MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle

Molinié, Thibaut; Cougouilles, Elodie; David, Claudine; Cahoreau, Edern; Portais, Jean‐Charles; Mourier, Arnaud

doi:10.1016/j.bbabio.2022.148532

Cited by 29 publications

(25 citation statements)

References 69 publications

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“…In contrast, basal OCR upon longer-term DCA treatment was not modified but was elevated under uncoupled conditions, suggesting a downstream control of ATP synthase on basal respiratory rate. Moreover, DCA-treated cells showed an increased sensitivity to rotenone, technically assessed as previously described [ 20 ], revealing the pivotal role of mitochondrial complex-I-dependent respiration. The resulting flux reorganization towards complex I led to increased ROS production in DCA-treated cells [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 71%

“…The oxygen consumption rate was measured under 3 different conditions: phosphorylating state (endogenous respiratory condition), non-phosphorylating state with addition of oligomycin (50 ng/mL), and uncoupled state by the successive addition of carbonyl cyanide m-chlorophenyl hydrazone (CCCP 0.5 μM) to reach the maximal respiration. The determine the sensibility to complex I and complex II, injections of rotenone (30 nM) or atpenin A5 (AtpnA5, 20 nM) were performed, respectively [ 20 , 21 ]. Antimycin A (100 nM) was added at the end of each experiment to evaluate the proportion of oxygen consumption not linked to the respiratory chain.…”

Section: Methodsmentioning

confidence: 99%

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Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

Larrieu

Storevik

Guyon

et al. 2022

Cancers

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Glioblastoma (GB) are the most frequent brain cancers. Aggressive growth and limited treatment options induce a median survival of 12–15 months. In addition to highly proliferative and invasive properties, GB cells show cancer-associated metabolic characteristics such as increased aerobic glycolysis. Pyruvate dehydrogenase (PDH) is a key enzyme complex at the crossroads between lactic fermentation and oxidative pathways, finely regulated by PDH kinases (PDHKs). PDHKs are often overexpressed in cancer cells to facilitate high glycolytic flux. We hypothesized that targeting PDHKs, by disturbing cancer metabolic homeostasis, would alter GB progression and render cells vulnerable to additional cancer treatment. Using patient databases, distinct expression patterns of PDHK1 and PDHK2 in GB tissues were obvious. To disturb protumoral glycolysis, we modulated PDH activity through the genetic or pharmacological inhibition of PDHK in patient-derived stem-like spheroids. Striking effects of PDHKs inhibition using dichloroacetate were observed in vitro on cell morphology and metabolism, resulting in increased intracellular ROS levels and decreased proliferation and invasion. In vivo findings confirmed a reduction in tumor size and better survival of mice implanted with PDHK1 and PDHK2 knockout cells. Adding a radiotherapeutic protocol further resulted in a reduction in tumor size and improved mouse survival in our model.

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Section: Discussionmentioning

confidence: 71%

Section: Methodsmentioning

confidence: 99%

Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

Larrieu

Storevik

Guyon

et al. 2022

Cancers

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“…This was triggered by physiological concentration of malate. These results suggest that oxidation of imported malate by MDH2 rewires the fuelling of the RC from CII to CI, facilitated by CoQ in its role as a common substrate to both complexes 16 . The discovery that malate import via MDH1 can modulate the activity of CoQ constitutes a major conceptual breakthrough in the field of mitochondrial energy metabolism: this novel regulatory ‘CoQ-contest’ mechanism enables the RC to prioritise metabolic flows by orchestrating the activities of coenzymes Q oxidoreductases.…”

Section: Introductionmentioning

confidence: 83%

“…It was recently observed that malate imported via the Malate-Aspartate Shuttle (MAS) resulted in a switch of electron fueling to CoQ from CII to CI at a physiological concentration of 2mM malate 16…”

