Thibaut Molinié

Université de Bordeaux

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Arnaud Mourier

Institut de Biochimie et Génétique Cellulaires

Cyrielle Bouchez

Centre National de la Recherche Scientifique

Claudine David

Institut de Biochimie et Génétique Cellulaires

Johannes F. Hevler

Utrecht University

Judy Hirst

Medical Research Council

Albert J. R. Heck

Utrecht University

Ilian Atanassov

Max Planck Institute for Biology of Ageing

Nils‐Göran Larsson

Karolinska Institutet

Anne Devin

Institut de Biochimie et Génétique Cellulaires

Stéphane Duvezin‐Caubet

Institut de Biochimie et Génétique Cellulaires

Cooperative Institutions

Centre National de la Recherche Scientifique

Inserm

Université de Bordeaux

Institut de Biochimie et Génétique Cellulaires

Université Paris Cité

Institut Mondor de Recherche Biomédicale

Université Paris-Est Créteil

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement

Université Paris-Saclay

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

Biochimica et Biophysica Acta (BBA) - Bioenergetics (2022)

Thibaut Molinié Elodie Cougouilles Claudine David Edern Cahoreau Jean‐Charles Portais

The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD+ and ATP. The oxidation by the RC of the NADH metabolically produced in the cytosol involves redox shuttles as the malate-aspartate shuttle (MAS) and is of paramount importance for cell fate. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD+ redox stress have not been elucidated. The recent discovery that complex I (NADH dehydrogenase), and not complex II (Succinate dehydrogenase), can assemble with other respiratory chain complexes to form functional entities called respirasomes, led to the assumption that this supramolecular organization would favour NADH oxidation. Unexpectedly, characterization of heart and liver mitochondria demonstrates that the RC systematically favours electrons provided by the 'respirasome free' complex II. Our results demonstrate that the preferential succinate driven respiration is tightly controlled by OAA levels, and that OAA feedback inhibition of complex II rewires RC fuelling increasing NADH oxidation capacity. This new regulatory mechanism synergistically increases RC's NADH oxidative capacity and rewires MDH2 driven anaplerosis of the TCA, preventing malate production from succinate to favour oxidation of cytosolic malate. This regulatory mechanism synergistically adjusts RC and TCA fuelling in response to extramitochondrial malate produced by the MAS.

Mitochondrial respiratory chain

Malate dehydrogenase

NADH dehydrogenase

10.1016/j.bbabio.2022.148532

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Citations (34)

Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes

Cell Metabolism (2023)

Dusanka Milenkovic Jelena Misic Johannes F. Hevler Thibaut Molinié Injae Chung

The mammalian respiratory chain complexes I, III

Mitochondrial respiratory chain

Respiratory physiology

10.1016/j.cmet.2023.07.015

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SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency

Brain (2023)

Carolina Montoro-Gámez Hendrik Nolte Thibaut Molinié G. Evangelista Simon E. Tröder

Hereditary spastic paraplegia is a neurological condition characterized by predominant axonal degeneration in long spinal tracts, leading to weakness and spasticity in the lower limbs. The nicotinamide adenine dinucleotide (NAD+)-consuming enzyme SARM1 has emerged as a key executioner of axonal degeneration upon nerve transection and in some neuropathies. An increase in the nicotinamide mononucleotide/NAD+ ratio activates SARM1, causing catastrophic NAD+ depletion and axonal degeneration. However, the role of SARM1 in the pathogenesis of hereditary spastic paraplegia has not been investigated. Here, we report an enhanced mouse model for hereditary spastic paraplegia caused by mutations in SPG7. The eSpg7 knockout mouse carries a deletion in both Spg7 and Afg3l1, a redundant homologue expressed in mice but not in humans. The eSpg7 knockout mice recapitulate the phenotypic features of human patients, showing progressive symptoms of spastic-ataxia and degeneration of axons in the spinal cord as well as the cerebellum. We show that the lack of SPG7 rewires the mitochondrial proteome in both tissues, leading to an early onset decrease in mito-ribosomal subunits and a remodelling of mitochondrial solute carriers and transporters. To interrogate mechanisms leading to axonal degeneration in this mouse model, we explored the involvement of SARM1. Deletion of SARM1 delays the appearance of ataxic signs, rescues mitochondrial swelling and axonal degeneration of cerebellar granule cells and dampens neuroinflammation in the cerebellum. The loss of SARM1 also prevents endoplasmic reticulum abnormalities in long spinal cord axons, but does not halt the degeneration of these axons. Our data thus reveal a neuron-specific interplay between SARM1 and mitochondrial dysfunction caused by lack of SPG7 in hereditary spastic paraplegia.

