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

Abstract

Mutations in succinate dehydrogenase (SDH) lead to the development of tumors in a restricted subset of cell types, including chromaffin cells and paraganglia.The molecular basis for this specificity is currently unknown. We show that loss of SDH activity in a chromaffin cell model does not perturb complex I function, retaining the ability to oxidize NADH within the electron transport chain. This activity supports continued oxidation of substrates within the tricarboxylic acid (TCA) cycle. However, due to the block in the TCA cycle at SDH, the high glutamine oxidation activity is only maintained through an efflux of succinate. We also show that although the mitochondria of SDH-deficient cells are less active per se, their higher mass per cell results in an overall respiratory rate that is comparable with wild-type cells. Finally, we observed that when their mitochondria are uncoupled, SDH-deficient cells are unable to preserve their viability, suggesting that the mitochondrial metabolic network is unable to compensate when exposed to additional stress. We therefore show that in contrast to models of SDH deficiency based on epithelial cells, a chromaffin cell model retains aspects of metabolic "health," which could form the basis of cell specificity of this rare tumor type. | KĽUČKOVÁ et al | MATERIALS AND METHODS | Cell culture and chemicalsPreviously characterized immortalized mouse chromaffin cell lines deficient in Sdhb (Sdhb −/− CL6 and CL8) as well K E Y W O R D S electron transport chain, metabolism, mitochondria, pheochromocytoma, succinate dehydrogenase

SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction

“…Switching to FAO may lead to more ETFDH‐dependent electron transfer rather than transfer through Complex II. A recent study (Kľučková et al, 2020 ) reported that SDH‐deficient murine chromaffin cells could maintain efficient FAO respiration that are higher than wildtype cells when palmitoylcarnitine is provided. Consistent with these observations, HepG2 cells treated with SDH inhibitor 3‐NPA blocks succinate‐dependent respiration completely but affects fatty acid oxidation minimally (Y. Qin, J. M. Denu, unpublished observation).…”

SIRT3 deficiency decreases oxidative-metabolism capacity but increases lifespan under caloric restriction

“…Switching to FAO may lead to more ETFDHdependent electron transfer rather than transfer through Complex II. A recent study (Kľučková et al, 2020) reported that SDH-deficient murine chromaffin cells could maintain efficient FAO respiration that are higher than wildtype cells when palmitoyl-carnitine is respired. With only minorly affected Complex I observed in our study, FAO could be preserved in Sirt3 -/-CR mice by increased flux through ETFDH, serving as a compensatory mechanism to drive FAO-dependent energy generation.…”

Epigenetic and metabolic reprogramming of SDH-deficient paragangliomas

“…Recently, several studies evaluating the respiration and mitochondrial complexes activity of different SDHdeficient cell types revealed some intriguing data that might be a first step in the understanding of the tissue specificity of tumor development in SDH-mutated patients. Indeed, while both respiration of intact cells and complex I-specific activity were found to be lower in SDH-deficient cells compared with WT adrenal fibroblast (Kľučková et al 2020), renal (Cardaci et al 2015, Lorendeau et al 2017 and breast epithelial cells (Bezawork-Geleta et al 2018), it is not the case in a chromaffin cell-derived model. This model retains complex I function and a respiratory activity comparable to WT cells, thereby maintaining the ability to oxidise NADH within the ETC (Kľučková et al 2020).…”

“…Indeed, while both respiration of intact cells and complex I-specific activity were found to be lower in SDH-deficient cells compared with WT adrenal fibroblast (Kľučková et al 2020), renal (Cardaci et al 2015, Lorendeau et al 2017 and breast epithelial cells (Bezawork-Geleta et al 2018), it is not the case in a chromaffin cell-derived model. This model retains complex I function and a respiratory activity comparable to WT cells, thereby maintaining the ability to oxidise NADH within the ETC (Kľučková et al 2020). These data showed that in contrast to models of SDH deficiency based on epithelial cells, a chromaffin cell model preserves some aspects of metabolic 'health', which could form the basis of cell specificity of this rare tumor type.…”