Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Exposome du cancer : reprogrammation métabolique du cancer du poumon par les nitrosamines spécifiques de la fumée de tabac

This Ph.D project focused on finding a link between the environmental cancer risk factors and metabolic reprogramming. Specifically, we analyzed the biochemical effects of nitrosamines contained in tobacco smoke on energy metabolism of lung cancer cells. Tobacco smoke is responsible for 40% of cancers. The analysis of the molecular mechanisms responsible for its deleterious effects could provide a better understanding of how tumors caused by "exposomes" develop. Many studies have described the mutagenic effects of tobacco smoke, but still there are little known about the effect of these nitrosamines on cell metabolism. However, the reprogramming of energy metabolism is recognized as an emerging hallmark of cancer.Non-cancer cells obtain biological energy through two main mechanisms: the glycolytic pathway and oxidative phosphorylation which take place in cytosol and mitochondria, respectively. A modification of energy transduction mechanisms in favor of oxidative phosphorylation associates with resistance to chemotherapeutic treatments and metastasis, suggesting an entanglement between cellular bioenergetics and other components of carcinogenesis. Conversely, amplification of the glycolysis pathways allows cancer cells to proliferate under conditions of hypoxia. Thus, the alteration of balance between glycolysis and oxidative phosophorylation participates in tumor development depending on the microenvironment and the mechanisms of cancer initiation.To study the effects of tobacco-specific nitrosamines (TSNAs) on energy metabolism, we exposed human lung cancer cells to "nicotine-derived nitrosamine ketone (NNK)" that its carcinogenic effect is well demonstrated. The impact of NNK on energy metabolism has been analyzed by bioenergetics methods such as high-resolution respirometry and prospective Omics’ technologies including proteomics and metabolomics.The results of this thesis made it possible to describe the metabolic reprogramming induced by NNK and to understand the signaling pathways involved. In particular, our work shows that NNK activates mitochondrial biogenesis by stimulating the beta-adrenergic axis via the transcription factors CREB and TFAM. In vivo analyzes in an orthotopic lung tumor model demonstrates the role of TFAM in stimulating tumor growth and the involvement of reactive oxygen species produced by the respiratory chain. Ectopic expression of superoxide dismutase (MnSOD), an antioxidant enzyme located in the mitochondria, blocks the pro-cancer effects of NNK. Likewise, analyzes of cell migration and invasion have shown the toxic effect of NNK and the protective effect of MnSOD. To conclude, our work provides a better understanding of the pro-carcinogenic effect of NNK contained in tobacco smoke and identifies a β-AR-CREB-TFAM-ROS signaling pathway involved in this action.Ce travail de thèse concerne l’étude des effets de l’environnement sur la biologie mitochondriale. Plus précisément, nous avons analysé les effets biochimiques des nitrosamines contenues dans la fumée de tabac sur le métabolisme énergétique de cellules cancéreuses de poumon. Le tabac est responsable de 40% des cancers et l’analyse des mécanismes moléculaires responsables de ses effets délétères pourrait permettre de mieux comprendre comment se développent les tumeurs causées par ‘l’exposome’. De nombreuses études ont décrit les effets mutagènes de la fumée de tabac mais peu de données sont disponibles quant à son action sur le métabolisme cellulaire. Pourtant, la reprogrammation des voies métabolique est reconnue comme une composante majeure du développement des cancers.Les cellules non-cancéreuses obtiennent de l’énergie biologique par deux mécanismes principaux : la voie de la glycolyse qui se déroule dans le cytosol et les oxydations phosphorylantes qui prennent place dans les mitochondries. Une modification des mécanismes de transduction d’énergie en faveur des oxydations phosphorylantes a été associée à la résistance aux traitements chimio-thérapeutique et à la métastase, suggérant une intrication entre la bioénergétique cellulaire et les autres composantes de la carcinogenèse. Inversement, l’amplification des voies de la glycolyse permet aux cellules cancéreuses de proliférer dans des conditions d’hypoxie. Ainsi, l’altération de la balance entre la glycolyse et les oxydations phosphorylantes participe au développement tumoral en fonction du micro-environnement et des mécanismes d’initiation du cancer.Pour étudier les effets des nitrosamines spécifiques à la fumée de tabac (TSNA) sur le métabolisme énergétique nous avons exposé des cellules humaines de cancer de poumon à la ‘nicotine-derived nitrosamine ketone (NNK)’ dont l’effet carcinogène est bien démontré. L’impact de la NNK sur le métabolisme énergétique a été analysé par des méthodes de bioénergétique comme la respirométrie haute-résolution et des technologies prospectives de type ‘Omiques’ incluant la protéomique et la métabolomique.Les résultats de cette thèse ont permis de décrire la reprogrammation métabolique induite par la NNK et de comprendre les mécanismes de signalisation impliqués. En particulier, nos travaux montrent que la NNK active la biogenèse mitochondriale par stimulation de l’axe béta-adrénergique via le facteur de transcription CREB et le facteur TFAM. Des analyses in vivo dans un modèle de tumeurs de poumon orthotopique ont démontré le rôle du facteur TFAM dans la stimulation de la croissance tumorale et l’implication des espèces oxygénées réactives produites par la chaîne respiratoire. L’expression ectopique de la superoxide dismutase (MnSOD), une enzyme anti-oxydante localisée dans le mitochondries, permet de bloquer les effets pro-cancéreux du NNK. Dans même, des analyses de migration et d’invasion cellulaire ont montré l’effet toxique de NNK et l’effet protecteur de la MnSOD. Pour conclure, nos travaux apportent une meilleure connaissance de l’effet pro-carcinogène de la NNK contenue dans la fumée de tabac et identifie une voie de signalisation B-AR-CREB-TFAM-ROS mise en jeu dans cette action

