Long-chain saturated fatty acids have been widely described as detrimental to metabolic health by promoting both metabolic inflammation and lipotoxicity Summers, ; Sears and Perry, ; Sergi et al. As discussed in the previous sections, lipid overconsumption appears to be detrimental to mitochondrial health.
This evidence was confirmed in Wistar rats in which a high-fat diet induced a decrease in mitochondrial respiration and ATP production in the soleus muscle, an effect which was also induced by a high-fructose diet Chanseaume et al. Furthermore, feeding mice a high-fat diet for 8 or 16 weeks has been reported to promote impaired fasting glucose and impaired glucose tolerance, which was parallel with a decrease in mitochondria number, ATP synthesis and mitochondrial membrane potential in skeletal muscle Xu et al.
A high-fat diet also increases muscle lipids and acylcarnitines, which correlated with insulin resistance and defective in vivo muscle mitochondrial oxidative metabolism Wessels et al. Thus, it appears that increased lipid supply to skeletal muscle represents a key driver of mitochondrial dysfunction Schrauwen et al.
Particularly, lipotoxicity and ROS have been proposed as the mediators of fatty acid oversupply-induced mitochondrial dysfunction Schrauwen et al. When mitochondrial oxidative capacity fails to match increased fatty acid supply to skeletal muscle, fatty acids accumulate in the proximity of mitochondria and can then translocate to the mitochondrial matrix via a flip-flop mechanism, which bypass both acyl-CoA synthase and carnitine palmitoyl acyl transferase 1 resulting in the accumulation of non-metabolisable fatty acids in the mitochondria Ho et al.
These fatty acids may undergo oxidative damage by ROS with the consequent formation of lipid peroxides, which in turn contribute to oxidative damage to mtDNA and proteins. In support of this possibility, despite obese insulin resistant subject presenting similar amount of intracellular triglycerides as endurance athletes, the degree of lipid peroxidation was 4.
Besides lipid peroxides, ceramide also takes the blame for the detrimental effect of fatty acid overload on mitochondrial function. Indeed, ceramide apart from its deleterious role in insulin signalling pathway Summers, ; Chavez and Summers, also negatively impacts upon mitochondrial function.
Particularly, treatment of muscle cell with the cell permeable ceramide C2 induced mitochondrial fission underpinned by the upregulation of dynamin-related protein 1. Furthermore, ceramide treatment resulted in a decrease in mitochondrial oxygen consumption paralleled by an increase in H 2 O 2 as well as an impairment of insulin signalling in myotubes as demonstrated by a decrease in AKT phosphorylation.
Remarkably, the detrimental effect of ceramide on mitochondrial bioenergetics and dynamics as well as insulin signalling were prevented by inhibiting mitochondrial fission Smith et al. Hence, a balanced mitochondrial dynamics is pivotal in preserving insulin sensitivity and preventing the deleterious effect of lipid overload on mitochondrial bioenergetics in skeletal muscle and possibly other tissues such as the hypothalamus and the liver.
Finally, a high-fat diet has also been reported to downregulate the protein levels of SIRT3 Palacios et al. Thus, the deleterious effect on a high-fat diet and the consequent increase in lipid supply to skeletal muscle is not only limited to the dysregulation of the expression of proteins and genes directly involved in mitochondrial function, dynamics and biogenesis, but also affects the post-translational modifications of these proteins by modulating upstream regulators of mitochondrial function as in the case of SIRT3.
Nonetheless, considering indistinguishably all fatty acids as detrimental is rather simplistic, especially considering that the impact of fatty acids on metabolic health is dictated by their chemical characteristics with unsaturated fatty acids, medium- and short-chain fatty acids being proven as beneficial to metabolic health, compared to long-chain saturated fatty acids Roche, ; Holland et al.
Mitochondria are not immune from the deleterious effect of long-chain saturated fatty acids. Indeed, the exposure to long-chain saturated fatty acids is not without consequences on mitochondrial health as demonstrated in the L6 rat cell line in which palmitic acid, the main long-chain saturated fatty acid in the Western diet, induced mitochondrial dysfunction associated with increased mtDNA damage, induction of c-Jun N-terminal kinases JNK , apoptosis, and insulin resistance all underlain by increased mitochondrial ROS generation Yuzefovych et al.
