SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas

Armstrong, N.; Storey, Claire M.; Noll, Sarah E; Margulis, Katherine; Soe, Myat Han; Xu, Haixia; Yeh, Benjamin; Fishbein, Lauren; Kebebew, Electron; Howitt, Brooke E.; Zare, Richard N.; Sage, Julien; Annes, Justin P.

doi:10.1016/j.celrep.2022.110453

Cited by 23 publications

(15 citation statements)

References 75 publications

(103 reference statements)

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“…Consequently, it is not fully understood how the loss of SDH profoundly impairs mitochondrial function. Proposed disease-causing consequences of SDH disruption are the intracellular accumulation of succinate, increased reactive oxygen species production, and impaired ATP generation (10)(11)(12).…”

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confidence: 99%

β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes

Lee

Vleck

et al. 2022

Diabetes

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Mitochondrial dysfunction plays a central role in Type 2 Diabetes (T2D); however, the pathogenic mechanisms in pancreatic β-cells are incompletely elucidated. Succinate dehydrogenase (SDH) is a key mitochondrial enzyme with dual functions in the TCA cycle and electron transport chain (ETC). Using human diabetic samples and a mouse model of β-cell-specific SDH ablation (SDHBβKO), we define SDH deficiency as a driver of mitochondrial dysfunction in β-cell failure and insulinopenic diabetes. β-Cell SDH deficiency impairs glucose-induced respiratory oxidative phosphorylation and mitochondrial membrane potential (ΔΨm) collapse, thereby compromising glucose-stimulated ATP production, insulin secretion and β-cell growth. Mechanistically, metabolomic and transcriptomic studies reveal that the loss of SDH causes excess succinate accumulation, which inappropriately activates mTORC1-regulated metabolic anabolism, including increased SREBP-regulated lipid synthesis. These alterations, which mirror diabetes-associated human β-cell dysfunction, are partially reversed by acute mTOR inhibition with rapamycin. We propose SDH deficiency as a contributing mechanism to the progressive β-cell failure of diabetes and identify mTORC1 inhibition as a potential mitigation strategy.

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confidence: 99%

β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes

Lee

Vleck

et al. 2022

Diabetes

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“…Historical attempts at generating GEMMS of cluster 1 pseudohypoxia ( VHL , SDH ) PPGL have failed to develop tumors or are embryonically lethal [ 277 ]. However, recent developments have changed this: The first successful pseudohypoxic PPGL GEMM was recently developed with a gain-of-function EPAS1 mutation, characterizing Pacak-Zhuang syndrome [ 148 ], and tetracycline-induced dual SDHB/NF1 mouse model was recently developed (showing that SDHB inactivation alone was insufficient for tumorigenesis, but coupling with NF1 lead to pheochromocytoma) [ 91 , 151 ].…”

Section: Resultsmentioning

confidence: 99%

Preclinical Models of Neuroendocrine Neoplasia

Sedlack

Saleh-Anaraki

Kumar

et al. 2022

Cancers

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Neuroendocrine neoplasia (NENs) are a complex and heterogeneous group of cancers that can arise from neuroendocrine tissues throughout the body and differentiate them from other tumors. Their low incidence and high diversity make many of them orphan conditions characterized by a low incidence and few dedicated clinical trials. Study of the molecular and genetic nature of these diseases is limited in comparison to more common cancers and more dependent on preclinical models, including both in vitro models (such as cell lines and 3D models) and in vivo models (such as patient derived xenografts (PDXs) and genetically-engineered mouse models (GEMMs)). While preclinical models do not fully recapitulate the nature of these cancers in patients, they are useful tools in investigation of the basic biology and early-stage investigation for evaluation of treatments for these cancers. We review available preclinical models for each type of NEN and discuss their history as well as their current use and translation.

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“…First DESI images of maize roots were acquired as described previously 25,26 . However, the probe and imaging parameters poorly resolved lateral features of the root (Extended Data Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Spectra were acquired in Xcalibur 2.5.5 (Thermo Fisher Scientific), where each row of the image was a separate .raw file. The .raw files were converted and compiled into one .imzML file, as described previously 25 . DESI-MS images were visualized in MSiReader 1.01 28,29 .All images were normalized to the total ion current (see Supplementary Fig.…”

Section: Desi-msi Data Analysismentioning

confidence: 99%

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Chemical Imaging Reveals Diverse Functions of Tricarboxylic Acid Metabolites in Root Growth and Development

Zhang

Noll

Peng

et al. 2022

Preprint

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Understanding how plants grow is critical for agriculture and fundamental for illuminating principles of multicellular development. Here, we apply chemical mapping of the developing maize root using desorption electrospray ionization mass spectrometry imaging (DESI-MSI). This technique reveals a range of small molecule distribution patterns across the gradient of stem cell differentiation in the root. To understand the developmental logic of these patterns, we examined tricarboxylic acid (TCA) cycle metabolites. In both Arabidopsis and maize, TCA metabolites are enriched in developmentally opposing regions, suggesting that stem-cell specific TCA metabolite localization may be conserved in evolutionarily divergent species. We find that these metabolites, particularly succinate, aconitate, citrate, and α-ketoglutarate, control root development in diverse and distinct ways. Critically, the effects of metabolites on stem cell behavior can be independent of their canonical role in ATP production. These results present new insights into development and suggest practical means for controlling plant growth.

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SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas

Cited by 23 publications

References 75 publications

β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes

β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes

Preclinical Models of Neuroendocrine Neoplasia

Chemical Imaging Reveals Diverse Functions of Tricarboxylic Acid Metabolites in Root Growth and Development

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