Cancer exposomics : metabolic reprograming of lung tumors by tobacco smoke specific nitrosamines

Ce travail de thèse concerne l’étude des effets de l’environnement sur la biologie mitochondriale. Plus précisément, nous avons analysé les effets biochimiques des nitrosamines contenues dans la fumée de tabac sur le métabolisme énergétique de cellules cancéreuses de poumon. Le tabac est responsable de 40% des cancers et l’analyse des mécanismes moléculaires responsables de ses effets délétères pourrait permettre de mieux comprendre comment se développent les tumeurs causées par ‘l’exposome’. De nombreuses études ont décrit les effets mutagènes de la fumée de tabac mais peu de données sont disponibles quant à son action sur le métabolisme cellulaire. Pourtant, la reprogrammation des voies métabolique est reconnue comme une composante majeure du développement des cancers.Les cellules non-cancéreuses obtiennent de l’énergie biologique par deux mécanismes principaux : la voie de la glycolyse qui se déroule dans le cytosol et les oxydations phosphorylantes qui prennent place dans les mitochondries. Une modification des mécanismes de transduction d’énergie en faveur des oxydations phosphorylantes a été associée à la résistance aux traitements chimio-thérapeutique et à la métastase, suggérant une intrication entre la bioénergétique cellulaire et les autres composantes de la carcinogenèse. Inversement, l’amplification des voies de la glycolyse permet aux cellules cancéreuses de proliférer dans des conditions d’hypoxie. Ainsi, l’altération de la balance entre la glycolyse et les oxydations phosphorylantes participe au développement tumoral en fonction du micro-environnement et des mécanismes d’initiation du cancer.Pour étudier les effets des nitrosamines spécifiques à la fumée de tabac (TSNA) sur le métabolisme énergétique nous avons exposé des cellules humaines de cancer de poumon à la ‘nicotine-derived nitrosamine ketone (NNK)’ dont l’effet carcinogène est bien démontré. L’impact de la NNK sur le métabolisme énergétique a été analysé par des méthodes de bioénergétique comme la respirométrie haute-résolution et des technologies prospectives de type ‘Omiques’ incluant la protéomique et la métabolomique.Les résultats de cette thèse ont permis de décrire la reprogrammation métabolique induite par la NNK et de comprendre les mécanismes de signalisation impliqués. En particulier, nos travaux montrent que la NNK active la biogenèse mitochondriale par stimulation de l’axe béta-adrénergique via le facteur de transcription CREB et le facteur TFAM. Des analyses in vivo dans un modèle de tumeurs de poumon orthotopique ont démontré le rôle du facteur TFAM dans la stimulation de la croissance tumorale et l’implication des espèces oxygénées réactives produites par la chaîne respiratoire. L’expression ectopique de la superoxide dismutase (MnSOD), une enzyme anti-oxydante localisée dans le mitochondries, permet de bloquer les effets pro-cancéreux du NNK. Dans même, des analyses de migration et d’invasion cellulaire ont montré l’effet toxique de NNK et l’effet protecteur de la MnSOD. Pour conclure, nos travaux apportent