Carney triad, SDH-deficient tumors, and Sdhb+/− mice share abnormal mitochondria

Abstract

Carney Triad(CTr) describes the association of paragangliomas(PGL), pulmonary chondromas, and gastrointestinal(GI) stromal tumors(GISTs) with a variety of other lesions including pheochromocytomas and adrenocortical tumors. The gene(s) causing CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues carrying SDH defects but they have not been studied in CTr. For this study, we examined mitochondrial structure in human tumors and GI tissue(GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), and those with isolated GIST(n=1), with CSS caused by SDHC(n=1), SDHD(n=2) mutations were studied by electron microscopy (EM). GIT from mice with a heterozygous deletion in Sdhb (Sdhb+/−, n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GIST of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained increased mitochondria with “hypoxic” phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities and of variable size. Occasionally, mitochondria were small/round, rarely thin, elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. Similar mitochondrial hypoxic phenotype was seen in Sdhb+/− mice. We conclude tissues from SDH-deficient tumors and mouse GIT and from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still elusive CTr defect(s) is(are) likely to affect mitochondrial function just like germline SDH-deficiency.

Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype

“…Inflammatory component as well as apoptosis rate was low and unchanged in the Sdhd-TpoKO compared to littermate controls (data not shown). Ultrastructure analysis of the thyroids revealed severe degeneration of the mitochondria in Sdhd-TpoKO mice, similar to previous reports (Szarek, et al 2015), suggesting altered bioenergetics (Figure 1D). …”

“…Previous efforts to study tumorigenesis in vivo did not identify an effect of mutant IDH , FH , or SDH genes, including in tissues clearly affected in human patients (Lu, et al 2013; Millan-Ucles et al 2014; Szarek et al 2015). In this report, we address the role of SDHD in thyroid cancer by ablating Sdhd in the thyroid gland.…”

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…The interpretation section of the report should clearly state whether any identified variant is likely to be responsible for the patient's PPGL development and should also include the evidence that supports the Gastrointestinal stromal tumours can associate with paragangliomas due to germ line SDH mutations (StratakisCarney dyad) 81,82 . EPAS1 mosaic mutations have been detected in patients with multiple paragangliomas, duodenal somatostatinomas and polycythaemia 80,83 .…”

Succinate dehydrogenase deficiency in a chromaffin cell model retains metabolic fitness through the maintenance of mitochondrial NADH oxidoreductase function

“…17 Increased mitochondrial mass downstream of SDH deficiency is consistent with previous observations made in SDH-mutated F I G U R E 4 Glutamine oxidation and succinate efflux in Sdhb −/− cells. 26,27 However, this increase may come at a cost to the cell; the mitochondria themselves are less efficient, and even small increases in electron flow were found to result in a reduction in viability ( Figure 1G). B, Relative contribution to effluxed succinate pool from 13 C 5 glutamine.…”