Section: Predicting Coq Contest Using Mitomousementioning

confidence: 99%

“…The recent discovery of an evolutionary conserved mechanism orchestrating the RC electron fuelling at the CoQ-oxidoreductase crossroad shed new light on the metabolic role played by mitochondria [14][15][16] . In mouse mitochondria, allosteric regulation by MAS produced malate, and subsequent conversion to oxaloacetate (OAA) reduced complex II (CII) activity due to increasing complex I (CI) activity, a feature first shown in yeast and thus, conserved in evolution [15][16][17][18][19] . As a consequence, electron flow from succinate towards NADH oxidation was rewired.…”

Section: Introductionmentioning

confidence: 99%

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MitoMouse is a model reconstruction of murine mitochondrial metabolism

Chapman

Molinié

Mourier

et al. 2023

Preprint

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Mitochondria, apart from being the powerhouses of our cells, are key players in cellular metabolism and homeostasis. As a consequence, the core bioenergetics and metabolism of mitochondria are well studied considering the role that dysregulated mitochondrial metabolism plays in disease. Flux Balance Analysis, used in conjunction with metabolic model reconstructions is a powerful computational tool that predicts metabolism. The resulting quantitative descriptions of metabolic dysregulation not only allows current hypotheses to be tested in silico, but can also lead to novel model driven hypotheses that can be experimentally verified. Several metabolic reconstructions for human and mouse metabolism exist, but no model specific to mouse mitochondrial metabolism exists. Here, we have created a mouse-specific mitochondrial metabolic model, mitoMouse, which is based on the high-quality human MitoCore mode. MitoMouse contains 390 genes and 445 metabolites involved in 560 unique reactions, is able to model central carbon metabolism and has been extended to contain reduction of the CoQ complex of Oxidative Phosphorylation by the enzyme DHODH. MitoMOuse was validated to accurately model the important metabolic switch involving CoQ reduction resulting from increased malate import, as recently shown in mouse cardiac tissue. We expect this model to be of immense interest and relevance to researchers working on murine mitochondrial metabolism.

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Complex I, V, and MDH2 deficient human skin fibroblasts reveal distinct metabolic signatures by ¹H HR‐MAS NMR

Meyer,

Hertig,

Arnold

et al. 2023

J of Inher Metab Disea

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In this study, we investigated the metabolic signatures of different mitochondrial defects (two different complex I and complex V, and the one MDH2 defect) in human skin fibroblasts (HSF). We hypothesized that using a selective culture medium would cause defect specific adaptation of the metabolome and further our understanding of the biochemical implications for the studied defects. All cells were cultivated under galactose stress condition and compared to glucose‐based cell culture condition. We investigated the bioenergetic profile using Seahorse XFe96 cell analyzer and assessed the extracellular metabolic footprints and the intracellular metabolic fingerprints using NMR. The galactose‐based culture condition forced a bioenergetic switch from a glycolytic to an oxidative state in all cell lines which improved overall separation of controls from the different defect groups. The extracellular metabolome was discriminative for separating controls from defects but not the specific defects, whereas the intracellular metabolome suggests CI and CV changes and revealed clear MDH2 defect‐specific changes in metabolites associated with the TCA cycle, malate aspartate shuttle, and the choline metabolism, which are pronounced under galactose condition.

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MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle

Cited by 29 publications

References 69 publications

Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

MitoMouse is a model reconstruction of murine mitochondrial metabolism

Complex I, V, and MDH2 deficient human skin fibroblasts reveal distinct metabolic signatures by ¹H HR‐MAS NMR

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MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle

Cited by 29 publications

References 69 publications

Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development

MitoMouse is a model reconstruction of murine mitochondrial metabolism

Complex I, V, and MDH2 deficient human skin fibroblasts reveal distinct metabolic signatures by 1H HR‐MAS NMR

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Complex I, V, and MDH2 deficient human skin fibroblasts reveal distinct metabolic signatures by ¹H HR‐MAS NMR