une meilleure connaissance de l’effet pro-carcinogène de la NNK contenue dans la fumée de tabac et identifie une voie de signalisation B-AR-CREB-TFAM-ROS mise en jeu dans cette action.This Ph.D project focused on finding a link between the environmental cancer risk factors and metabolic reprogramming. Specifically, we analyzed the biochemical effects of nitrosamines contained in tobacco smoke on energy metabolism of lung cancer cells. Tobacco smoke is responsible for 40% of cancers. The analysis of the molecular mechanisms responsible for its deleterious effects could provide a better understanding of how tumors caused by "exposomes" develop. Many studies have described the mutagenic effects of tobacco smoke, but still there are little known about the effect of these nitrosamines on cell metabolism. However, the reprogramming of energy metabolism is recognized as an emerging hallmark of cancer.Non-cancer cells obtain biological energy through two main mechanisms: the glycolytic pathway and oxidative phosphorylation which take place in cytosol and mitochondria, respectively. A modification of energy transduction mechanisms in favor of oxidative phosphorylation associates with resistance to chemotherapeutic treatments and metastasis, suggesting an entanglement between cellular bioenergetics and other components of carcinogenesis. Conversely, amplification of the glycolysis pathways allows cancer cells to proliferate under conditions of hypoxia. Thus, the alteration of balance between glycolysis and oxidative phosophorylation participates in tumor development depending on the microenvironment and the mechanisms of cancer initiation.To study the effects of tobacco-specific nitrosamines (TSNAs) on energy metabolism, we exposed human lung cancer cells to "nicotine-derived nitrosamine ketone (NNK)" that its carcinogenic effect is well demonstrated. The impact of NNK on energy metabolism has been analyzed by bioenergetics methods such as high-resolution respirometry and prospective Omics’ technologies including proteomics and metabolomics.The results of this thesis made it possible to describe the metabolic reprogramming induced by NNK and to understand the signaling pathways involved. In particular, our work shows that NNK activates mitochondrial biogenesis by stimulating the beta-adrenergic axis via the transcription factors CREB and TFAM. In vivo analyzes in an orthotopic lung tumor model demonstrates the role of TFAM in stimulating tumor growth and the involvement of reactive oxygen species produced by the respiratory chain. Ectopic expression of superoxide dismutase (MnSOD), an antioxidant enzyme located in the mitochondria, blocks the pro-cancer effects of NNK. Likewise, analyzes of cell migration and invasion have shown the toxic effect of NNK and the protective effect of MnSOD. To conclude, our work provides a better understanding of the pro-carcinogenic effect of NNK contained in tobacco smoke and identifies a β-AR-CREB-TFAM-ROS signaling pathway involved in this action

Exposome du cancer : reprogrammation métabolique du cancer du poumon par les nitrosamines spécifiques de la fumée de tabac