Hereditary Spastic Paraplegia

Cerebellar ataxia

Degeneration (medical)

10.1093/brain/awad136

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Mitochondria: Ultrastructure, dynamics, biogenesis, and main functions

Elsevier eBooks (2021)

Michel Rigoulet Cyrielle Bouchez Thibaut Molinié Sylvain Cuvellier Jean‐Pierre Mazat

Organelle

Adenosine triphosphate

10.1016/b978-0-12-821562-3.00025-3

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Citations (2)

MitoMouse is a model reconstruction of murine mitochondrial metabolism

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Stephen P. Chapman Thibaut Molinié Arnaud Mourier Bianca Habermann

Abstract 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.

Flux Balance Analysis

Bioenergetics

Metabolic pathway

10.1101/2023.01.02.522468

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Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Dusanka Milenkovic Jelena Misic Johannes F. Hevler Thibaut Molinié Injae Chung

SUMMARY The mammalian respiratory chain complexes I, III 2 and IV (CI, CIII 2 and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI- CIII 2 -CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knock-in mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in the mouse, but raises questions about their alternate functions, such as relating to regulation of protein stability and prevention of age-associated protein aggregation.

Bioenergetics

Mitochondrial respiratory chain

Chain (unit)

10.1101/2023.06.19.545560

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Citations (1)

Maintained respiratory chain capacity in mice with severely reduced levels of mitochondrial respirasomes

Biochimica et Biophysica Acta (BBA) - Bioenergetics (2024)

Jelena Misic Dusanka Milenkovic Johannes F. Hevler Thibaut Molinié Injae Chung

Mitochondrial respiratory chain

Chain (unit)

10.1016/j.bbabio.2024.149274

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Citations (0)

Study of the mechanism of electron donor competition in the respiratory chain : A metabolic regulation more than structural

HAL (Le Centre pour la Communication Scientifique Directe) (2021)

Thibaut Molinié

Mitochondrial respiratory chain

Source

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Mitochondria: Ultrastructure, Dynamics, Biogenesis and Main Functions

Elsevier eBooks (2019)

Anne Devin Cyrielle Bouchez Thibaut Molinié Claudine David Stéphane Duvezin‐Caubet

Dynamics

10.1016/b978-0-12-811752-1.00001-8

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Citations (5)

Specific expression of lactate dehydrogenases in glioblastoma controls intercellular lactate transfer to promote tumor growth and invasion

Research Square (Research Square) (2021)

Joris Guyon Ignacio Fernández‐Moncada Claire Larrieu Cyrielle Bouchez Tiffanie Chouleur

Abstract Lactate is a central metabolite in brain physiology, involved in the astrocyte-neuron lactate shuttle, but also contributes to tumor development. Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. By adapting their glycolytic or oxidative metabolism, GBM stem-like cells are able to resist chemo- and radiotherapy. We show herein that lactate fuels GBM anaplerosis by replenishing the TCA cycle in absence of glucose. Lactate dehydrogenases (LDH) catalyze the interconversion of pyruvate and lactate. Deletion of either LDHA or LDHB did not alter significantly GBM growth and invasion. However, ablation of both LDH isoforms led to a reduction of tumor growth, and, consequently, to an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OxPhos) in the double LDHA/B KO group which sensitized tumors to cranial irradiation, massively improving mouse survival. Survival was also increased when control mice were treated with the antiangiogenic treatment, bevacizumab, and the antiepileptic drug, stiripentol which targets LDH activity. Taken together, this highlights the complex metabolic network in which both LDH A and B are integrated and underscores that combined inhibition of LDHA and B is necessary to impact tumor development. Targeting of these enzymes in combination with anti-angiogenic and repurposed drugs may be of therapeutic benefit, especially when associated with radiotherapy.

Lactate dehydrogenase A

10.21203/rs.3.rs-690811/v1

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Citations (2)