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Complex II assembly drives metabolic adaptation to OXPHOS dysfunction

ABSTRACT: During acute oxidative phosphorylation (OXPHOS) dysfunction, the reverse activity of succinate dehydrogenase (Complex II) maintains the redox state of the Coenzyme Q pool by utilizing either fumarate or oxygen as terminal electron acceptors. The tendency for one over another has been suggested to be tissue specific. We identified the action of SDHAF2 protein, a Complex II assembly factor that enhances the flavination of catalytic subunit SDHA, as critical for metabolic adaptation during Complex III dysfunction in HEK293T cells. Loss of SDHAF2 during Complex III inhibition led to a net reductive TCA cycle from loss of succinate oxidation, loss of SDHA active site derived reactive oxygen species (ROS)-signaling, insufficient adaptation to glycolysis, and a severe growth impairment. Cell lines adapted to glycolysis did not accumulate SDHAF2 upon Coenzyme Q-pool stress, exhibited a net reductive TCA cycle and mild growth phenotypes with or without SDHAF2 being present. Thus, our study reveals how Complex II assembly controls a balance between dynamics of TCA cycle directionality, protection from Q-pool stress, and an ability to utilize ROS-meditated signaling to overcome acute OXPHOS dysfunction in cells reliant on mitochondrial respiration.

INSTRUMENT(S): Orbitrap Ascend, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Kidney

SUBMITTER: David Stroud

LAB HEAD: David A. Stroud

PROVIDER: PXD064649 | Pride | 2025-06-06

REPOSITORIES: Pride

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			Action	DRS
	211221_KR-3420_01_SDHAF2KO_SDHAF2FLAG_DOX15.raw	Raw
	211221_KR-3420_02_SDHAF2KO_SDHAF2FLAG_DOX15.raw	Raw
	211221_KR-3420_03_SDHAF2KO_SDHAF2FLAG_DOX15.raw	Raw
	250210_TS-10238_01_SDHBKO_SDHBFLAG.raw	Raw
	250210_TS-10238_02_SDHBKO_SDHBFLAG.raw	Raw

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Complex II assembly drives metabolic adaptation to OXPHOS dysfunction

Project description:During acute oxidative phosphorylation (OXPHOS) dysfunction, the reverse activity of succinate dehydrogenase (Complex II) maintains the redox state of the Coenzyme Q pool by utilizing either fumarate or oxygen as terminal electron acceptors. The tendency for one over another has been suggested to be tissue specific. We identified the action of SDHAF2 protein, a Complex II assembly factor that enhances the flavination of catalytic subunit SDHA, as critical for metabolic adaptation during Complex III dysfunction in HEK293T cells. Loss of SDHAF2 during Complex III inhibition led to a net reductive TCA cycle from loss of succinate oxidation, loss of SDHA active site derived reactive oxygen species (ROS)-signaling, insufficient adaptation to glycolysis, and a severe growth impairment. Cell lines adapted to glycolysis did not accumulate SDHAF2 upon Coenzyme Q-pool stress, exhibited a net reductive TCA cycle and mild growth phenotypes with or without SDHAF2 being present. Thus, our study reveals how Complex II assembly controls a balance between dynamics of TCA cycle directionality, protection from Q-pool stress, and an ability to utilize ROS-meditated signaling to overcome acute OXPHOS dysfunction in cells reliant on mitochondrial respiration.

2025-06-06 | PXD064653 | Pride

Complex II assembly drives metabolic adaptation to OXPHOS dysfunction

2025-06-06 | PXD064658 | Pride

Complex II assembly drives metabolic adaptation to OXPHOS dysfunction.

2025-06-06 | PXD064675 | Pride

One deficiency, different outcomes: Succinate dehydrogenase loss in chromaffin cell vs. fibroblast models of paraganglioma

Project description:Heterozygosity for loss‐of‐function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional Sdhx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. Here we characterize two available murine SDH-loss cell lines, one representing PPGL-susceptible chromaffin cells and the other PPGL-resistant fibroblasts. Consistent with previous analyses, we find strikingly different effects of SDH loss in these two cellular contexts, including evidence of residual Complex I activity only in SDH-loss immortalized mouse chromaffin cells. This work supports the hypothesis that chromaffin cells may uniquely tolerate SDH loss and sets the stage for analyses of unique vulnerabilities in SDH-loss chromaffin cells.