This Ph.D project focused on finding a link between the environmental cancer risk factors and metabolic reprogramming. Specifically, we analyzed the biochemical effects of nitrosamines contained in tobacco smoke on energy metabolism of lung cancer cells. Tobacco smoke is responsible for 40% of cancers. The analysis of the molecular mechanisms responsible for its deleterious effects could provide a better understanding of how tumors caused by "exposomes" develop. Many studies have described the mutagenic effects of tobacco smoke, but still there are little known about the effect of these nitrosamines on cell metabolism. However, the reprogramming of energy metabolism is recognized as an emerging hallmark of cancer.Non-cancer cells obtain biological energy through two main mechanisms: the glycolytic pathway and oxidative phosphorylation which take place in cytosol and mitochondria, respectively. A modification of energy transduction mechanisms in favor of oxidative phosphorylation associates with resistance to chemotherapeutic treatments and metastasis, suggesting an entanglement between cellular bioenergetics and other components of carcinogenesis. Conversely, amplification of the glycolysis pathways allows cancer cells to proliferate under conditions of hypoxia. Thus, the alteration of balance between glycolysis and oxidative phosophorylation participates in tumor development depending on the microenvironment and the mechanisms of cancer initiation.To study the effects of tobacco-specific nitrosamines (TSNAs) on energy metabolism, we exposed human lung cancer cells to "nicotine-derived nitrosamine ketone (NNK)" that its carcinogenic effect is well demonstrated. The impact of NNK on energy metabolism has been analyzed by bioenergetics methods such as high-resolution respirometry and prospective Omics’ technologies including proteomics and metabolomics.The results of this thesis made it possible to describe the metabolic reprogramming induced by NNK and to understand the signaling pathways involved. In particular, our work shows that NNK activates mitochondrial biogenesis by stimulating the beta-adrenergic axis via the transcription factors CREB and TFAM. In vivo analyzes in an orthotopic lung tumor model demonstrates the role of TFAM in stimulating tumor growth and the involvement of reactive oxygen species produced by the respiratory chain. Ectopic expression of superoxide dismutase (MnSOD), an antioxidant enzyme located in the mitochondria, blocks the pro-cancer effects of NNK. Likewise, analyzes of cell migration and invasion have shown the toxic effect of NNK and the protective effect of MnSOD. To conclude, our work provides a better understanding of the pro-carcinogenic effect of NNK contained in tobacco smoke and identifies a β-AR-CREB-TFAM-ROS signaling pathway involved in this action.Ce travail de thèse concerne l’étude des effets de l’environnement sur la biologie mitochondriale. Plus précisément, nous avons analysé les effets biochimiques des nitrosamines contenues dans la fumée de tabac sur le métabolisme énergétique de cellules cancéreuses de poumon. Le tabac est responsable de 40% des cancers et l’analyse des mécanismes moléculaires responsables de ses effets délétères pourrait permettre de mieux comprendre comment se développent les tumeurs causées par ‘l’exposome’. De nombreuses études ont décrit les effets mutagènes de la fumée de tabac mais peu de données sont disponibles quant à son action sur le métabolisme cellulaire. Pourtant, la reprogrammation des voies métabolique est reconnue comme une composante majeure du développement des cancers.Les cellules non-cancéreuses obtiennent de l’énergie biologique par deux mécanismes principaux : la voie de la glycolyse qui se déroule dans le cytosol et les oxydations phosphorylantes qui prennent place dans les mitochondries. Une modification des mécanismes de transduction d’énergie en faveur des oxydations phosphorylantes a été associée à la résistance aux traitements chimio-thérapeutique et à la métastase, suggérant une intrication entre la bioénergétique cellulaire et les autres composantes de la carcinogenèse. Inversement, l’amplification des voies de la glycolyse permet aux cellules cancéreuses de proliférer dans des conditions d’hypoxie. Ainsi, l’altération de la balance entre la glycolyse et les oxydations phosphorylantes participe au développement tumoral en fonction du micro-environnement et des mécanismes d’initiation du cancer.Pour étudier les effets des nitrosamines spécifiques à la fumée de tabac (TSNA) sur le métabolisme énergétique nous avons exposé des cellules humaines de cancer de poumon à la ‘nicotine-derived nitrosamine ketone (NNK)’ dont l’effet carcinogène est bien démontré. L’impact de la NNK sur le métabolisme énergétique a été analysé par des méthodes de bioénergétique comme la respirométrie haute-résolution et des technologies prospectives de type ‘Omiques’ incluant la protéomique et la métabolomique.Les résultats de cette thèse ont permis de décrire la reprogrammation métabolique induite par la NNK et de comprendre les mécanismes de signalisation impliqués. En particulier, nos travaux montrent que la NNK active la biogenèse mitochondriale par stimulation de l’axe béta-adrénergique via le facteur de transcription CREB et le facteur TFAM. Des analyses in vivo dans un modèle de tumeurs de poumon orthotopique ont démontré le rôle du facteur TFAM dans la stimulation de la croissance tumorale et l’implication des espèces oxygénées réactives produites par la chaîne respiratoire. L’expression ectopique de la superoxide dismutase (MnSOD), une enzyme anti-oxydante localisée dans le mitochondries, permet de bloquer les effets pro-cancéreux du NNK. Dans même, des analyses de migration et d’invasion cellulaire ont montré l’effet toxique de NNK et l’effet protecteur de la MnSOD. Pour conclure, nos travaux apportent une meilleure connaissance de l’effet pro-carcinogène de la NNK contenue dans la fumée de tabac et identifie une voie de signalisation B-AR-CREB-TFAM-ROS mise en jeu dans cette action