The effect of long-chain saturated fatty acids was confirmed in C2C12 muscle cell line in which both palmitic and stearic acid challenge induced mitochondrial dysfunction characterised by mitochondria membrane hyperpolarisation and defective ATP generation Hirabara et al. Mitochondrial dynamics is also susceptible to long-chain saturated fatty acids thereby representing a further target which bridges the gap between increased long-chain saturated fatty acid availability and mitochondrial dysfunction.
In support of this notion, exposure of C2C12 muscle cells to palmitic acid resulted in increased mitochondria fission as demonstrated by increased mitochondrial fragmentation orchestrated by the upregulation of dynamin-related protein 1 and mitochondrial fission 1 protein Jheng et al. Not surprisingly, this process was associated with increased oxidative stress and loss of ATP synthesis Jheng et al.
Remarkably, exposure of muscle cells to long-chain saturated fatty acids, apart from inducing mitochondrial dysfunction, also impairs insulin sensitivity, further strengthening the relationship between mitochondrial function and insulin-induced glucose metabolism.
Diverse dietary fat sources may differently affect mitochondrial function and insulin resistance development in skeletal muscle via different mechanisms Putti et al. As described earlier, long-chain saturated fatty acids play a key role in promoting insulin resistance by impairing mitochondrial bioenergetics and dynamic behaviour. On the contrary, omega-3 PUFAs have been reported to improve skeletal muscle insulin sensitivity by modulating mitochondrial function.
In recent years, studies in rodents and humans have indicated that omega-3 PUFAs elicit beneficial effects on metabolic health by reducing obesity and improving insulin resistance with a mechanism, which relies, at least in part, on their ability to increase fat oxidation and energy expenditure and reduce fat deposition Xu, ; Lalia and Lanza, Current knowledge on the potential role of omega-3 fatty acids to improve insulin sensitivity has been recently reviewed by Lalia and Lanza Moreover, an up-to-date commentary on the potential mechanisms by which omega-3 PUFAs may exert beneficial effects on insulin sensitivity at the cellular level has been the focus on a recent review describing the link among mitochondria, ER stress and inflammatory pathways Lepretti et al.
In addition, several studies suggested that omega-3 PUFAs can prevent or reverse the impairments in skeletal muscle mitochondrial function by increasing fatty acid oxidation. The increased fatty acid utilisation is likely to contribute to a decrease in ectopic lipid accumulation playing an important role in counteracting lipotoxicity and insulin resistance onset.
Mitochondrial uncoupling results in a decrease in mitochondrial energy production efficiency leading to an increase in fatty acid catabolism and lower ectopic lipid accumulation, which may represent a further mechanism by which omega-3 PUFAs exert their beneficial effects on insulin sensitivity.
Moreover, the upregulation of UCP3 may be beneficial in counteracting ROS production and the subsequent impairment of insulin signalling pathways, with a similar mechanism being suggested for omega-3 PUFA effects on liver mitochondrial function and prevention of high-fat diet-induced insulin resistance Lionetti et al.
As previously discussed, the role of mitochondrial morphology and dynamic behaviour in determining mitochondrial dysfunction and insulin resistance onset has been the object of growing interest in the recent years. Therefore, another aspect to be considered when analysing the beneficial effect of omega-3 PUFAs is their impact on mitochondrial dynamic behaviour and morphology.
In skeletal muscle, a higher immunoreactivity for Mfn2 and OPA1 proteins was observed in high-fish oil fed rats compared to high-lard fed littermates suggesting a shift in mitochondrial dynamics towards fusion, which was further confirmed by the weaker immunostaining for DRP1 and Fis1 and a prominent presence of fusion events observed by electron microscopy in high-fish oil relative to high lard fed rats Lionetti et al.
This effect of fish oil on mitochondrial dynamic behaviour was associated with an improvement in skeletal muscle insulin signalling as demonstrated by normalisation of IRS1 and pIRS Tyr immunoreactivity in skeletal muscle to the levels of the control diet and improved systemic insulin sensitivity Lionetti et al. Noteworthy, the tendency to mitochondrial fusion induced by dietary omega-3 PUFAs, compared to dietary long-chain saturated fatty acids, may also be related to the well-known anti-inflammatory effect of omega-3 PUFAs as opposed to long-chain saturated fatty acid, which, instead, has been reported to be pro-inflammatory Sergi et al.
