Succinate Dehydrogenase and Ribonucleic Acid Networks in Cancer and Other Diseases

Succinate dehydrogenase (SDH) complex connects both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) in the mitochondria. However, SDH mutation or dysfunction-induced succinate accumulation results in multiple cancers and non-cancer diseases. The mechanistic studies show that succinate activates hypoxia response and other signal pathways via binding to 2-oxoglutarate-dependent oxygenases and succinate receptors. Recently, the increasing knowledge of ribonucleic acid (RNA) networks, including non-coding RNAs, RNA editors, and RNA modifiers has expanded our understanding of the interplay between SDH and RNA networks in cancer and other diseases. Here, we summarize recent discoveries in the RNA networks and their connections to SDH. Additionally, we discuss current therapeutics targeting SDH in both pre-clinical and clinical trials. Thus, we propose a new model of SDH–RNA network interaction and bring promising RNA therapeutics against SDH-relevant cancer and other diseases.

The Emerging Role of Succinate Dehyrogenase Genes (SDHx) in Tumorigenesis

Transformation of a normal cell to cancerous one is dependent on the accumulation of several genetic and epigenetic alterations. One of the candidate driver genetic alterations can happen in succinate dehydrogenases (SDHx) coding gene include SDHA, SDHB, SDHC, SDHD, and SDHAF2. The most important SDH mutation is in the SDHD gene, which encodes the smallest subunit of mitochondrial complex II (SDH). It has key function both in familial and non-familial hereditary paraganglioma/phaeochromocytoma syndrome (HPGL/PCC). SDHx genes mutations can have resulted in genetic and epigenetic changes like histone hypermethylation. These properties can lead to succinate-mediated inhibition of α-ketoglutarate-dependent dioxygenases. So hypoxic conditions can generate subsequent neoplastic transformation, and in this review, we are presenting the role of SDHx in several malignancies.

The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis

Amino acid catabolism is frequently executed in mitochondria; however, it is largely unknown how aberrant amino acid metabolism affects mitochondria. Here we report the requirement for mitochondrial saccharopine degradation in mitochondrial homeostasis and animal development. In Caenorhbditis elegans, mutations in the saccharopine dehydrogenase (SDH) domain of the bi-functional enzyme α-aminoadipic semialdehyde synthase AASS-1 greatly elevate the lysine catabolic intermediate saccharopine, which causes mitochondrial damage by disrupting mitochondrial dynamics, leading to reduced adult animal growth. In mice, failure of mitochondrial saccharopine oxidation causes lethal mitochondrial damage in the liver, leading to postnatal developmental retardation and death. Importantly, genetic inactivation of genes that raise the mitochondrial saccharopine precursors lysine and α-ketoglutarate strongly suppresses SDH mutation-induced saccharopine accumulation and mitochondrial abnormalities in C. elegans. Thus, adequate saccharopine catabolism is essential for mitochondrial homeostasis. Our study provides mechanistic and therapeutic insights for understanding and treating hyperlysinemia II (saccharopinuria), an aminoacidopathy with severe developmental defects.

SDHB mutated paraganglioma imitating thyroid tumor: A case report and review of literature

Paragangliomas of the head and neck are uncommon tumors arising from parasympathetic ganglia. Paragangliomas are mostly asymptomatic and may manifest as palpable mass of neck. The morphologic features are non-specific and comparable to the other neuroendocrine tumors. Most of hereditary cases are associated with alterations in genes of succinate dehydrogenase (SDH). SDHA and SDHB immunohistochemistry is considered as reliable screening method to detect tumors with genetical alterations. Of note, SDHB mutated paragangliomas have the highest risk of local recurrence, distant metastasis and the development of other tumor phenotypes, which are associated with mutation. Therefore, active surveillance of patients and early surgical treatment are essential. In contrast, SDHB mutated head and neck paragangliomas was considered as completely benign tumors, although, the latest literature describes more controversial cases, which may increase awareness. Here, we present a rare case of 21 years old female with asymptomatic neck paraganglioma, which was unexpectedly diagnosed after pathological and immunohistochemical testing of removed thyroid gland and showed unusual immunohistochemical variation for SDH mutation.

Avoiding and Nonexpressing: Coping Styles of Patients With Paragangliomas

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.

Chromosomal changes in sporadic and familial head and neck paragangliomas

Objective: Paragangliomas (PGLs) of the head and neck are benign neoplasms derived from the autonomic nervous system. Familial PGLs have been associated with germline mutations in succinate dehydrogenase (SDH) genes, and occasionally in Von Hippel–Lindau (VHL) and RET. The aim of this study was to compare somatic DNA copy number changes in tumors of familial and sporadic origin. Material and Methods: Eight familial and 16 sporadic patients were analyzed for germline mutations and exon deletions in SDHB, SDHC, SDHD, VHL, and RET by direct sequencing and MLPA. Microarray CGH analysis was applied to map genome-wide somatic copy number changes. Results: Fifteen cases carried a germline mutation in SDHB or SDHD, four of which not described before. Microarray CGH detected abnormalities in 10 of 18 cases, most frequently concerning deletions at 1p, 1q, and 11q, the sites where SDH are located. However, these deletions occurred in both SDH mutation–positive and SDH mutation–negative cases. Conclusions: These data suggest that inactivating germline SDH mutations and somatic deletions of SDH genes as a “second hit” are involved in a subset, but not in all PGLs. Additional genes and mechanisms may need to be studied, especially in the group of sporadic PGL showing no chromosomal aberrations.