Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Kacso, Gergely; Ravasz, Dora; Dóczi, Judit; Németh, Beáta; Madgar, Ory; Saada, Ann; Ilin, Polina; Miller, Chaya; Østergaard, Elsebet; Iordanov, I; Adams, Daniel J.; Vargedo, Zsuzsanna; Araki, Masatake; Araki, Kimi; Nakahara, Mai; Ito, Haruka; Gál, Anikó; Molnár, Mária Judit; Nagy, Zoltán; Patócs, Attila; Ádám-Vizi, Vera; Chinopoulos, Christos

doi:10.1042/bcj20160594

Cited by 30 publications

(26 citation statements)

References 78 publications

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“…19,47 Second, from an overall carbon economy perspective, utilizing TCA cycle intermediates for ALA production would require large-scale replenishment of the TCA cycle via anaplerotic reactions, not to mention the energetic costs of running the SCS reaction backward to generate succinyl-CoA for heme. Third, mice heterozygous for SUCLA2 knockout 48 and human patients with SUCLA2 deficiency (MIM ID #612073) exhibit no signs of anemia, which one would anticipate if the ALAS2-SUCLA2 interaction is essential for the supply of succinyl-CoA for heme synthesis. Fourth, mRNA expression profiling during erythropoiesis shows a negative correlation (20.7) between SUCLA2 and ALAS2 gene expression.…”

Section: Discussionmentioning

confidence: 99%

Glutamine via α-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis

Burch¹,

Marcero

Maschek

et al. 2018

Blood

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During erythroid differentiation, the erythron must remodel its protein constituents so that the mature red cell contains hemoglobin as the chief cytoplasmic protein component. For this, ∼10 molecules of heme must be synthesized, consuming 10 molecules of succinyl-CoA. It has long been assumed that the source of succinyl-coenzyme A (CoA) for heme synthesis in all cell types is the tricarboxylic acid (TCA) cycle. Based upon the observation that 1 subunit of succinyl-CoA synthetase (SCS) physically interacts with the first enzyme of heme synthesis (5-aminolevulinate synthase 2, ALAS2) in erythroid cells, it has been posited that succinyl-CoA for ALA synthesis is provided by the adenosine triphosphate-dependent reverse SCS reaction. We have now demonstrated that this is not the manner by which developing erythroid cells provide succinyl-CoA for ALA synthesis. Instead, during late stages of erythropoiesis, cellular metabolism is remodeled so that glutamine is the precursor for ALA following deamination to α-ketoglutarate and conversion to succinyl-CoA by α-ketoglutarate dehydrogenase (KDH) without equilibration or passage through the TCA cycle. This may be facilitated by a direct interaction between ALAS2 and KDH. Succinate is not an effective precursor for heme, indicating that the SCS reverse reaction does not play a role in providing succinyl-CoA for heme synthesis. Inhibition of succinate dehydrogenase by itaconate, which has been shown in macrophages to dramatically increase the concentration of intracellular succinate, does not stimulate heme synthesis as might be anticipated, but actually inhibits hemoglobinization during late erythropoiesis.

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Section: Discussionmentioning

confidence: 99%

Glutamine via α-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis

Burch¹,

Marcero

Maschek

et al. 2018

Blood

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“…Recently, a significant decrease in the oxygen consumption rate was observed using pyruvate and malate as substrates in isolated mitochondria from heart tissue of 6-month-old heterozygous Sucla2 +/− mice compared to wild type, suggesting a defect in heart muscle PDC or ETC, but direct assay of these functions in heart and SM tissue homogenates were not performed [28]. Assaying PDC, KDC and ETC activities in SM from individuals with A-SCS deficiency and/or conditional homozygous deficient mouse models [28, 29], or other genetic disorders in which acyl-CoAs accumulate could be useful in this respect.…”

Section: Discussionmentioning

confidence: 99%

“…Assaying PDC, KDC and ETC activities in SM from individuals with A-SCS deficiency and/or conditional homozygous deficient mouse models [28, 29], or other genetic disorders in which acyl-CoAs accumulate could be useful in this respect.…”

Section: Discussionmentioning

confidence: 99%

Succinyl-CoA synthetase ( SUCLA2 ) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion

