Fumarate is a terminal electron acceptor in the mammalian electron transport chain

Spinelli, Jessica B.; Rosen, Paul; Sprenger, Hans‐Georg; Puszynska, Anna M.; Mann, Jessica L.; Roessler, Julian M.; Cangelosi, Andrew L.; Henne, Antonia; Condon, Kendall J.; Zhang, Tong; Kunchok, Tenzin; Lewis, Caroline A.; Chandel, Navdeep S.; Sabatini, David M.

doi:10.1126/science.abi7495

Cited by 114 publications

(102 citation statements)

References 64 publications

(94 reference statements)

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“…Recently, Spinelli et al. showed that in human osteosarcoma 143B cells and in several normal tissues, fumarate can act as the terminal electron acceptor when oxygen is limiting, involving reverse electron flow through succinate dehydrogenase (SDH, Complex II) ( 38 ). This would have the effect of maintaining de novo pyrimidine biosynthesis by oxidizing ubiquinol, and thus ensuring continued Dhodh activity.…”

Section: Changes In Metabolic Reprogramming and The Glycolysis-oxphos...mentioning

confidence: 99%

“…Mitochondrial DNA copy number is depleted in many solid tumors ( 47 ), while expression of different protein-encoding genes in mtDNA and even within a particular respiratory complex can vary by more than two orders of magnitude, with genes encoding subunits of Complex I (Ndu1) and V (Atp6 and Atp8) being the most highly expressed in 4T1 cells ( 38 ). In contrast to individual respiratory complexes where protein synthesis of mitochondrial and nuclear-encoded subunit genes are in general closely correlated across primary cells from different tissues and tumor cell lines ( 40 – 45 ), mitochondrial and cytosolic mRNA abundance for subunits of the respiratory complexes are less well matched ( 44 ).…”

Section: The Mito-nuclear Crosstalk Dilemma In Cancer Cell Energy Met...mentioning

confidence: 99%

“…Recent results involving rapidly dividing tumor cell lines suggest that base level respiration of about 10% of normal oxygen consumption is required to support cell proliferation ( 36 ). Another recent study identified fumarate as an alternative electron sink for maintaining ubiquinone levels essential for DHODH activity, de novo pyrimidine biosynthesis and nucleic acid production ( 38 ). Ideally, these strategies would be expected to minimize ROS production, and consequently reduce damage to mtDNA proximal to CI and CIII, where most superoxide radicals are generated.…”

Section: The Primary Cancer-metastatic Trajectory Affects Energy Meta...mentioning

confidence: 99%

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Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis

et al. 2022

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The ability of cancer cells to adjust their metabolism in response to environmental changes is a well-recognized hallmark of cancer. Diverse cancer and non-cancer cells within tumors compete for metabolic resources. Metabolic demands change frequently during tumor initiation, progression and metastasis, challenging our quest to better understand tumor biology and develop novel therapeutics. Vascularization, physical constraints, immune responses and genetic instability promote tumor evolution resulting in immune evasion, opportunities to breach basement membrane barriers and spread through the circulation and lymphatics. In addition, the unfolded protein response linked to the ubiquitin proteasome system is a key player in addressing stoichiometric imbalances between nuclear and mitochondrially-encoded protein subunits of respiratory complexes, and nuclear-encoded mitochondrial ribosomal protein subunits. While progressive genetic changes, some of which affect metabolic adaptability, contribute to tumorigenesis and metastasis through clonal expansion, epigenetic changes are also important and more dynamic in nature. Understanding the role of stromal and immune cells in the tumor microenvironment in remodeling cancer cell energy metabolism has become an increasingly important area of research. In this perspective, we discuss the adaptations made by cancer cells to balance mitochondrial and glycolytic energy metabolism. We discuss how hypoxia and nutrient limitations affect reductive and oxidative stress through changes in mitochondrial electron transport activity. We propose that integrated responses to cellular stress in cancer cells are central to metabolic flexibility in general and bioenergetic adaptability in particular and are paramount in tumor progression and metastasis.