Metabolic reprogramming by tobacco-specific nitrosamines (TSNAs) in cancer

International audienceMetabolic reprogramming is a hallmark of cancer and the link between oncogenes activation, tumor supressors inactivation and bioenergetics modulation is well established. However, numerous carcinogenic environmental factors are responsible for early cancer initiation and their impact on metabolic reprogramming just starts to be deciphered. For instance, it was recently shown that UVB irradiation triggers metabolic reprogramming at the pre-cancer stage with implication for skin cancer detection and therapy. These observations foster the need to study the early changes in tissue metabolism following exposure to other carcinogenic events. According to the International Agency for Research on Cancer (IARC), tobacco smoke is a major class I-carcinogenic environmental factor that contains different carcinogens, but little is known on the impact of tobacco smoke on tissue metabolism and its participation to cancer initiation. In particular, tobacco-specific nitrosamines (TSNAs) play a central role in tobacco-smoke mediated cancer initiation. Here we describe the recent advances that have led to a new hypothesis regarding the link between nitrosamines signaling and metabolic reprogramming in cancer

Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells.

Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells

Lung Tumor Growth Promotion by Tobacco-Specific Nitrosamines Involves the β2-Adrenergic Receptors-Dependent Stimulation of Mitochondrial REDOX Signaling

none17si: Aims: Lung cancer is the leading cause of cancer death worldwide, and tobacco smoking is a recognized major risk factor for lung tumor development. We analyzed the effect of tobacco-specific nitrosamines (TSNAs) on human lung adenocarcinoma metabolic reprogramming, an emergent hallmark of carcinogenesis. Results: A series of in vitro and in vivo bioenergetic, proteomic, metabolomic, and tumor biology studies were performed to analyze changes in lung cancer cell metabolism and the consequences for hallmarks of cancer, including tumor growth, cancer cell invasion, and redox signaling. The findings revealed that nicotine-derived nitrosamine ketone (NNK) stimulates mitochondrial function and promotes lung tumor growth in vivo. These malignant properties were acquired from the induction of mitochondrial biogenesis induced by the upregulation and activation of the beta-2 adrenergic receptors (β2-AR)-cholinergic receptor nicotinic alpha 7 subunit (CHRNAα7)-dependent nitrosamine canonical signaling pathway. The observed NNK metabolic effects were mediated by TFAM overexpression and revealed a key role for mitochondrial reactive oxygen species and Annexin A1 in tumor growth promotion. Conversely, ectopic expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase rescued the reprogramming and malignant metabolic effects of exposure to NNK and overexpression of TFAM, underlining the link between NNK and mitochondrial redox signaling in lung cancer. Innovation: Our findings describe the metabolic changes caused by NNK in a mechanistic framework for understanding how cigarette smoking causes lung cancer. Conclusion: Mitochondria play a role in the promotion of lung cancer induced by tobacco-specific nitrosamines. Antioxid. Redox Signal. 36, 525-549.mixedSarlak, Saharnaz; Lalou, Claude; Sant'Anna-Silva, Ana Carolina B; Mafhouf, Walid; De Luise, Monica; Rousseau, Benoît; Izotte, Julien; Claverol, Stéphane; Lacombe, Didier; Nikitopoulou, Efterpi; Yang, Ming; Oliveira, Marcus; Frezza, Christian; Gasparre, Giuseppe; Rezvani, Hamid Reza; Amoedo, Nivea Dias; Rossignol, RodrigueSarlak, Saharnaz; Lalou, Claude; Sant'Anna-Silva, Ana Carolina B; Mafhouf, Walid; De Luise, Monica; Rousseau, Benoît; Izotte, Julien; Claverol, Stéphane; Lacombe, Didier; Nikitopoulou, Efterpi; Yang, Ming; Oliveira, Marcus; Frezza, Christian; Gasparre, Giuseppe; Rezvani, Hamid Reza; Amoedo, Nivea Dias; Rossignol, Rodrigu

Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas

Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: High (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [18F]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [18F]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas