Rabbit Anti-Human SDHC (a.a. 1-169) Polyclonal antibody

Context: Paraganglioma (PGL) patients and succinate dehydrogenase (SDH) gene mutation carriers at risk for PGLs have a decreased quality of life (QoL). QoL may be affected by the strategy an individual uses when dealing with a stressful situation, ie, specific coping styles. Understanding the various approaches to coping may allow the development of targeted interventions to improve patient QoL. Objective: The objective of the study was to assess coping styles in PGL patients and SDH mutation carriers. Design: This was a cross-sectional study. Setting: The study was conducted at a tertiary referral center. Patients and Methods: Coping styles were assessed using the Utrecht Coping List. The results from the study cohort were compared with a control group and data derived from the literature. Potential differences in coping styles between the various SDH mutation carriers and PGL patients without an SDH mutation were explored. Results: Of the 174 patients who responded, 122 were SDHD, 25 SDHB, and 2 SDHC mutation carriers. An additional 25 patients lacked an SDH mutation. They recruited 100 peers as controls. Compared with the general population, the study cohort was more avoidant of problems (P < .001) and reported less expression of emotion (P < .01). Compared with patients with other conditions, they sought more social support (P < .001). There were no significant differences in coping styles between the various categories of mutation carriers or PGL patients lacking a mutation. Conclusions: Coping styles of PGL patients and SDH mutation carriers differ from those of control and reference groups and include an avoidant coping style and a lack of emotional expression. (J Clin Endocrinol Metab 98: 3608-3614, 2013)

Mutations in mitochondrial complex II (succinate dehydrogenase; SDH) genes predispose to paraganglioma tumors that show constitutive activation of hypoxia responses. We recently showed that SDHB mRNAs in hypoxic monocytes gain a stop codon mutation by APOBEC3A-mediated C-to-U RNA editing. Here, we test the hypothesis that inhibition of complex II facilitates hypoxic gene expression in monocytes using an integrative experimental approach. By RNA sequencing, we show that specific inhibition of complex II by atpenin A5 in normoxic conditions mimics hypoxia and induces hypoxic transcripts as well as APOBEC3A-mediated RNA editing in human monocytes. Myxothiazol, a complex III inhibitor, has similar effects in normoxic monocytes. Atpenin A5 partially inhibits oxygen consumption, and neither hypoxia nor atpenin A5 in normoxia robustly stabilizes hypoxia-inducible factor (HIF)-1 alpha in primary monocytes. Several earlier studies in transformed cell lines suggested that normoxic stabilization of HIF-1 alpha explains the persistent expression of hypoxic genes upon complex II inactivation. On the contrary, we find that atpenin A5 antagonizes the stabilization of HIF-1 alpha and reduces hypoxic gene expression in transformed cell lines. Accordingly, compound germline heterozygosity of mouse Sdhb/Sdhc/Sdhd null alleles blunts chronic hypoxia-induced increases in hemoglobin levels, an adaptive response mainly regulated by HIF-2 alpha. In contrast, atpenin A5 or myxothiazol does not reduce hypoxia-induced gene expression or RNA editing in monocytes. These results reveal a novel role for mitochondrial respiratory inhibition in induction of the hypoxic transcriptome in monocytes and suggest that inhibition of complex II activates a distinct hypoxia signaling pathway in a cell-type specific manner.