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Section: Changes In Metabolic Reprogramming and The Glycolysis-oxphos...mentioning

confidence: 99%

Section: The Mito-nuclear Crosstalk Dilemma In Cancer Cell Energy Met...mentioning

confidence: 99%

Section: The Primary Cancer-metastatic Trajectory Affects Energy Meta...mentioning

confidence: 99%

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Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis

et al. 2022

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“…Although under normal cellular conditions, reversal of mammalian SDH is thermodynamically unfavorable, the standard reduction potential of UQ is only slightly higher than fumarate, suggesting that net reversal of SDH might occur under certain conditions. Indeed, hypoxia or inhibition of complex III by antimycin was recently shown to lead to UQH2 accumulation and fumarate reduction, reversing SDH activity and electron flow [ 66 ]. This process ensures continuing electron transport from complex I and UQ-dependent enzymes such as DHODH, allowing NADH reoxidation and maintenance of the redox balance.…”

Section: Sdhaf2mentioning

confidence: 99%

Hypothesis: Why Different Types of SDH Gene Variants Cause Divergent Tumor Phenotypes

Bayley

Devilee

2022

Genes

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Despite two decades of paraganglioma-pheochromocytoma research, the fundamental question of how the different succinate dehydrogenase (SDH)-related tumor phenotypes are initiated has remained unanswered. Here, we discuss two possible scenarios by which missense (hypomorphic alleles) or truncating (null alleles) SDH gene variants determine clinical phenotype. Dysfunctional SDH is a major source of reactive oxygen species (ROS) but ROS are inhibited by rising succinate levels. In scenario 1, we propose that SDH missense variants disrupt electron flow, causing elevated ROS levels that are toxic in sympathetic PPGL precursor cells but well controlled in oxygen-sensing parasympathetic paraganglion cells. We also suggest that SDHAF2 variants, solely associated with HNPGL, may cause the reversal of succinate dehydrogenase to fumarate reductase, producing very high ROS levels. In scenario 2, we propose a modified succinate threshold model of tumor initiation. Truncating SDH variants cause high succinate accumulation and likely initiate tumorigenesis via disruption of 2-oxoglutarate-dependent enzymes in both PPGL and HNPGL precursor tissues. We propose that missense variants (including SDHAF2) cause lower succinate accumulation and thus initiate tumorigenesis only in very metabolically active tissues such as parasympathetic paraganglia, which naturally show very high levels of succinate.

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“…Many bacteria perform respiration with terminal electron acceptors such as fumarate and nitrate instead of oxygen [38]. Recent work has shown that under conditions of hypoxia or inhibition of Complex IV of the mitochondrial electron transport chain, mammalian cells can similarly use fumarate as the terminal electron acceptor [39]. Under these conditions OCR does not quantify respiratory activity, and alternative methods such as the measurement of NADH/NAD + flux [40] may be necessary.…”

Section: Measuring Glycolytic and Respiratory Fluxes Using Calorimetrymentioning

confidence: 99%

Dissecting flux balances to measure energetic costs in cell biology: techniques and challenges

Arunachalam¹,

Ireland²,

Yang³

et al. 2022

Preprint

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Life is a nonequilibrium phenomenon: metabolism provides a continuous supply of energy that drives nearly all cellular processes. However, very little is known about how much energy different cellular processes use, i.e. their energetic costs. The most direct experimental measurements of these costs involve modulating the activity of cellular processes and determining the resulting changes in energetic fluxes. In this review, we present a flux balance framework to aid in the design and interpretation of such experiments, and discuss the challenges associated with measuring the relevant metabolic fluxes. We then describe selected techniques that enable measurement of these fluxes. Finally, we review prior experimental and theoretical work that has employed techniques from biochemistry and nonequilibrium physics to determine the energetic costs of cellular processes.

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Fumarate is a terminal electron acceptor in the mammalian electron transport chain

Cited by 114 publications

References 64 publications

Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis

Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis

Hypothesis: Why Different Types of SDH Gene Variants Cause Divergent Tumor Phenotypes

Dissecting flux balances to measure energetic costs in cell biology: techniques and challenges

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