Reduced expression of PGC-1α partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex

Witte, Maarten E.; Nijland, Philip G.; Drexhage, Joost; Gerritsen, Wouter; Geerts, Dirk; Hof, Bert van het; Reijerkerk, Arie; Vries, Helga E. de; Valk, Paul van der; Horssen, Jack van

doi:10.1007/s00401-012-1052-y

Cited by 123 publications

(94 citation statements)

References 49 publications

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“…The mechanisms involved in cortical pathology are not clear, but current hypotheses describe dysfunction of the mitochondria in the cortex in MS. In studies analyzing postmortem brain tissue, the expression of genes involved in mitochondrial respiration has been found to be altered in normal appearing gray matter (NAGM) in MS brains compared to NAGM in non-diseased brains (Dutta et al 2006; Pandit et al 2009; Witte et al 2013). In a subsequent proteomic analysis of mitochondria in MS and control cortical tissue, hemoglobin β (Hbb) was found to be expressed in neurons and was more abundant in MS postmortem cortex compared to non-diseased cortex (Broadwater et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology

et al. 2016

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Multiple sclerosis (MS) is characterized by demyelination and progressive neurological disability. Previous studies have reported defects to mitochondria in MS including decreased expression of nuclear encoded electron transport chain subunit genes and inhibition of respiratory complexes. We previously reported increased levels of the hemoglobin β subunit (Hbb) in mitochondrial fractions isolated from postmortem MS cortex compared to controls. In the present study, we performed immunohistochemistry to determine the distribution of Hbb in postmortem MS cortex and identified proteins which interact with Hbb by liquid chromatography tandem mass spectrometry (LC-MS/MS). We found that Hbb was enriched in pyramidal neurons in internal layers of the cortex and interacts with subunits of ATP synthase, histones, and a histone lysine demethylase. We also found that Hbb is present in the nucleus and that expression of Hbb in SH-SY5Y neuroblastoma cells increased trimethylation of histone H3 on lysine 4 (H3K4me3), a histone mark that regulates cellular metabolism. These data suggest that Hbb may be a part of a mechanism linking neuronal energetics with epigenetic changes to histones in the nucleus and may provide neuroprotection in MS by supporting neuronal metabolism.

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Section: Introductionmentioning

confidence: 99%

Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology

et al. 2016

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“…The mechanisms responsible for cortical pathology are not clear, but we and others have reported mitochondrial damage in MS cortex. Mitochondrial defects including decreased expression of mitochondrial electron transport chain subunit genes in neurons and cytochrome oxidase inhibition have been reported in normal appearing gray matter (NAGM) in MS (Dutta et al 2006; Pandit et al 2009; Broadwater et al 2011; Campbell et al 2011; Witte et al 2013). It has also been demonstrated that the neuronal metabolite NAA is decreased in the MS brain (Gonen et al 2000; Inglese et al 2004) and that NAA synthesis is regulated by electron transport chain activity (Li et al 2013), suggesting a dysfunction of neuronal metabolism in MS (Cader et al 2007).…”

Section: Introductionmentioning

confidence: 99%

The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition

Singhal

Huang

et al. 2016

Exp Brain Res

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The neuronal mitochondrial metabolite N-acetylaspartate (NAA) is decreased in the multiple sclerosis (MS) brain. NAA is synthesized in neurons by the enzyme N-acetyltransferase-8-like (NAT8L) and broken down in oligodendrocytes by aspartoacylase (ASPA) into acetate and aspartate. We have hypothesized that NAA links the metabolism of axons with oligodendrocytes to support myelination. To test this hypothesis, we performed lipidomic analyses using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and high-performance thin-layer chromatography (HPTLC) to identify changes in myelin lipid composition in postmortem MS brains and in NAT8L knockout (NAT8L−/−) mice which do not synthesize NAA. We found reduced levels of sphingomyelin in MS normal appearing white matter that mirrored decreased levels of NAA. We also discovered decreases in the amounts of sphingomyelin and sulfatide lipids in the brains of NAT8L−/− mice compared to controls. Metabolomic analysis of primary cultures of oligodendrocytes treated with NAA revealed increased levels of α-ketoglutarate, which has been reported to regulate histone demethylase activity. Consistent with this, NAA treatment resulted in alterations in the levels of histone H3 methylation, including H3K4me3, H3K9me2, and H3K9me3. The H3K4me3 histone mark regulates cellular energetics, metabolism, and growth, while H3K9me3 has been linked to alterations in transcriptional repression in developing oligodendrocytes. We also noted the NAA treatment was associated with increases in the expression of genes involved in sulfatide and sphingomyelin synthesis in cultured oligodendrocytes. This is the first report demonstrating that neuronal-derived NAA can signal to the oligodendrocyte nucleus. These data suggest that neuronal-derived NAA signals through epigenetic mechanisms in oligodendrocytes to support or maintain myelination.

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“…Cortical gray matter pathology, including demyelination, axonal degeneration, and brain atrophy, is recognized as a major factor contributing to disability in MS (Inglese et al, 2004;Bö et al, 2006;Fisher et al, 2008). Previous studies suggest that mitochondrial defects, including reductions in neuronal expression of nuclear encoded mitochondrial electron transport chain genes, decreased synthesis of the neuronal mitochondrial metabolite N-acetylaspartate (NAA), and inhibition of mitochondrial respiration contribute to cortical pathology in MS (Dutta et al, 2006;Pandit et al, 2009;Broadwater et al, 2011;Campbell et al, 2011;Li et al, 2013;Witte et al, 2013); however, the mechanisms involved in these mitochondrial changes are not clear.…”

Section: Introductionmentioning

confidence: 99%

Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis

Singhal¹,

Arning

et al. 2015

J. Neurosci.

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Mitochondrial changes, including decreased expression of electron transport chain subunit genes and impaired energetic, have been reported in multiple sclerosis (MS), but the mechanisms involved in these changes are not clear. To determine whether epigenetic mechanisms are involved, we measured the concentrations of methionine metabolites by liquid chromatography tandem mass spectrometry, histone H3 methylation patterns, and markers of mitochondrial respiration in gray matter from postmortem MS and control cortical samples. We found decreases in respiratory markers as well as decreased concentrations of the methionine metabolites S-adenosylmethionine, betaine, and cystathionine in MS gray matter. We also found expression of the enzyme betaine homocysteine methyltransferase in cortical neurons. This enzyme catalyzes the remethylation of homocysteine to methionine, with betaine as the methyl donor, and has previously been thought to be restricted to liver and kidney in the adult human. Decreases in the concentration of the methyl donor betaine were correlated with decreases in histone H3 trimethylation (H3K4me3) in NeuNϩ neuronal nuclei in MS cortex compared with controls. Mechanistic studies demonstrated that H3K4me3 levels and mitochondrial respiration were reduced in SH-SY5Y cells after exposure to the nitric oxide donor sodium nitroprusside, and betaine was able to rescue H3K4me3 levels and respiratory capacity in these cells. Chromatin immunoprecipitation experiments showed that betaine regulates metabolic genes in human SH-SY5Y neuroblastoma cells. These data suggest that changes to methionine metabolism may be mechanistically linked to changes in neuronal energetics in MS cortex.

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Reduced expression of PGC-1α partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex

Cited by 123 publications

References 49 publications

Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology

Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology

The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition

Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis

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