Mitochondrial dysfunction has been implicated in the pathogenesis of insulin resistance, the hallmark of type 2 diabetes mellitus (T2DM). However, the cause-effect relationship remains to be fully ...elucidated. Compelling evidence suggests that boosting mitochondrial function may represent a valuable therapeutic tool to improve insulin sensitivity. Mitochondria are highly dynamic organelles, which adapt to short- and long-term metabolic perturbations by undergoing fusion and fission cycles, spatial rearrangement of the electron transport chain complexes into supercomplexes and biogenesis governed by peroxisome proliferator-activated receptor γ co-activator 1α (PGC 1α). However, these processes appear to be dysregulated in type 2 diabetic individuals. Herein, we describe the mechanistic link between mitochondrial dysfunction and insulin resistance in skeletal muscle alongside the intracellular pathways orchestrating mitochondrial bioenergetics. We then review current evidence on nutritional tools, including fatty acids, amino acids, caloric restriction and food bioactive derivatives, which may enhance insulin sensitivity by therapeutically targeting mitochondrial function and biogenesis.
Maize is a sensitive crop to drought and heat stresses, particularly at the reproductive stages of development. The present study investigated the individual and interactive effects of drought (50% ...field capacity) and heat (38 °C/30 °C) stresses on morpho-physiological growth, yield, nutrient uptake and oxidative metabolism in two maize hybrids i.e., 'Xida 889' and 'Xida 319'. The stress treatments were applied at tasseling stage for 15 days. Drought, heat and drought + heat stress caused oxidative stress by the over-production of ROS (O
, H
O
, OH
) and enhanced malondialdehyde contents, which led to reduced photosynthetic components, nutrients uptake and yield attributes. The concurrent occurrence of drought and heat was more severe for maize growth than the single stress. However, both stresses induced the metabolites accumulation and enzymatic and non-enzymatic antioxidants to prevent the oxidative damage. The performance of Xida 899 was more prominent than the Xida 319. The greater tolerance of Xida 889 to heat and drought stresses was attributed to strong antioxidant defense system, higher osmolyte accumulation, and maintenance of photosynthetic pigments and nutrient balance compared with Xida 319.
Human studies suggest that a meal elevates glucose uptake in brown adipose tissue (BAT). However, in postprandial state the thermogenic activity and the metabolism of non-esterified fatty acids ...(NEFAs) in BAT remain unclear. Using indirect calorimetry combined with positron emission tomography and computed tomography (PET/CT), we showed that whole-body and BAT thermogenesis (oxygen consumption) increases after the ingestion of a mixed carbohydrate-rich meal, to the same extent as in cold stress. Postprandial NEFA uptake into BAT is minimal, possibly due to elevated plasma insulin inhibiting lipolysis. However, the variation in postprandial NEFA uptake is linked to BAT thermogenesis. We identified several genes participating in lipid metabolism to be expressed at higher levels in BAT compared with white fat in postprandial state, and to be positively correlated with BAT UCP1 expression. These findings suggest that substrates preferred by BAT in postprandial state are glucose or LPL-released NEFAs due to insulin stimulation.
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•A carbohydrate-dominant meal triggers human brown fat thermogenesis•After a meal, the genes involved in fatty acid metabolism are highly expressed in BAT•BAT uptake of circulatory fatty acids after meal consumption is minimal•Postprandial thermogenesis in BAT is linked to circulatory fatty acid uptake
Using PET/CT imaging, U Din et al. show that eating a carbohydrate-rich meal triggers human brown adipose tissue (hBAT) thermogenesis to the same extent as cold stress, though the substrates used are different. Glucose and LPL-derived fatty acids are preferentially taken up by hBAT in the postprandial state.
Mistakenly thought to be the consequence of oxygen lack in contracting skeletal muscle we now know that the L-enantiomer of the lactate anion is formed under fully aerobic conditions and is utilized ...continuously in diverse cells, tissues, organs and at the whole-body level. By shuttling between producer (driver) and consumer (recipient) cells lactate fulfills at least three purposes: 1 a major energy source for mitochondrial respiration; 2 the major gluconeogenic precursor; and 3 a signaling molecule. Working by mass action, cell redox regulation, allosteric binding, and reprogramming of chromatin by lactylation of lysine residues on histones, lactate has major influences in energy substrate partitioning. The physiological range of tissue lactate is 0.5–20 mM and the cellular Lactate/Pyruvate ratio (L/P) can range from 10 to >500; these changes during exercise and other stress-strain responses dwarf other metabolic signals in magnitude and span. Hence, lactate dynamics have rapid and major short- and long-term effects on cell redox and other control systems. By inhibiting lipolysis in adipose via HCAR-1, and muscle mitochondrial fatty acid uptake via malonyl-CoA and CPT1, lactate controls energy substrate partitioning. Repeated lactate exposure from regular exercise results in major effects on the expression of regulatory enzymes of glycolysis and mitochondrial respiration. Lactate is the fulcrum of metabolic regulation in vivo.
Maintaining heart viability in states of unfavorable metabolite/oxygen supply has become a prime challenge in cardiac medicine. Mitochondria have been recognised as key actors in cardioprotection. ...Our goal was to reveal the myocardial protective phenotype related to mitochondrial bioenergetic pathways in the state of limited metabolite supply and low temperature using the physiological model of mammalian hibernation.
European ground squirrels (Spermophilus citellus) were exposed to cold (4 ± 1°C) and divided into two groups: (1) animals that fell into torpor (hibernating group) and (2) animals that stayed active and euthermic for 1, 3, 7, 12, or 21 days (cold-exposed group). We found increased protein levels of electron transport chain components and ATP synthase in late cold acclimation and in hibernation. Also, protein level of PGC-1α was upregulated. Phospho-AMPKα protein content was increased during early cold acclimation. HIF1α protein level was unchanged. Protein levels of manganese and copper-zinc superoxide dismutase and glutathione peroxidase were increased in hibernation.
The hibernation related phenotype of the heart is characterised by controlled improvement of mitochondrial energy and antioxidative capacity. Its reproduction could have broad implications, from myocardial protection in ischaemia/reperfusion to the hypothermic survival and cold preservation of organs.
In vitro and in vivo studies have shown that glutamate can be oxidized for energy by brain astrocytes. The ability to harvest the energy from glutamate provides astrocytes with a mechanism to offset ...the high ATP cost of the uptake of glutamate from the synaptic cleft. This brief review focuses on oxidative metabolism of glutamate by astrocytes, the specific pathways involved in the complete oxidation of glutamate and the energy provided by each reaction.
Itaconate is one of the best examples of the consequences of metabolic reprogramming during immunity. It is made by diverting aconitate away from the tricarboxylic acid cycle during inflammatory ...macrophage activation. The main reason macrophages exhibit this response currently appears to be for an anti-inflammatory effect, with itaconate connecting cell metabolism, oxidative and electrophilic stress responses and immune responses. A role for itaconate in the regulation of type I interferons during viral infection has also been described, as well as in M2 macrophage function under defined circumstances. Finally, macrophage-specific itaconate production has also been shown to have a pro-tumour effect. All of these studies point towards itaconate being a critical immunometabolite that could have far-reaching consequences for immunity, host defence and tumorigenesis.
Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated ...membranes: MAMs) are highly dynamic and involved in many functions; however, whether MAM dysfunction plays a causal role in hepatic insulin resistance and steatosis is not clear. Thus, we aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment.
We analyzed hepatic ER-mitochondria interactions and calcium exchange in a time-dependent and reversible manner in mice with diet-induced obesity. Additionally, we used recombinant adenovirus to express a specific organelle spacer or linker in mouse livers, to determine the causal impact of MAM dysfunction on hepatic metabolic alterations.
Disruption of ER-mitochondria interactions and calcium exchange is an early event preceding hepatic insulin resistance and steatosis in mice with diet-induced obesity. Interestingly, an 8-week reversal diet concomitantly reversed hepatic organelle miscommunication and insulin resistance in obese mice. Mechanistically, disrupting structural and functional ER-mitochondria interactions through the hepatic overexpression of the organelle spacer FATE1 was sufficient to impair hepatic insulin action and glucose homeostasis. In addition, FATE1-mediated organelle miscommunication disrupted lipid-related mitochondrial oxidative metabolism and induced hepatic steatosis. Conversely, reinforcement of ER-mitochondria interactions through hepatic expression of a synthetic linker prevented diet-induced glucose intolerance after 4 weeks’ overnutrition. Importantly, ER-mitochondria miscommunication was confirmed in the liver of obese patients with type 2 diabetes, and correlated with glycemia, HbA1c and HOMA-IR index.
ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be reversed by switching to a healthy diet. Thus, targeting MAMs could help to restore metabolic homeostasis.
The literature suggests that interactions between the endoplasmic reticulum and mitochondria could play a role in hepatic insulin resistance and steatosis during chronic obesity. In the present study, we reappraised the time-dependent regulation of hepatic endoplasmic reticulum-mitochondria interactions and calcium exchange, investigating reversibility and causality, in mice with diet-induced obesity. We also assessed the relevance of our findings to humans. We show that organelle miscommunication is an early causal trigger of hepatic insulin resistance and steatosis that can be improved by nutritional strategies.
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•Reduced ER-mitochondria interactions and calcium exchange is an early event in diet-induced obese mice.•Disrupting ER-mitochondria communication is sufficient to induce hepatic insulin resistance and steatosis.•Reinforcing ER-mitochondria interactions prevents diet-induced glucose intolerance.•Switching on a healthy diet concomitantly reverses ER-mitochondria miscommunication and improves hepatic insulin sensitivity.•ER-mitochondria miscommunication was confirmed in the liver of patients with MAFLD and type 2 diabetes.
Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, ...especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5‐fluorouracil (5‐FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5‐FU resistance. Some are disease‐specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5‐FU. In this review, we construct a global outline of different mechanisms from disruption of 5‐FU‐metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial‐mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.
Colorectal cancer is the third most common cancer worldwide. 5‐Fluorouracil (5‐FU), a synthetic fluorinated pyrimidine analog requiring intracellular conversion into active metabolites, is the main chemotherapy used when colorectal cancer is at an advanced stage or at high risk of recurrence. However, resistance to this treatment exists, explaining a low 5‐year survival rate. We review the main mechanisms of 5‐FU resistance, especially those linked to tumor microenvironment and genetic alterations.
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