Emerging Role of TCA Cycle-Related Enzymes in Human Diseases

Kang, Woojin; Suzuki, Miki; Saitô, Takako; Miyado, Kenji

doi:10.3390/ijms222313057

Cited by 60 publications

(36 citation statements)

References 104 publications

(142 reference statements)

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“…Aging and metabolic diseases such as type 2 diabetes are closely associated with a decrease in the mitochondrial capacity including the TCA cycle activities (7)(8)(9)(10), which could lead to the disruption of nutrient metabolism and a shortage of cellular energy. Recent studies have reported that the dysfunction of the TCA cycle along with a loss or a decrease in the activity of its related enzymes is involved in the etiology of various diseases (11). However, the effects of such TCA cycle impairment on the flexibility and capacity of substrate metabolism in the heart and skeletal muscles have not yet been thoroughly investigated.…”

Section: Introductionmentioning

confidence: 99%

Citrate Synthase Insufficiency Leads to Specific Metabolic Adaptations in the Heart and Skeletal Muscles Upon Low-Carbohydrate Diet Feeding in Mice

Sumi

Hatanaka²,

Takahashi³

et al. 2022

Front. Nutr.

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A decrease in TCA cycle activity may lead to impaired nutrition metabolism and cellular energy shortage. Herein, we aimed to characterize the detailed metabolic changes that compensate for energy shortages in energy-consuming organs (heart and skeletal muscles) in mice with knockout of citrate synthase (CS), an important enzyme in the TCA cycle. CS hetero knockout (CS +/−) mice and wild-type mice were fed a low-carbohydrate ketogenic diet (LCKD) or high-fat, high-carbohydrate diet (HFHCD) to induce metabolic changes. Body weight, blood serum parameters, metabolic gene expression, and adenosine triphosphate (ATP) levels were measured in the heart and skeletal muscles. Glycogen content, anabolic and catabolic biomarkers, and morphological changes were also assessed in the skeletal muscles. After diet feeding, there were no differences observed in the body weight and blood serum parameters between wild-type and CS +/− mice. The cardiac expression of genes related to the utilization of fatty acids, monocarboxylates, and branched amino acids increased in LCKD-fed CS +/− mice. In contrast, no significant differences in gene expression were observed in the muscles of LCKD-fed mice or the heart and muscles of HFHCD-fed mice. ATP levels decreased only in the skeletal muscles of LCKD-fed CS +/− mice. Additionally, the decrease in glycogen content, suppression of p70 S6 kinase, and presence of type I fiber atrophy were observed in the muscles of LCKD-fed CS +/− mice. These results suggest that the energy-consuming organs with CS insufficiency may undergo tissue-specific adaption to compensate for energy shortages when the carbohydrate supply is limited.

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Section: Introductionmentioning

confidence: 99%

Citrate Synthase Insufficiency Leads to Specific Metabolic Adaptations in the Heart and Skeletal Muscles Upon Low-Carbohydrate Diet Feeding in Mice

Sumi

Hatanaka²,

Takahashi³

et al. 2022

Front. Nutr.

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“…The TCA cycle is able to produce ATP as well as NADH and FADH2 during the oxidization of acetyl-coenzyme A (acetyl-CoA). 25 The NADH and FADH2 produced from TCA cycle then further feed the ETC complex I (NADH dehydrogenase) and complex II (succinate dehydrogenase), respectively. The two complexes then transfer their electrons through the ETC and eventually generate ATP via oxidative phosphorylation (OXPHOS).…”

Section: Cellular Respiration and Atp Synthesismentioning

confidence: 99%

The underestimated role of mitochondria in vitiligo: From oxidative stress to inflammation and cell death

Lin

Ding

et al. 2023

Experimental Dermatology

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Vitiligo is an acquired depigmentary disorder characterized by the depletion of melanocytes in the skin. Mitochondria shoulder multiple functions in cells, such as production of ATP, maintenance of redox balance, initiation of inflammation and regulation of cell death. Increasing evidence has implicated the involvement of mitochondria in the pathogenesis of vitiligo. Mitochondria alteration will cause the abnormalities of mitochondria functions mentioned above, ultimately leading to melanocyte loss through various cell death modes. Nuclear factor erythroid 2‐related factor 2 (Nrf2) plays a critical role in mitochondrial homeostasis, and the downregulation of Nrf2 in vitiligo may correlate with mitochondria damage, making both mitochondria and Nrf2 promising targets in treatment of vitiligo. In this review, we aim to discuss the alterations of mitochondria and its role in the pathogenesis of vitiligo.

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“…Cancer cells are characterized by metabolic and epigenetic changes in TCA cycle enzymes that correlate with disease progression. Therefore, some enzymes have become a potential therapeutic target, but a limitation is the high toxicity of the tested compounds [ 200 , 201 ].…”

Section: The Krebs Cyclementioning

confidence: 99%

Targeting Energy Metabolism in Cancer Treatment

Kubik

Humeniuk

Adamczuk

et al. 2022

IJMS

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Cancer is the second most common cause of death worldwide after cardiovascular diseases. The development of molecular and biochemical techniques has expanded the knowledge of changes occurring in specific metabolic pathways of cancer cells. Increased aerobic glycolysis, the promotion of anaplerotic responses, and especially the dependence of cells on glutamine and fatty acid metabolism have become subjects of study. Despite many cancer treatment strategies, many patients with neoplastic diseases cannot be completely cured due to the development of resistance in cancer cells to currently used therapeutic approaches. It is now becoming a priority to develop new treatment strategies that are highly effective and have few side effects. In this review, we present the current knowledge of the enzymes involved in the different steps of glycolysis, the Krebs cycle, and the pentose phosphate pathway, and possible targeted therapies. The review also focuses on presenting the differences between cancer cells and normal cells in terms of metabolic phenotype. Knowledge of cancer cell metabolism is constantly evolving, and further research is needed to develop new strategies for anti-cancer therapies.

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Emerging Role of TCA Cycle-Related Enzymes in Human Diseases

Cited by 60 publications

References 104 publications

Citrate Synthase Insufficiency Leads to Specific Metabolic Adaptations in the Heart and Skeletal Muscles Upon Low-Carbohydrate Diet Feeding in Mice

Citrate Synthase Insufficiency Leads to Specific Metabolic Adaptations in the Heart and Skeletal Muscles Upon Low-Carbohydrate Diet Feeding in Mice

The underestimated role of mitochondria in vitiligo: From oxidative stress to inflammation and cell death

Targeting Energy Metabolism in Cancer Treatment

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