Which way does the citric acid cycle turn during hypoxia? The critical role of α‐ketoglutarate dehydrogenase complex

Chinopoulos, Christos

doi:10.1002/jnr.23196

Cited by 112 publications

(106 citation statements)

References 197 publications

(196 reference statements)

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“…3E), despite decreased succinate downstream, which could be explained by the fall in both α-ketoglutarate dehydrogenase and isocitrate dehydrogenase, as reported previously in Lowlanders following an identical ascent to EBC (21). α-Ketoglutarate plays regulatory roles in hypoxia, including suppression of HIF stabilization (35), but also supporting glutathione synthesis (36). Taken together, these results indicate different TCA cycle regulation in Sherpas and Lowlanders.…”

Section: Resultssupporting

confidence: 73%

Metabolic basis to Sherpa altitude adaptation

Horscroft

Kotwica

Laner

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

180

219

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The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature. metabolism | altitude | skeletal muscle | hypoxia | mitochondria

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Section: Resultssupporting

confidence: 73%

Metabolic basis to Sherpa altitude adaptation

Horscroft

Kotwica

Laner

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

180

219

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“…Furthermore, the notion that both ATP-and GTPforming SUCL activity should exhibit an extremely lowif any-rate in human astrocytes, hints at peculiarities of the directionality of citric acid cycle in these cells (Chinopoulos 2013). Although the citric acid cycle is branded as a ''cycle'', it does not necessarily operate as one (Chinopoulos 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Although the citric acid cycle is branded as a ''cycle'', it does not necessarily operate as one (Chinopoulos 2013). It is well known, that astrocytes produce and release large quantities of succinate (Westergaard et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Exclusive neuronal expression of SUCLA2 in the human brain

et al. 2013

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SUCLA2 encodes the ATP-forming b subunit (A-SUCL-b) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here, we show that immunoreactivity of A-SUCL-b in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL-b immunoreactivity colocalized [99 % with that of the d subunit of the mitochondrial F 0 -F 1 ATP synthase. Specificity of the anti-A-SUCL-b antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL-b immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming b subunit (G-SUCL-b) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL-b immunoreactivity that was, however, not upregulated in samples obtained from diabetic versus nondiabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex.

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“…As it is mentioned in the "Introduction", succinyl CoA ligase is a reversible enzyme; when it proceeds towards generation of succinyl-CoA, this product may only follow heme-or ketone body metabolism (Labbe et al 1965;Ottaway et al 1981;Dringen et al 2007;Lopes-Cardozo et al 1986) because it cannot be processed further by the irreversible α-ketoglutarate dehydrogenase complex (Chinopoulos 2013). When succinyl CoA ligase operates in the opposite direction towards ATP or GTP formation (a process termed 'substratelevel phosphorylation'), it yields succinate that can be either further processed by succinate dehydrogenase, and advance in the citric acid cycle, or act as a metabolic signal in inflammation (Mills and O'Neill 2014).…”

Section: Discussionmentioning

confidence: 99%

Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain

Dobolyi

Bagó

Gál

et al. 2014

J Bioenerg Biomembr

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We have recently shown that the ATP-forming SUCLA2 subunit of succinyl-CoA ligase, an enzyme of the citric acid cycle, is exclusively expressed in neurons of the human cerebral cortex; GFAP-and S100-positive astroglial cells did not exhibit immunohistoreactivity or in situ hybridization reactivity for either SUCLA2 or the GTP-forming SUCLG2. However, Western blotting of post mortem samples revealed a minor SUCLG2 immunoreactivity. In the present work we sought to identify the cell type(s) harboring SUCLG2 in paraformaldehyde-fixed, free-floating surgical human cortical tissue samples. Specificity of SUCLG2 antiserum was supported by co-localization with mitotracker orange staining of paraformaldehyde-fixed human fibroblast cultures, delineating the mitochondrial network. In human cortical tissue samples, microglia and oligodendroglia were identified by antibodies directed against Iba1 and myelin basic protein, respectively. Double immunofluorescence for SUCLG2 and Iba1 or myelin basic protein exhibited no costaining; instead, SUCLG2 appeared to outline the cerebral microvasculature. In accordance to our previous work there was no co-localization of SUCLA2 immunoreactivity with either Iba1 or myelin basic protein. We conclude that SUCLG2 exist only in cells forming the vasculature or its contents in the human brain. The absence of SUCLA2 and SUCLG2 in human glia is in compliance with the presence of alternative pathways occurring in these cells, namely the GABA shunt and ketone body metabolism which do not require succinyl CoA ligase activity, and glutamate dehydrogenase 1, an enzyme exhibiting exquisite sensitivity to inhibition by GTP.

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Which way does the citric acid cycle turn during hypoxia? The critical role of α‐ketoglutarate dehydrogenase complex

Cited by 112 publications

References 197 publications

Metabolic basis to Sherpa altitude adaptation

Metabolic basis to Sherpa altitude adaptation

Exclusive neuronal expression of SUCLA2 in the human brain

Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain

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