Buffering mitochondrial DNA variation

Baughman, Joshua M.; Mootha, Vamsi K.

doi:10.1038/ng1106-1232

Cited by 25 publications

(14 citation statements)

References 11 publications

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“…It is interesting to note that redox sensing cell signaling, via ROS-dependent pathways, is emerging as a regulator of glucose and lipid metabolism in health, aging, and disease [46]. If huntingtin proves to be involved, the molecules and gene products that modify oxidation-sensitive signaling in metabolic disorders may become candidates for modifying huntingtin-regulated mitochondrial metabolism in HD.…”

Section: Result/discussionmentioning

confidence: 99%

Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism

et al. 2007

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The Huntington's disease (HD) CAG repeat, encoding a polymorphic glutamine tract in huntingtin, is inversely correlated with cellular energy level, with alleles over ∼37 repeats leading to the loss of striatal neurons. This early HD neuronal specificity can be modeled by respiratory chain inhibitor 3-nitropropionic acid (3-NP) and, like 3-NP, mutant huntingtin has been proposed to directly influence the mitochondrion, via interaction or decreased PGC-1α expression. We have tested this hypothesis by comparing the gene expression changes due to mutant huntingtin accurately expressed in STHdhQ111/Q111 cells with the changes produced by 3-NP treatment of wild-type striatal cells. In general, the HD mutation did not mimic 3-NP, although both produced a state of energy collapse that was mildly alleviated by the PGC-1α-coregulated nuclear respiratory factor 1 (Nrf-1). Moreover, unlike 3-NP, the HD CAG repeat did not significantly alter mitochondrial pathways in STHdhQ111/Q111 cells, despite decreased Ppargc1a expression. Instead, the HD mutation enriched for processes linked to huntingtin normal function and Nf-κB signaling. Thus, rather than a direct impact on the mitochondrion, the polyglutamine tract may modulate some aspect of huntingtin's activity in extra-mitochondrial energy metabolism. Elucidation of this HD CAG-dependent pathway would spur efforts to achieve energy-based therapeutics in HD.

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Section: Result/discussionmentioning

confidence: 99%

Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism

et al. 2007

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“…Mitochondria are the major site of ROS production within the cell [22]. Over‐production of ROS will change mitochondrial morphology [21] and mtDNA replication [23].…”

Section: Discussionmentioning

confidence: 99%

Decreased peripheral blood mitochondrial DNA content is related to HbA_1c, fasting plasma glucose level and age of onset in Type 2 diabetes mellitus

Zhou

Shen

et al. 2012

Diabetic Medicine

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“…It is likely that patients with diabetic complications have worse glycaemic control than those without complications; moreover, the presence of diabetes complications is causally associated with overproduction of ROS primarily derived from mitochondria [36]. Interestingly, high glucose-induced overproduction of ROS has been shown to change mitochondrial morphology [37] and has a regulatory role in growth factor signalling and mtDNA replication [38]. Furthermore, different mtDNA haplotypes are associated with differences in ROS generation [38,39].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, high glucose-induced overproduction of ROS has been shown to change mitochondrial morphology [37] and has a regulatory role in growth factor signalling and mtDNA replication [38]. Furthermore, different mtDNA haplotypes are associated with differences in ROS generation [38,39]. So in addition to exogenous factors impacting on ROS, e.g.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA content in peripheral blood monocytes: relationship with age of diabetes onsetand diabetic complications

et al. 2009

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Aims/hypothesis We examined whether age of type 2 diabetes onset is related to mitochondrial DNA content in peripheral blood monocytes (PBMCs). Methods PBMCs were isolated from 65 patients with type 2 diabetes. To minimise age as a confounder, only patients aged ≥50 years were studied. Sample mitochondrial DNA (mtDNA) content was determined by amplification of the mitochondrial gene CYT-B (also known as MT-CYB) and adjusted for single-copy nuclear control genes (36B4 [also known as RPLPO] and GAPDH). Results Age of diabetes onset ranged from 25 to 69 years. There was a significant positive relationship between age of diabetes onset in quartiles and mtDNA content for the whole group (p= 0.02 for trend). When stratified by the presence of diabetes complications, a strong positive relationship was observed between age of diagnosis and mtDNA content for participants without diabetic complications (r = 0.7; p = 0.0002), but not for those with complications (r=−0.04; p=0.8). Multivariate analysis confirmed age of onset and complication status as independent determinants. There was co-linearity between age of onset and disease duration, with similar relationships also seen between duration and mtDNA content. Conclusions/interpretation An earlier age of type 2 diabetes onset is associated with a lower PBMC mtDNA content, but only in patients without diabetes complications. This may reflect a differing biology of PBMC mtDNA in those with early-onset diabetes and those who are prone to complications. PBMC mtDNA depletion may accelerate diabetes onset; however the independent effect of diabetes duration remains to be evaluated.

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Buffering mitochondrial DNA variation

Cited by 25 publications

References 11 publications

Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism

Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism

Decreased peripheral blood mitochondrial DNA content is related to HbA_1c, fasting plasma glucose level and age of onset in Type 2 diabetes mellitus

Mitochondrial DNA content in peripheral blood monocytes: relationship with age of diabetes onsetand diabetic complications

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Buffering mitochondrial DNA variation

Cited by 25 publications

References 11 publications

Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism

Unbiased Gene Expression Analysis Implicates the huntingtin Polyglutamine Tract in Extra-mitochondrial Energy Metabolism

Decreased peripheral blood mitochondrial DNA content is related to HbA1c, fasting plasma glucose level and age of onset in Type 2 diabetes mellitus

Mitochondrial DNA content in peripheral blood monocytes: relationship with age of diabetes onsetand diabetic complications

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Decreased peripheral blood mitochondrial DNA content is related to HbA_1c, fasting plasma glucose level and age of onset in Type 2 diabetes mellitus