Mitochondrial TCA cycle metabolites control physiology and disease

Martínez‐Reyes, Inmaculada; Chandel, Navdeep S.

doi:10.1038/s41467-019-13668-3

Cited by 1,483 publications

(1,255 citation statements)

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“…Conversely, the reduction of TCA activity could be an indirect indication for increased lactate fermentation. It should be noted that additional processes affecting TCA metabolite abundance exist, as some TCA intermediates can be used for biosynthesis and be replenished by other mechanisms such as glutaminolysis [39]. However, this is beyond the scope of this investigation, which compares the hematomas of one tissue separately for each time point.…”

Section: Discussionmentioning

confidence: 99%

“…The enzyme succinate dehydrogenase subunit A catalyzes the conversion of succinic acid to fumaric acid. This enzyme participates in both the TCA cycle and the electron transport chain/OXPHOS and thereby couples both processes [39,40]. A higher rate of TCA cycle and succinate dehydrogenase activity could suggest that aerobic respiration can still take place and, therefore, less pyruvic acid would be fermented to lactate, leading to reduced tissue acidification and a less pronounced pH drop.…”

Section: Discussionmentioning

confidence: 99%

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Early pH Changes in Musculoskeletal Tissues upon Injury—Aerobic Catabolic Pathway Activity Linked to Inter-Individual Differences in Local pH

Berkmann

Martin

Ellinghaus

et al. 2020

IJMS

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Local pH is stated to acidify after bone fracture. However, the time course and degree of acidification remain unknown. Whether the acidification pattern within a fracture hematoma is applicable to adjacent muscle hematoma or is exclusive to this regenerative tissue has not been studied to date. Thus, in this study, we aimed to unravel the extent and pattern of acidification in vivo during the early phase post musculoskeletal injury. Local pH changes after fracture and muscle trauma were measured simultaneously in two pre-clinical animal models (sheep/rats) immediately after and up to 48 h post injury. The rat fracture hematoma was further analyzed histologically and metabolomically. In vivo pH measurements in bone and muscle hematoma revealed a local acidification in both animal models, yielding mean pH values in rats of 6.69 and 6.89, with pronounced intra- and inter-individual differences. The metabolomic analysis of the hematomas indicated a link between reduction in tricarboxylic acid cycle activity and pH, thus, metabolic activity within the injured tissues could be causative for the different pH values. The significant acidification within the early musculoskeletal hematoma could enable the employment of the pH for novel, sought-after treatments that allow for spatially and temporally controlled drug release.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Early pH Changes in Musculoskeletal Tissues upon Injury—Aerobic Catabolic Pathway Activity Linked to Inter-Individual Differences in Local pH

Berkmann

Martin

Ellinghaus

et al. 2020

IJMS

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“…Hypoxia occurs when tumors outgrow their blood supply and the overall amount of oxygen available for cancer cell respiration decreases (39). Hypoxic environments cause mitochondria to produce ROS, which can promote EMT and metastasis (40–42). Exposure to hypoxia in vitro does not change overall vimentin protein content of A549 cells ( Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Berr¹,

