Is the mitochondrial DNA involved in determining susceptibility to multiple sclerosis?

Kálmán, Bernadette; Alden, Herbert S.

doi:10.1111/j.1600-0404.1998.tb07301.x

Cited by 35 publications

(24 citation statements)

References 48 publications

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“…It was also stated that mitochondrial complex I gene variants are associated with MS (67). On the other hand, many patients suffering from Leber's hereditary optic neuropathy disease, caused by mutations in the mitochondrially encoded subunits of complex I, display symptoms of MS (33). The MS pathology in patients with mutations in genes of complex I is not understood; therefore, our data warrant investigation of whether CD95L expression plays a role in its development.…”

Section: Discussionmentioning

confidence: 93%

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

Kamiński

Kießling

Süss

et al. 2007

Molecular and Cellular Biology

124

153

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Reactive oxygen species (ROS) play a key role in regulation of activation-induced T-cell death (AICD) by induction of CD95L expression. However, the molecular source and the signaling steps necessary for ROS production are largely unknown. Here, we show that the proximal T-cell receptor-signaling machinery, including ZAP70 (zeta chain-associated protein kinase 70), LAT (linker of activated T cells), SLP76 (SH2 domaincontaining leukocyte protein of 76 kDa), PLC␥1 (phospholipase C␥1), and PKC (protein kinase C), are crucial for ROS production. PKC is translocated to the mitochondria. By using cells depleted of mitochondrial DNA, we identified the mitochondria as the source of activation-induced ROS. Inhibition of mitochondrial electron transport complex I assembly by small interfering RNA (siRNA)-mediated knockdown of the chaperone NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS are converted into a hydrogen peroxide signal by the mitochondrial superoxide dismutase. This signal is essential for CD95L expression, as inhibition of complex I assembly by NDUFAF1-specific siRNA prevents AICD. Similar results were obtained when metformin, an antidiabetic drug and mild complex I inhibitor, was used. Thus, we demonstrate for the first time that PKC-dependent ROS generation by mitochondrial complex I is essential for AICD.Because CD95L expression is crucial for the induction of activation-induced T-cell death (AICD), efforts have been made to explore the connection between T-cell receptor (TCR) signaling and regulation of CD95L transcription. Following TCR engagement, ZAP70 (zeta chain-associated protein kinase 70) is activated (11). ZAP70 phosphorylates the adaptor protein LAT (linker of activated T cells) (19), which recruits PLC␥1 (phospholipase C␥1) subsequently. The activation of PLC␥1 results in the generation of inositol 3,4,5-triphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 mediates an increase in cytosolic calcium (Ca 2ϩ ), whereas DAG activates protein kinase C (PKC). The rise in cytosolic Ca 2ϩ causes activation of the transcription factor NF-AT (nuclear factor of activated T cells) (69), one of the key regulators of CD95L expression (41). In addition, reactive oxygen species (ROS) are shown to be crucial for activation-induced CD95L expression (7,15,25), possibly via the ROS-inducible transcription factors NF-B and AP-1 (17). Recently, we demonstrated that a hydrogen peroxide (H 2 O 2 )-mediated signal combined with simultaneous Ca 2ϩ influx into the cytosol constitutes the minimal requirement for CD95L expression (25). However, the molecular source of TCR-induced ROS remains largely unclear. Aerobic organisms produce ROS by several means: in mitochondria as a by-product of respiration (63), at the endoplasmic reticulum by cytochrome P450 (50), in the cytoplasm by xanthine oxidase (20), at the plasma membrane by NADPH oxidases (35, 46) and phospholipases (54), and in peroxisomes (56). Recently, the phagocytic NADPH oxidase (NOX2) was shown to be one source for TCR-triggered ROS. However,...

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Section: Discussionmentioning

confidence: 93%

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

Kamiński

Kießling

Süss

et al. 2007

Molecular and Cellular Biology

124

153

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“…Despite the high potential of ROS for causing ultrastructural changes and degeneration through oxidative damage in plaques, they have not been thoroughly investigated in MS. In this preliminary study, we asked if ROS production correlates with disease activity, mtDNA haplotypes associated with MS, or with production of cytokines (TNF-a, IFN-g) known to parallel disease activity [20][21][22][23][24]. We also addressed what subcellular pathway is involved in ROS production, and how it relates to the immunopathology of MS.…”

Section: Introductionmentioning

confidence: 99%

The activation of protein kinase C induces higher production of reactive oxygen species by mononuclear cells in patients with multiple sclerosis than in controls

Vladimirova¹,

Lu²,

Shawver³

et al. 1999

Inflamm. res.

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The detected phase difference between the highest ROS production vs TNF-alpha expression is compatible with the hypothesis that different subpopulations of monocytes/macrophages are involved. We suggest that the ROS producing subpopulation preferentially migrates into the central nervous system (CNS) during a relapse. The present study together with our previous observation on oxidative damage to DNA in active plaques delineates a molecular pathway likely involved in the histologic evolution of inflammatory demyelination.

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“…LHON-related mtDNA mutations were also described for the myelodysplastic syndrome (Linnartz et al 2004). Strikingly, LHON progression is often associated with an autoimmune multiple sclerosis (MS)-like syndrome (Kalman and Alder 1998). MS is a T cell-mediated autoimmune disorder of the brain and spinal cord, manifested by inflammation and demyelination of nerve tissue.…”

Section: Mitochondrial Disordersmentioning

confidence: 99%

Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

Kamiński

Röth

Krammer

et al. 2013

Arch. Immunol. Ther. Exp.

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Is the mitochondrial DNA involved in determining susceptibility to multiple sclerosis?

Cited by 35 publications

References 48 publications

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

The activation of protein kinase C induces higher production of reactive oxygen species by mononuclear cells in patients with multiple sclerosis than in controls

Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

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