Huang

Bedoyan²,

Demirbas

et al. 2017

Molecular Genetics and Metabolism

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Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype. Both siblings shared bilateral progressive hearing loss, encephalopathy, global developmental delay, generalized myopathy, and dystonia with choreoathetosis. Prior to diagnosis and because of lactic acidosis and low activity of muscle pyruvate dehydrogenase complex (PDC), sibling 1 (S1) was placed on dichloroacetate, while sibling 2 (S2) was on a ketogenic diet. S1 developed severe cyclic vomiting refractory to therapy, while S2 developed Leigh syndrome, severe GI dysmotility, intermittent anemia, hypogammaglobulinemia and eventually succumbed to his disorder. The mitochondrial DNA contents in skeletal muscle (SM) were normal in both siblings. Pyruvate dehydrogenase complex, ketoglutarate dehydrogenase complex, and several mitochondrial electron transport chain (ETC) complexes activities were low or at the low end of the reference range in frozen SM from S1 and/or S2. In contrast, activities of PDC, other mitochondrial enzymes of pyruvate metabolism, ETC and, integrated oxidative phosphorylation, in skin fibroblasts were not significantly impaired. Although we show that propionyl-CoA inhibits PDC, it does not appear to account for decreased PDC activity in SM. A better understanding of the mechanisms of phenotypic variability and the etiology for tissue-specific secondary deficiencies of mitochondrial enzymes of oxidative metabolism, and independently mitochondrial DNA depletion (common in other cases of A-SCS deficiency), is needed given the implications for control of lactic acidosis and possible clinical management.

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“…Of note, succinate CoA ligase (SUCL) – which catalyzes succinyl-CoA and ADP/GDP to CoASH, succinate, and ATP/GTP – is subject to inhibition by the accumulation succinate 45 . This product inhibition of SUCL could lead to a buildup of upstream CoA species such as propionyl-CoA and methylmalonyl-CoA, which in turn would likely inhibit the catabolism of many macromolecules that are normally metabolized to succinyl-CoA, including branched-chain amino acids, cholesterol, propionate, and odd-chain fatty acids 57,58 . Future studies focusing on how succinate engages other metabolic networks will help to clarify how elevated succinate levels result in impaired muscle repair/regeneration and contribute to cancer-associated muscle wasting.…”

Section: Discussionmentioning

confidence: 99%

The wasting-associated metabolite succinate disrupts myogenesis and impairs skeletal muscle regeneration

Arneson

Hogan

Shin

et al. 2019

Preprint

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Background: Loss of muscle mass and function are major clinical phenomena 1 affecting most advanced cancer patients. Recent work shows that defects in 2 muscle regeneration contribute to cancer-associated wasting. Among the factors 3 implicated in wasting-associated suppression of muscle regeneration are 4 cytokines that interfere with myogenic signal transduction pathways. Less 5 understood is how other cancer/wasting-associated cues, such as 6 oncometabolites, contribute to muscle dysfunction. This study investigates how 7 the oncometabolite succinate affects myogenesis and muscle regeneration. 8 Methods:We leveraged an established ectopic metabolite treatment strategy to 9 evaluate the ability of intracellular succinate elevation to 1) affect myoblast 10 homeostasis (growth/proliferation, apoptosis), 2) stimulate wasting-associated 11 catabolism, and 3) modulate in vitro myogenesis. In vivo succinate 12 supplementation experiments were utilized to corroborate and extend in vitro 13 observations. Metabolic studies were then performed to investigate the impact of 14 succinate elevation on mitochondria function. 15Results: We found that in vitro succinate elevation in myoblasts interferes with 16 protein homeostasis and myogenic differentiation. Mice orally administered 17 succinate displayed smaller muscle myofiber diameters and exhibited impaired 18 skeletal muscle regeneration when challenged with barium chloride-induced 19 muscle injury. Finally, we found that succinate elevation was associated with 20 functional mitochondria deficits. 21 Conclusions: Overall, this study broadens the repertoire of wasting-associated 22 factors that can directly modulate muscle progenitor cell function and strengthens 23 the hypothesis that metabolic derangements are major contributors to cancer-24 associated muscle wasting. 25 Keywords: Muscle wasting, skeletal muscle, succinate, myogenesis 26 27 Succinate is an oncometabolite best known for its role as a TCA cycle 57 intermediate and central player in mitochondria metabolism and ATP generation. 58 Recently, new roles for succinate have emerged and include immune cell 59 modulation13, HIF-1a stabilization in cancer14, epigenome remodeling via 60 inhibition of alpha-ketoglutarate dependent dioxygenases15, and post-61 translational protein modification (succinylation)16. This expanding repertoire of 62 cellular activities suggests a broader role for succinate in regulating cellular 63 processes such as differentiation, fate decisions, and survival. Interestingly, a 64 recent study reported serum succinate accumulation as a biomarker capable of 65 distinguishing non-wasting, tumor-bearing, and tumor-bearing with weight loss 66 patients17. In the present study, we sought to determine if succinate elevation 67 directly impacts muscle cell function, with a particular emphasis on myogenic 68 differentiation given prior studies linking succinate levels to cell fate 69 decisions18,19. 70Alterations in the balance between muscle breakdown and 71 repair/regeneration underlie cancer-asso...

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Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Cited by 30 publications

References 78 publications

Glutamine via α-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis

Glutamine via α-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis

Succinyl-CoA synthetase ( SUCLA2 ) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion

The wasting-associated metabolite succinate disrupts myogenesis and impairs skeletal muscle regeneration

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