Wiese²,

Santos³

et al. 2020

Preprint

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1Vimentin, a type III intermediate filament, is highly expressed in aggressive epithelial 2 cancers and is associated with increased rates of metastasis. We show that vimentin is causally 3 required for lung cancer metastasis using a genetic mouse model of lung adenocarcinoma (LSL-4 Kras G12D ;Tp53 fl/fl , termed KPV +/+ ) crossed with vimentin-null mice (thereby creating KPV −/− mice). 5Both KPV +/+ and KPV −/− mice developed lung tumors, yet KPV −/− mice had delayed tumorigenesis 6 and prolonged survival. KPV +/+ cells implanted in the flank metastasized to the lung while KPV −/− 7 cells did not, providing additional evidence that vimentin is required for metastasis. Differential 8 expression analysis of RNA-seq data demonstrated that KPV −/− cells had suppressed expression 9 of genes that drive epithelial-to-mesenchymal transition, migration, and invasion, processes that 10 are critical to the metastatic cascade. Integrative metabolomic and transcriptomic analysis 11 revealed altered glutaminolysis, with KPV −/− cells accumulating glutathione, leading to impaired 12 cell motility in response to oxidative stress. Together, these results show that loss of vimentin 13 impairs epithelial-to-mesenchymal transition and regulation of the oxidative stress response, 14 resulting in decreased metastasis in murine lung adenocarcinoma. 15 16 17 18Non-small-cell lung cancers (NSCLCs) represent 80% of all lung cancers and are often 20 diagnosed at more advanced stages of the disease resulting in high rates of mortality (1). 21Adenocarcinoma is the most common subtype of NSCLC and is characterized by activating 22 mutations in the Kras proto-oncogene in up to 30% of diagnoses and by inactivating mutations in 23 the tumor suppressor gene Tp53 in up to 60% of diagnoses (2)(3)(4)(5). Despite the prevalence of lung 24 adenocarcinoma, the metastatic mechanisms that drive lung cancer progression are incompletely 25 understood. 26The type III intermediate filament vimentin is associated with increased metastatic spread 27 and lower rates of survival in patients with NSCLC (6-8). Vimentin is a canonical marker of 28 epithelial-to-mesenchymal transition (EMT), an initiating event of the metastatic cascade (9). EMT 29 is the process by which epithelial cells remodel cell-cell and cell-extracellular-matrix (ECM) 30 contacts, lose their apical-basal polarity, and adopt the spindle-shaped morphology associated 31 with a mesenchymal cell phenotype (10). During EMT, cells undergo a downregulation of 32 epithelial cell associated genes, including E-cadherin and cytokeratins, and an upregulation of 33 mesenchymal cell associated genes, including N-cadherin and vimentin. In addition to acting as 34 a marker of EMT, vimentin is functionally involved in EMT. Structurally, vimentin intermediate 35 filaments control cell shape, and thus facilitate the transition toward a mesenchymal phenotype 36(11). Twist1, a transcription factor critical to EMT, upregulates vimentin expression (12). Vimentin 37 also serves as a scaffold for Slug, another transc...

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“…As mentioned previously, α-KG is an important intermediate from the TCA cycle that is appreciated not only as a metabolite, but also a cofactor for several epigenetic-modifying enzymes involved in histone or DNA demethylation [134,135]. Glutaminolysis of glutamine can generate α-KG that is essential to sustain mitochondrial fitness and promote M2 activation [66].…”

Section: Macrophages-m2 Macrophagementioning

confidence: 99%

Carbohydrate and Amino Acid Metabolism as Hallmarks for Innate Immune Cell Activation and Function

Zhao

Raines

Huang

2020

Cells

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Immune activation is now understood to be fundamentally linked to intrinsic and/or extrinsic metabolic processes which are essential for immune cells to survive, proliferate, and perform their effector functions. Moreover, disruption or dysregulation of these pathways can result in detrimental outcomes and underly a number of pathologies in both communicable and non-communicable diseases. In this review, we discuss how the metabolism of carbohydrates and amino acids in particular can modulate innate immunity and how perturbations in these pathways can result in failure of these immune cells to properly function or induce unfavorable phenotypes.

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Mitochondrial TCA cycle metabolites control physiology and disease

Cited by 1,483 publications

References 99 publications

Early pH Changes in Musculoskeletal Tissues upon Injury—Aerobic Catabolic Pathway Activity Linked to Inter-Individual Differences in Local pH

Early pH Changes in Musculoskeletal Tissues upon Injury—Aerobic Catabolic Pathway Activity Linked to Inter-Individual Differences in Local pH

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Carbohydrate and Amino Acid Metabolism as Hallmarks for Innate Immune Cell Activation and Function

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