2025-01-02 | GSE263778 | GEO

Investigation of post-translational histone modifications in pheochromocytomas and paragangliomas

Project description:Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumours affecting a range of body sites and have the highest degree of heritability of any cancer type. SDHA, SDHB, SDHC, SDHD and SDHAF2 (collectively SDHx) code for subunits of succinate dehydrogenase, an enzyme complex in the tricarboxylic cycle that converts succinate to fumarate. Mutations in all SDHx genes play a role in PPGL pathogenesis and completely abolish succinate dehydrogenase enzymatic activity causing intracellular accumulation of oncometabolites which competitively inhibit 2-oxoglutarate-dependent oxygenases. This is a family of enzymes includes TET DNA demethylases and Jumonji C (JmjC) domain-containing histone demethylates. We and others have found that the inhibition of DNA demethylation leads to profound global DNA hypermethylation which influences expression of genes responsible for important clinical characteristics of these tumours but cannot explain the full spectrum of transcriptomic changes. We profiled histone PMTs to complement DNA methylation data and fully characterise the epigenome of these tumours.

2024-01-26 | PXD025689 | Pride

Succinate Dehydrogenase Regulates Homeostasis and Metabolic Integrity of Alveolar Macrophages

Project description:Lung tissue-resident macrophages (TRMs), including alveolar macrophages (AMs) and interstitial macrophages (IMs), are pivotal in maintaining both immune defense and tissue homeostasis. Although the distinct functional roles of these macrophage populations are well recognized, the specific metabolic pathways that support their functions are not fully understood. Comparative RNA sequencing analysis identified Sdha, a key enzyme in mitochondrial metabolism, as one of the most highly expressed and differentially regulated genes involved in metabolic pathways in AMs relative to IMs. This finding led us to investigate the role of succinate dehydrogenase complex subunit A (SDHA) in regulating AM metabolism and function. Here, we demonstrated that SDHA is crucial for maintaining AM homeostasis. Deletion of SDHA resulted in a significant reduction in AM populations without affecting IMs, highlighting an AM-specific requirement for SDHA. In the absence of SDHA, AMs underwent metabolic reprogramming towards glycolysis compared with IMs, along with significant transcriptional changes and cell death. Furthermore, SDHA-deficient AMs showed lipid accumulation and increased endoplasmic reticulum (ER) stress. These findings establish SDHA as a crucial regulator of AM metabolism and underscore the importance of maintaining metabolic integrity for AM function and survival within the lung microenvironment.

2025-02-07 | GSE288614 | GEO

Spo11-oligo mapping in S. cerevisiae Ctf19/CCAN kinetochore sub-complex mutant mcm21

Project description:During meiosis, crossover recombination is essential to link homologous chromosomes and drive faithful chromosome segregation. Crossover recombination is non-random across the genome, and centromere-proximal crossovers are associated with an increased risk of aneuploidy, including Trisomy 21 in humans. Here, we identify the conserved Ctf19/CCAN kinetochore sub-complex as a major factor that minimizes potentially deleterious centromere-proximal crossovers in budding yeast. We uncover multi-layered suppression of pericentromeric recombination by the Ctf19 complex, operating across distinct chromosomal distances. The Ctf19 complex prevents meiotic DNA break formation, the initiating event of recombination, proximal to the centromere. The Ctf19 complex independently drives the enrichment of cohesin throughout the broader pericentromere to suppress crossovers, but not DNA breaks. This non-canonical role of the kinetochore in defining a chromosome domain that is refractory to crossovers adds a new layer of functionality by which the kinetochore prevents the incidence of chromosome segregation errors that generate aneuploid gametes. Two samples total: two biological replicate Spo11-oligo maps of S. cerevisiae SK1 mcm21 null mutant

