Complex II ambiguities—FADH2 in the electron transfer system

Gnaiger, Erich

doi:10.1016/j.jbc.2023.105470

Cited by 13 publications

(6 citation statements)

References 358 publications

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“…In normoxia, CII catalyzes the oxidation of succinate to fumarate, reducing the covalently bound prosthetic group FAD to FADH 2 ; in turn, FADH 2 reduces UQ to UQH 2 , regenerating FAD [ 46 ]. The reversibility of the overall reaction has being extensively addressed for many reasons, reviewed in [ 47 ].…”

Section: Reverse Complex II Activity In Hypoxiamentioning

confidence: 99%

Complex I activity in hypoxia: implications for oncometabolism

Chinopoulos

2024

Biochemical Society Transactions

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Certain cancer cells within solid tumors experience hypoxia, rendering them incapable of oxidative phosphorylation (OXPHOS). Despite this oxygen deficiency, these cells exhibit biochemical pathway activity that relies on NAD+. This mini-review scrutinizes the persistent, residual Complex I activity that oxidizes NADH in the absence of oxygen as the electron acceptor. The resulting NAD+ assumes a pivotal role in fueling the α-ketoglutarate dehydrogenase complex, a critical component in the oxidative decarboxylation branch of glutaminolysis — a hallmark oncometabolic pathway. The proposition is that through glutamine catabolism, high-energy phosphate intermediates are produced via substrate-level phosphorylation in the mitochondrial matrix substantiated by succinyl-CoA ligase, partially compensating for an OXPHOS deficiency. These insights provide a rationale for exploring Complex I inhibitors in cancer treatment, even when OXPHOS functionality is already compromised.

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Section: Reverse Complex II Activity In Hypoxiamentioning

confidence: 99%

Complex I activity in hypoxia: implications for oncometabolism

Chinopoulos

2024

Biochemical Society Transactions

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“…FAD is a covalently bound prosthetic group of electron transport chain complex II and a prosthetic group/coenzyme of some other enzymes, including those participating in fatty acid degradation ( Figure 2 ). Complex II is a part of the electron transfer chain and Krebs cycle, and transfers two electrons from succinate through the reduction of FAD to the electron transport chain and yields fumarate in the Krebs cycle [ 53 ]. On the other hand, electrons transferred to FAD during fatty acid degradation also enter ETC through CoQ independently of complex II [ 53 ].…”

Section: Increasing Mitochondrial Efficiencymentioning

confidence: 99%

“…Complex II is a part of the electron transfer chain and Krebs cycle, and transfers two electrons from succinate through the reduction of FAD to the electron transport chain and yields fumarate in the Krebs cycle [ 53 ]. On the other hand, electrons transferred to FAD during fatty acid degradation also enter ETC through CoQ independently of complex II [ 53 ]. In this way, electrons originating from the oxidation of fatty acids via FADH 2 enter ETC through complex II from the oxidation of acetyl-coenzyme A in the Krebs cycle and independently of complex II if the electrons are transferred to FADH 2 during β-oxidation.…”

Section: Increasing Mitochondrial Efficiencymentioning

confidence: 99%

“…The main metabolic fuels, pyruvate from glucose and fatty acids (magenta) are terminally oxidized in the Krebs cycle in mitochondria to yield the reducing equivalents NADH and FADH2, which donate electrons to the electron transport chain that maintains a proton gradient necessary for the ATP synthesis. Vitamins A, B, C, K, E and lipoic acid are necessary for mitochondrial energy production and are depicted in green next to the resulting cofactor or molecule [ 52 ]; vitamin B7 (biotin) is necessary for fatty acid oxidation [ 53 ]; vitamin B9 (folic acid) is also required for mitochondrial DNA integrity—its deficiency can interfere with the gene expression of mitochondrially encoded transport chain components [ 77 ]. The oxidized form of vitamin E interferes with the activity of the respiratory chain complexes I (CI), II (CII), and III (CIII).…”

Section: Increasing Mitochondrial Efficiencymentioning

confidence: 99%

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Decreasing Intracellular Entropy by Increasing Mitochondrial Efficiency and Reducing ROS Formation—The Effect on the Ageing Process and Age-Related Damage

Poljšak,

Milisav

2024

IJMS

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A hypothesis is presented to explain how the ageing process might be influenced by optimizing mitochondrial efficiency to reduce intracellular entropy. Research-based quantifications of entropy are scarce. Non-equilibrium metabolic reactions and compartmentalization were found to contribute most to lowering entropy in the cells. Like the cells, mitochondria are thermodynamically open systems exchanging matter and energy with their surroundings—the rest of the cell. Based on the calculations from cancer cells, glycolysis was reported to produce less entropy than mitochondrial oxidative phosphorylation. However, these estimations depended on the CO2 concentration so that at slightly increased CO2, it was oxidative phosphorylation that produced less entropy. Also, the thermodynamic efficiency of mitochondrial respiratory complexes varies depending on the respiratory state and oxidant/antioxidant balance. Therefore, in spite of long-standing theoretical and practical efforts, more measurements, also in isolated mitochondria, with intact and suboptimal respiration, are needed to resolve the issue. Entropy increases in ageing while mitochondrial efficiency of energy conversion, quality control, and turnover mechanisms deteriorate. Optimally functioning mitochondria are necessary to meet energy demands for cellular defence and repair processes to attenuate ageing. The intuitive approach of simply supplying more metabolic fuels (more nutrients) often has the opposite effect, namely a decrease in energy production in the case of nutrient overload. Excessive nutrient intake and obesity accelerate ageing, while calorie restriction without malnutrition can prolong life. Balanced nutrient intake adapted to needs/activity-based high ATP requirement increases mitochondrial respiratory efficiency and leads to multiple alterations in gene expression and metabolic adaptations. Therefore, rather than overfeeding, it is necessary to fine-tune energy production by optimizing mitochondrial function and reducing oxidative stress; the evidence is discussed in this paper.

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“…The electron transport system defines the pathways followed by electrons from various substrates before they enter the ETC. Electrons enter the ETC through four distinct pathways 15 (Figure 1 All these pathways transfer electrons to ubiquinone (Q), which exists in three redox states: ubiquinone (Q, fully oxidized), semiquinone (Q•À, partially reduced), and ubiquinol (QH 2 , fully reduced). The Q-cycle involves two steps: Initially, one electron from ubiquinol is transferred to cytochrome c, and the other to the Qi site of CIII, reducing ubiquinone to semiquinone.…”

Section: Current View Of the Electron Transport Systemmentioning

confidence: 99%

Mitochondrial puzzle in muscle: Linking the electron transport system to overweight

Casuso

2024

Obesity Reviews

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SummaryHuman skeletal muscle mitochondria regulate energy expenditure. Research has shown that the functionality of muscle mitochondria is altered in subjects with overweight, as well as in response to nutrient excess and calorie restriction. Two metabolic features of obesity and overweight are (1) incomplete muscular fatty acid oxidation and (2) increased circulating lactate levels. In this study, I propose that these metabolic disturbances may originate from a common source within the muscle mitochondrial electron transport system. Specifically, a reorganization of the supramolecular structure of the electron transport chain could facilitate the maintenance of readily accessible coenzyme Q pools, which are essential for metabolizing lipid substrates. This approach is expected to maintain effective electron transfer, provided that there is sufficient complex III to support the Q‐cycle. Such an adaptation could enhance fatty acid oxidation and prevent mitochondrial overload, thereby reducing lactate production. These insights advance our understanding of the molecular mechanisms underpinning metabolic dysregulation in overweight states. This provides a basis for targeted interventions in the quest for metabolic health.

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Complex II ambiguities—FADH2 in the electron transfer system

Cited by 13 publications

References 358 publications

Complex I activity in hypoxia: implications for oncometabolism

Complex I activity in hypoxia: implications for oncometabolism

Decreasing Intracellular Entropy by Increasing Mitochondrial Efficiency and Reducing ROS Formation—The Effect on the Ageing Process and Age-Related Damage

Mitochondrial puzzle in muscle: Linking the electron transport system to overweight

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