scholarly journals The Significance of Mitochondrial Dysfunction in Cancer

2020 ◽  
Vol 21 (16) ◽  
pp. 5598 ◽  
Author(s):  
Yongde Luo ◽  
Jianjia Ma ◽  
Weiqin Lu
Keyword(s):  
Mitochondrial Dysfunction ◽  
Wide Spectrum ◽  
Tca Cycle ◽  
Redox Balance ◽  
Genetic Mutations ◽  
Cycle Enzyme ◽  
Human Cancers ◽  
The Tca Cycle ◽  
Transport Chain ◽  
Enzyme Defects

As an essential organelle in nucleated eukaryotic cells, mitochondria play a central role in energy metabolism, maintenance of redox balance, and regulation of apoptosis. Mitochondrial dysfunction, either due to the TCA cycle enzyme defects, mitochondrial DNA genetic mutations, defective mitochondrial electron transport chain, oxidative stress, or aberrant oncogene and tumor suppressor signaling, has been observed in a wide spectrum of human cancers. In this review, we summarize mitochondrial dysfunction induced by these alterations that promote human cancers.

scholarly journals SUN-219 Electron Transport Chain Complex 2 in Mitochondrial Pregnenolone Synthesis

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Himangshu S Bose ◽  
Brendan Marshall ◽  
Dilip Debnath ◽  
Elizabeth W Perry ◽  
Randy M Whittal
Keyword(s):  
Electron Transport ◽  
Intermediate State ◽  
Electron Transport Chain ◽  
Molten Globule ◽  
Tca Cycle ◽  
Steroid Synthesis ◽  
Aberrant Expression ◽  
Complex Ii ◽  
The Tca Cycle ◽  
Transport Chain

Abstract The mitochondrial P450 family of enzymes (SCC), which require the electron transport chain (ETC) complexes III, IV and V, initiate steroidogenesis by cleaving the sidechain of cholesterol to synthesize steroid hormones, an essential component for mammalian survival. SCC is required for full-term gestation, and aberrant expression may cause pseudohermaphroditism, breast cancer or polycystic ovary syndrome. Complex II or succinate dehydrogenase (quinone) is shared with the TCA cycle and has no proton pumping capacity and no known role in steroid synthesis. We now show that succinate is an intermediate metabolite in the TCA cycle and plays a central role physiologically. Specifically, complex II is required for SCC activation, where the proton pump facilitates an active intermediate state conformation at the matrix, so that in the presence of succinate, ATP can add phosphate. A longer intermediate equilibrium state generates a transient stabilization to enhance the binding of phosphate anions in the presence of succinate anions, resulting in higher enthalpy and activity. An inhibition of the processing at the intermediate state stops phosphate addition and activity. We further describe that phosphate circulation brings the molten globule, an intermediate, to an active folded state. This is the first report showing that an intermediate state activated by succinate facilitates ETC complex II interaction with complexes III and IV for metabolism.

Protein hyperacylation links mitochondrial dysfunction with nuclear organization

2020 ◽  
Author(s):  
John Smestad ◽  
Micah McCauley ◽  
Matthew Amato ◽  
Yuning Xiong ◽  
Juan Liu ◽  
...  
Keyword(s):  
Chromatin Structure ◽  
Metabolic Regulation ◽  
Tca Cycle ◽  
Interphase Chromatin ◽  
Histone Octamer ◽  
The Tca Cycle ◽  
Transport Chain ◽  
Topologically Associated Domains ◽  
Biophysical Effects ◽  
Liquid Liquid Phase Separation

SummaryCellular metabolism is linked to epigenetics, but the biophysical effects of metabolism on chromatin structure and implications for gene regulation remain largely unknown. Here, using a broken tricarboxylic acid (TCA) cycle and disrupted electron transport chain (ETC) exemplified by succinate dehydrogenase subunit C (SDHC) deficiency, we investigated the effects of metabolism on chromatin architecture over multiple distance scales [nucleosomes (∼102 bp), topologically-associated domains (TADs; ∼105 – 106 bp), and chromatin compartments (106 – 108 bp)]. Metabolically-driven hyperacylation of histones led to weakened nucleosome positioning in multiple types of chromatin, and we further demonstrate that lysine acylation directly destabilizes histone octamer-DNA interactions. Hyperacylation of cohesin subunits correlated with decreased mobility on interphase chromatin and increased TAD boundary strength, suggesting that cohesin is metabolically regulated. Erosion of chromatin compartment distinctions reveals metabolic regulation of chromatin liquid-liquid phase separation. The TCA cycle and ETC thus modulate chromatin structure over multiple distance scales.

scholarly journals Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta

2019 ◽  
Author(s):  
Emelyne Teo ◽  
Sudharshan Ravi ◽  
Diogo Barardo ◽  
Hyung-Seok Kim ◽  
Sheng Fong ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Mitochondrial Dysfunction ◽  
Amyloid Beta ◽  
Metabolic Stress ◽  
Tca Cycle ◽  
The Elderly ◽  
Protein Carbonyl ◽  
Protein Aggregate ◽  
Protein Carbonyl Content ◽  
Cycle Enzyme

AbstractAlzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on a deeper analysis of these metabolic changes associated with Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics, biochemical studies and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 show reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects are associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurs before any significant increase in global protein aggregate is detectable. Treatment with an antidiabetes drug, Metformin, reverses Aβ-induced metabolic defects, reduces protein aggregation and normalizes the lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in AD pathology and a promising target for intervention.

scholarly journals The existence of a nonclassical TCA cycle in the nucleus that wires the metabolic-epigenetic circuitry

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xujun Liu ◽  
Wenzhe Si ◽  
Lin He ◽  
Jianguo Yang ◽  
Yani Peng ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Citrate Synthase ◽  
Fumarate Hydratase ◽  
Tca Cycle ◽  
Chromatin Dynamics ◽  
Metabolic Intermediates ◽  
The Tca Cycle ◽  
Transport Chain ◽  
Outstanding Question ◽  
Aconitase 2

AbstractThe scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid (TCA) cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus. We report here the identification of a nonclassical TCA cycle in the nucleus (nTCA cycle). We found that all the TCA cycle-associated enzymes including citrate synthase (CS), aconitase 2 (ACO2), isocitrate dehydrogenase 3 (IDH3), oxoglutarate dehydrogenase (OGDH), succinyl-CoA synthetase (SCS), fumarate hydratase (FH), and malate dehydrogenase 2 (MDH2), except for succinate dehydrogenase (SDH), a component of electron transport chain for generating ATP, exist in the nucleus. We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria. We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates, not for energy production. We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation. Together, our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.

scholarly journals TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 68 ◽  
Author(s):  
Simona Todisco ◽  
Paolo Convertini ◽  
Vito Iacobazzi ◽  
Vittoria Infantino
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Redox Balance ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Aberrant Gene Expression ◽  
The Tca Cycle ◽  
Aberrant Gene

Hepatocellular carcinoma (HCC) is a common malignancy. Despite progress in treatment, HCC is still one of the most lethal cancers. Therefore, deepening molecular mechanisms underlying HCC pathogenesis and development is required to uncover new therapeutic strategies. Metabolic reprogramming is emerging as a critical player in promoting tumor survival and proliferation to sustain increased metabolic needs of cancer cells. Among the metabolic pathways, the tricarboxylic acid (TCA) cycle is a primary route for bioenergetic, biosynthetic, and redox balance requirements of cells. In recent years, a large amount of evidence has highlighted the relevance of the TCA cycle rewiring in a variety of cancers. Indeed, aberrant gene expression of several key enzymes and changes in levels of critical metabolites have been observed in many solid human tumors. In this review, we summarize the role of the TCA cycle rewiring in HCC by reporting gene expression and activity dysregulation of enzymes relating not only to the TCA cycle but also to glutamine metabolism, malate/aspartate, and citrate/pyruvate shuttles. Regarding the transcriptional regulation, we focus on the link between NF-κB-HIF1 transcriptional factors and TCA cycle reprogramming. Finally, the potential of metabolic targets for new HCC treatments has been explored.

scholarly journals Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

2020 ◽  
Author(s):  
Minervo Perez ◽  
Daniel W. Bak ◽  
Sarah E. Bergholtz ◽  
Daniel R. Crooks ◽  
Youfeng Yang ◽  
...  
Keyword(s):  
Cell Line ◽  
Fumarate Hydratase ◽  
Tca Cycle ◽  
Covalent Modification ◽  
Cysteine Residues ◽  
Posttranslational Regulation ◽  
Equal Proportion ◽  
Cancer Syndrome ◽  
Cycle Enzyme ◽  
The Tca Cycle

ABSTRACTMetabolism and signaling intersect in the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a disease in which mutation of the TCA cycle enzyme fumarate hydratase (FH) causes hyperaccumulation of fumarate. This electrophilic oncometabolite can alter gene activity at the level of transcription, via reversible inhibition of epigenetic dioxygenases, as well as posttranslationally, via covalent modification of cysteine residues. To better understand how metabolites function as covalent signals, here we report a chemoproteomic analysis of a kidney-derived HLRCC cell line. Building on previous studies, we applied a general reactivity probe to compile a dataset of cysteine residues sensitive to rescue of cellular FH activity. This revealed a broad upregulation of cysteine reactivity upon FH rescue, caused by an approximately equal proportion of transcriptional and posttranslational regulation in the rescue cell line. Gene ontology analysis highlights new targets and pathways potentially modulated by FH mutation. Comparison of the new dataset to literature studies highlights considerable heterogeneity in the adaptive response of cysteine-containing proteins in different models of HLRCC. Our analysis provides a resource for understanding the proteomic adaptation to fumarate accumulation, and a foundation for future efforts to exploit this knowledge for cancer therapy.