2015-12-15 | E-GEOD-72683 | biostudies-arrayexpress

Identification and Characterization of the Mammalian Nuclear RNA N6-Adenosine Methyltransferase Core Complex

Project description:N6-methyladenosine (m6A) is the most prevalent internal modification found in mammalian messenger and non-coding RNAs. The discoveries of functionally significant demethylases that reverse this methylation as well as the recently revealed m6A distributions in mammalian transcriptomes strongly indicate regulatory functions of this modification. Here we report the identification and characterization of the mammalian nuclear RNA N6-adenosine methyltransferase core (RNMTC) complex. Besides METTL3, a methyltransferase which was the only known component of RNMTC in the past, we discovered that a previously uncharacterized methyltransferase, METTL14, exhibits a N6-adenosine methyltransferase activity higher than METTL3. Together with WTAP, the third component that dramatically affects the cellular m6A level, these three proteins form the core complex that orchestrates m6A deposition on mammalian nuclear RNA. Biochemistry assays, imaging experiments, as well as transcriptome-wide analyses of the binding sites and their effects on m6A methylation support methylation function and reveal new insights of RNMTC. PAR-CLIP and m6A-seq in HeLa cells

2013-11-29 | E-GEOD-46705 | biostudies-arrayexpress

Drp1 Controls Complex II assembly and Fatty Acid Oxidation by Sdhaf2 Action on Mitochondria

Project description:The Dynamin-related GTPase, Drp1 (encoded by Dnm1l) plays a central role in mitochondrial fission and is requisite for numerous cellular processes however its role in oxidative metabolism remains unclear. Herein, we show that among human tissues, skeletal muscle exhibits the strongest correlations with the DNM1L gene. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and accumulation of intramyocellular lipids along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced Complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2, normalized Complex II activity and lipid oxidation in Drp1-KD myocytes. Drp1 appears critical in maintaining mitochondrial Complex II assembly and fatty acid oxidation, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle lipid metabolism which is of clinical significance in combatting metabolic diseases.

2024-01-26 | GSE248081 | GEO

SDHA/B reduction promotes hepatocellular carcinoma proliferation by removing cullin1 NEDDylation and stabilizing YAP/TAZ

Project description:Background & Aims: Succinate dehydrogenase enzyme (SDH) is frequently found to be diminished in Hepatocellular carcinoma (HCC) patient samples, and SDH reduction is associated with elevated succinate level and poor prognosis in HCC patients. But the underlying mechanisms about how impaired SDH activity promotes HCC malignancy remain unclear. Approach & Results: In this study, we observed remarkable downregulations of SDH subunits A and B (SDHA/B) in chronic liver injury-induced murine HCC models and HCC patient samples. Subsequent RNA sequencing, hematoxylin & eosin (H&E) staining and immunohistochemistry (IHC) analyses of HCC samples revealed that Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) were significantly upregulated in HCC, with their levels inversely correlating with that of SDHA/B. The protein stability of YAP/TAZ was greatly enhanced in SDHA/B-depleted HCC cells along with accumulation of succinate. Further mechanistic analyses demonstrated that impaired activity of SDHA/B resulted in succinate accumulation which facilitated the removal of NEDDylation on cullin1, therefore disrupted the E3 ubiquitin ligase SCFβ-TrCP complex, consequently led to YAP/TAZ stabilization and activation in HCC cells. The accelerated in vitro cell proliferation and in vivo tumor growth caused by SDHA/B reduction or succinate exposure were largely dependent on the aberrant activation of YAP/TAZ. Conclusions: Our study demonstrated that SDHA/B reduction promotes HCC proliferation by preventing the proteasomal degradation of YAP/TAZ through modulating cullin1 NEDDylation, thus addicts SDH-deficient HCC cells to YAP/TAZ pathway and renders these cells vulnerable to YAP/TAZ inhibition. Our findings warrant further investigation on the therapeutic effects of targeting YAP/TAZ in HCC patients displaying reduced SDHA/B or elevated succinate levels.

2023-05-31 | GSE207147 | GEO

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