A homozygous genetic variant of mitochondrial uncoupling protein 4 affects the occurrence of leukoaraiosis

Szolnoki, Z.; Kondacs, András; Mándi, Yvette; Bodor, Anita; Somogyvári, Ferenc

doi:10.1111/j.1600-0404.2010.01391.x

Cited by 10 publications

(5 citation statements)

References 30 publications

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“…Accordingly, the expression of UCP4 has been found significantly reduced in brains of subjects affected by Alzheimer disease [91]. Moreover, it was found that CC genotype for rs10807344 of UCP4 gene, not found to be associated in the present study with the longevity phenotype, exerts a protective effect on the occurrence of multiple sclerosis and of leukoaraiosis, a vascular demyelinization of the white matter of the brain [92], [93]. Thus, it is likely that variants affecting the UCP4 function might have consequences on the aging of the nervous system, and then might have a potential impact on health and longevity.…”

Section: Discussionmentioning

confidence: 52%

Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity

et al. 2011

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In humans Uncoupling Proteins (UCPs) are a group of five mitochondrial inner membrane transporters with variable tissue expression, which seem to function as regulators of energy homeostasis and antioxidants. In particular, these proteins uncouple respiration from ATP production, allowing stored energy to be released as heat. Data from experimental models have previously suggested that UCPs may play an important role on aging rate and lifespan. We analyzed the genetic variability of human UCPs in cohorts of subjects ranging between 64 and 105 years of age (for a total of 598 subjects), to determine whether specific UCP variability affects human longevity. Indeed, we found that the genetic variability of UCP2, UCP3 and UCP4 do affect the individual's chances of surviving up to a very old age. This confirms the importance of energy storage, energy use and modulation of ROS production in the aging process. In addition, given the different localization of these UCPs (UCP2 is expressed in various tissues including brain, hearth and adipose tissue, while UCP3 is expressed in muscles and Brown Adipose Tissue and UCP4 is expressed in neuronal cells), our results may suggest that the uncoupling process plays an important role in modulating aging especially in muscular and nervous tissues, which are indeed very responsive to metabolic alterations and are very important in estimating health status and survival in the elderly.

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Section: Discussionmentioning

confidence: 52%

Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity

et al. 2011

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“…However, in keeping with the hypothesis that ucp4 and ucp5 may not regulate canonical uncoupling, no similar associations have been reported for ucp4 and ucp5 (29). Interestingly, single nucleotide polymorphisms (rs10807344 CC) in ucp4 have been linked to protection against both multiple sclerosis susceptibility and brain leukoaraiosis (30,31), and others link the same ucp4 mutation to increased schizophrenia incidence (32). We found that mutant ucp4 nematodes exhibited decreased respiration and increased levels of stored triglycerides and several fatty acids species when compared with N2.…”

Section: Discussionmentioning

confidence: 74%

Caenorhabditis elegans UCP4 Protein Controls Complex II-mediated Oxidative Phosphorylation through Succinate Transport

Pfeiffer

Kayzer²,

Yang

et al. 2011

Journal of Biological Chemistry

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Background:The function of the C. elegans mitochondrial uncoupling protein 4 (ceUCP4) has not been characterized. Results: Worms deficient in ceUCP4 displayed hypometabolic phenotypes and complex II dysfunction that corresponded with a significant loss of mitochondrial succinate import. Conclusion: ceUCP4 plays a novel role in the regulation of complex II by controlling succinate transport into mitochondria. Significance: Understanding how extramitochondrial succinate and ceUCP4 regulate complex II-mediated metabolism is critical for understanding the mechanisms of cellular respiration.

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“…This finding suggests that impaired mitochondrial physiology is sufficient to generate a delay in OPC differentiation and implies a possible explanation for the observed association between genetic variants of UCPs in two types of demyelinating disorders: MS and leukoaraiosis. [41][42][43][44] In addition, a concomitant increase in ROS would worsen the impairment of differentiation, explaining the correlation between increased ROS levels and the severity of the demyelinating disorder. 38,39 On the basis of these results, the cells exposed to TNF-a were expected to exhibit metabolic impairments.…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

et al. 2014

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Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-a) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-a exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-a induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.

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A homozygous genetic variant of mitochondrial uncoupling protein 4 affects the occurrence of leukoaraiosis

Abstract: The present findings indirectly raise the possibility that a shift or imbalance in the finely regulated MMP may play a role in the development of LA.

Cited by 10 publications

References 30 publications

Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity

Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity

Caenorhabditis elegans UCP4 Protein Controls Complex II-mediated Oxidative Phosphorylation through Succinate Transport

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

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