scholarly journals DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ning Shen ◽  
Sovannarith Korm ◽  
Theodoros Karantanos ◽  
Dun Li ◽  
Xiaoyu Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tca Cycle ◽  
Free Survival ◽  
Cycle Enzyme ◽  
Therapeutic Implications ◽  
Tnbc Cell ◽  
The Tca Cycle ◽  
Metabolic Heterogeneity

AbstractTriple-negative breast cancer (TNBC) is traditionally considered a glycolytic tumor with a poor prognosis while lacking targeted therapies. Here we show that high expression of dihydrolipoamide S-succinyltransferase (DLST), a tricarboxylic acid (TCA) cycle enzyme, predicts poor overall and recurrence-free survival among TNBC patients. DLST depletion suppresses growth and induces death in subsets of human TNBC cell lines, which are capable of utilizing glutamine anaplerosis. Metabolomics profiling reveals significant changes in the TCA cycle and reactive oxygen species (ROS) related pathways for sensitive but not resistant TNBC cells. Consequently, DLST depletion in sensitive TNBC cells increases ROS levels while N-acetyl-L-cysteine partially rescues cell growth. Importantly, suppression of the TCA cycle through DLST depletion or CPI-613, a drug currently in clinical trials for treating other cancers, decreases the burden and invasion of these TNBC. Together, our data demonstrate differential TCA-cycle usage in TNBC and provide therapeutic implications for the DLST-dependent subsets.

scholarly journals The hexokinase ″HKDC1″ interaction with the mitochondria is essential for hepatocellular carcinoma progression

2021 ◽  
Author(s):  
Md. Wasim Khan ◽  
Alexander Terry ◽  
Medha Priyadarshini ◽  
Grace Guzman ◽  
Jose Cordoba-Chacon ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mitochondrial Dysfunction ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Selective Approach ◽  
Glucose Flux ◽  
The Tca Cycle

Hepatocellular carcinoma (HCC) is a leading cause of death from cancer malignancies. Recently, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in HCC compared to healthy tissue. Using in vitro and in vivo tools, we examined the role of HKDC1 in HCC progression. Importantly, HKDC1 ablation stops HCC progression by promoting metabolic reprogramming by shifting glucose flux away from the TCA cycle. Next, HKDC1 ablation leads to mitochondrial dysfunction resulting in less cellular energy which cannot be compensated by enhanced glucose uptake. And finally, we show that the interaction of HKDC1 with the mitochondria is essential for its role in HCC progression, and without this mitochondrial interaction mitochondrial dysfunction occurs. In sum, HKDC1 is highly expressed in HCC cells compared to normal hepatocytes, therefore targeting HKDC1, specifically its interaction with the mitochondria, reveals a highly selective approach to target cancer cells in HCC.

scholarly journals Thioredoxin, a master regulator of the tricarboxylic acid cycle in plant mitochondria

2015 ◽  
Vol 112 (11) ◽  
pp. E1392-E1400 ◽  
Author(s):  
Danilo M. Daloso ◽  
Karolin Müller ◽  
Toshihiro Obata ◽  
Alexandra Florian ◽  
Takayuki Tohge ◽  
...  
Keyword(s):  
Tricarboxylic Acid Cycle ◽  
Plant Mitochondria ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Mitochondrial Enzymes ◽  
Atp Citrate Lyase ◽  
Cycle Enzyme ◽  
The Tca Cycle

Plant mitochondria have a fully operational tricarboxylic acid (TCA) cycle that plays a central role in generating ATP and providing carbon skeletons for a range of biosynthetic processes in both heterotrophic and photosynthetic tissues. The cycle enzyme-encoding genes have been well characterized in terms of transcriptional and effector-mediated regulation and have also been subjected to reverse genetic analysis. However, despite this wealth of attention, a central question remains unanswered: “What regulates flux through this pathway in vivo?” Previous proteomic experiments withArabidopsisdiscussed below have revealed that a number of mitochondrial enzymes, including members of the TCA cycle and affiliated pathways, harbor thioredoxin (TRX)-binding sites and are potentially redox-regulated. We have followed up on this possibility and found TRX to be a redox-sensitive mediator of TCA cycle flux. In this investigation, we first characterized, at the enzyme and metabolite levels, mutants of the mitochondrial TRX pathway inArabidopsis: theNADP-TRX reductasea and b double mutant (ntra ntrb) and the mitochondrially locatedthioredoxin o1(trxo1) mutant. These studies were followed by a comparative evaluation of the redistribution of isotopes when13C-glucose,13C-malate, or13C-pyruvate was provided as a substrate to leaves of mutant or WT plants. In a complementary approach, we evaluated the in vitro activities of a range of TCA cycle and associated enzymes under varying redox states. The combined dataset suggests that TRX may deactivate both mitochondrial succinate dehydrogenase and fumarase and activate the cytosolic ATP-citrate lyase in vivo, acting as a direct regulator of carbon flow through the TCA cycle and providing a mechanism for the coordination of cellular function.

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