondrial mass as quantified by mitochondrial DNA copy number and citrate synthase activity was stable in murine HD-model tissue compared to control. mRNA levels of key enzymes were determined to characterize mitochondrial metabolic pathways in HdhQ mice. We demonstrated the feasibility to perform high-resolution respirometry measurements from small human HD muscle biopsies. Furthermore, we conclude that alterations in respiratory parameters of pre-manifest human muscle biopsies are rather limited and mirrored by a similar absence of marked alterations in HdhQ skeletal muscle. In contrast, the HdhQ111 murine cortex and liver did show respiratory alterations highlighting the tissue specific nature of mutant huntingtin effects on respiration.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 86%

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High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington’s disease expansion mutation carriers shows normal mitochondrial respiratory function

et al. 2017

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“…In general, the higher prevalence of SN hyperechogenicities in HD and other neurodegenerative disorders might reflect a faster cell aging possibly triggered by a mitochondrial impairment in these patients (Hagenah et al 2010;Bishop et al 2010;Quintanilla and Johnson 2009;Stuwe et al 2013;Saft et al 2005). The more frequent detection of SN alterations compared to nucleus caudate or lentiformis alteration and the high correlations of the bradykinesia score with different functional scores would support the high relevance of bradykinesia in HD (Thompson et al 1988;Sanchez-Pernaute et al 2000).…”

Section: Discussionmentioning

confidence: 91%

Echogenicity of basal ganglia structures in different Huntington’s disease phenotypes

et al. 2014

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In Huntington's disease (HD), a neurodegenerative-inherited disease, chorea as the typical kind of movement disorder is described. Beside chorea, however, all other kinds of movement disturbances, such as bradykinesia, dystonia, tremor or myoclonus can occur. Aim of the current study was to investigate alterations in the echogenicity of basal ganglia structures in different Huntington's disease phenotypes. 47 patients with manifest and genetically confirmed HD were recruited. All participants underwent a thorough neurological examination. According to a previously described method, classification into predominantly choreatic, mixed or bradykinetic-rigid motor phenotypes was performed depending on subscores of the Unified Huntington's Disease Rating Scale. In addition, findings in juvenile HD were compared to adult HD. Transcranial sonography was performed by investigators blinded to clinical classification. There were no significant differences in basal ganglia echogenicities between the three phenotypes. Size of echogenic area of substantia nigra (SN) correlated positively with CAG repeat and bradykinesia subscore, and negatively with age of onset and chorea subscore. Comparing juvenile and adult HD subtypes, SN hyperechogenicity was significantly more often detectable in the juvenile form (100 vs. 29.3 %, p = 0.002). Regarding echogenicity of caudate or lentiform nuclei, no significant differences were detected. HD patients with the juvenile variant exhibit marked hyperechogenicity of substantia nigra. No significant differences in basal ganglia echogenicities between predominantly choreatic, mixed or bradykinetic-rigid motor phenotypes were detected.

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“…Alterations in mitochondrial metabolism are known to play a role in rare childhood diseases (Borchert et al 2002; Shrikhande et al 2010), but they have has also been implicated in many other more common diseases (Vafai and Mootha 2012). In particular, there has been much research into the role of mitochondrial function in neuronal diseases, such as Alzheimer’s disease (Sultana et al 2013), Parkinson’s disease (Mortiboys et al 2013), Huntington’s disease (Stuwe et al 2013), amyotrophic lateral sclerosis (ALS) (Pickles et al 2013), and mental retardation (Haddad et al 2013). It is also well known that mitochondrial dysfunction is associated with metabolic syndrome (James et al 2012), although the underlying molecular mechanisms are not fully elucidated.…”

Section: Common Diseases Associated With Mitochondriamentioning

confidence: 99%

Environmental exposure and mitochondrial epigenetics: study design and analytical challenges

Byun

Baccarelli

2014

Hum Genet

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The environment can influence human health and disease in many harmful ways. Many epidemiological studies have been conducted with the aim of elucidating the association between environmental exposure and human disease at the molecular and pathological levels, and such associations can often be through induced epigenetic changes. One such mechanism for this is through environmental factors increasing oxidative stress in the cell, and this stress can subsequently lead to alterations in DNA molecules. The two cellular organelles that contain DNA are the nucleus and mitochondria, and the latter are particularly sensitive to oxidative stress, with mitochondrial functions often disrupted by increased stress. There has been a substantial increase over the past decade in the number of epigenetic studies investigating the impact of environmental exposures upon genomic DNA, but to date there has been insufficient attention paid to the impact upon mitochondrial epigenetics in studying human disease with exposure to environment. Here, in this review, we will discuss mitochondrial epigenetics with regards to epidemiological studies, with particular consideration given to study design and analytical challenges. Furthermore, we suggest future directions and perspectives in the field of mitochondrial epigenetic epidemiological studies.

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Hepatic mitochondrial dysfunction in manifest and premanifest Huntington disease

Abstract: This study demonstrates for the first time in vivo a subclinical, hepatic involvement in manifest and premanifest HD.

Cited by 54 publications

References 10 publications

High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington’s disease expansion mutation carriers shows normal mitochondrial respiratory function

High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington’s disease expansion mutation carriers shows normal mitochondrial respiratory function

Echogenicity of basal ganglia structures in different Huntington’s disease phenotypes

Environmental exposure and mitochondrial epigenetics: study design and analytical challenges

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