Thus, it can be speculated that the pro-inflammatory effects of long-chain saturated fatty acids may be responsible for the reduction in Mfn2 , which in turn may contribute to the development of insulin resistance as discussed previously. On the contrary, the anti-inflammatory effect of omega-3 PUFA may contribute to induce Mfn2 expression, thereby counteracting insulin resistance. In agreement with the pro-fusion effect of omega-3 PUFAs on skeletal muscle mitochondria, the positive effect of omega-3 PUFAs on inflammation and insulin resistance was also associated with improved mitochondrial function and a shift towards fusion processes in rat liver Lionetti et al.
Caloric restriction CR improves insulin sensitivity and delays the onset of metabolic and age-related diseases in a wide variety of organisms, including non-human primates. However, the impacts of CR on mitochondrial function and bioenergetics are controversial.
A number of studies have shown that CR increases mitochondrial biogenesis Nisoli et al. However, this is not consistent across studies or across tissues Hancock et al. Hancock et al. Similarly, long-term CR did not alter any markers of mitochondrial biogenesis, although CR prevented age-related loss of mitochondrial oxidative capacity and efficiency in isolated mitochondria and in muscle fibres, and reduced oxidative damage Hancock et al.
Of note, significant reduction in ROS production was more likely if the duration of the caloric restriction exceeded 20 months. Discrepancies in outcomes between studies could be due to differences in the tissue examined, the duration of CR, the degree of energy restriction, the dietary fat load or source imposed.
The mouse strain under investigation, and gender, is also likely to affect outcomes. Mulvey et al. CR for 10 months did not alter the nDNA:MtDNA ratio, protein levels of markers of mitochondrial biogenesis in liver or skeletal muscle, in any of the mouse strains that were investigated.
Reduced oxygen consumption rates in isolated mitochondria from hepatocytes were observed in animals whose lifespans are shortened by CR. This study could not demonstrate a beneficial effect of CR on mitochondrial dysfunction in the long-lived strain. The effects on mitochondrial ultrastructure and markers of mitochondrial fission and fusion have been investigated in recent studies of CR. Khraiwesh et al.
They also observed that proteins related to mitochondrial fission e. In humans, the impacts of caloric restriction on mitochondrial function are also controversial. Civitarese et al. However, there was no change in key enzymes involved in mitochondrial activity. However, citrate synthase, a marker of mitochondrial content was increased Menshikova et al.
Similarly, 16 weeks of CR increased insulin sensitivity in 11 individuals who were obese but did not affect skeletal muscle mitochondrial oxidative capacity or oxidant emissions Johnson et al. These studies were conducted in small cohorts.
Recently, Sparks et al. In this study, CR reduced intramyocellular lipid in soleus, and mRNA levels of genes involved in lipogenesis and lipid transport. Contrary to expectations, individuals who had a more coupled phenotype at baseline were able to better improve mitochondrial function in response to CR. Intermittent fasting IF is a dietary alternative to CR that is characterised by intermittent periods of fasting typically 24 h , interspersed with ad-libitum AL access to food.
In contrast to CR, body weight is not changed, or modestly reduced, in chow fed IF vs. AL animals Goodrick et al. The impacts of intermittent fasting on mitochondrial function have only been investigated by a handful of studies. Chausse et al. Increases in markers of oxidative damage were observed in liver and brain, but IF provided protection against oxidative damage in the heart.
No difference in mitochondrial bioenergetics or redox homeostasis was observed in skeletal muscle. By contrast, Singh et al. A separate study reported IF enhanced mitochondrial respiration in white adipose tissue, but did not impact liver, skeletal muscle or brown adipose tissue Boutant et al. The effects of IF on mitochondrial ultrastructure and dynamics are unclear. Numerous studies have fed animal and humans varying types of protein-rich supplements and demonstrated modest associations between increased postprandial plasma amino acid concentrations, particularly the branched chain AAs i.
Given impaired mitochondrial function in skeletal muscle is one of the major predisposing factors to metabolic diseases such as insulin resistance, T2DM and cardiovascular diseases, understanding the effects of specific amino acids on mitochondrial function is pivotal to determining what type of dietary proteins are optimal for preventing disease associated with mitochondrial dysfunction.
While our understanding regarding how dietary protein or specific amino acid supplements promote mitochondrial biogenesis in metabolically active tissues and the exact molecular mechanisms through which they occur remains limited, it has been postulated that amino acid supplementation induces mitochondrial biogenesis to promote catabolism of amino acids themselves Valerio et al.
In support for a putative effect of amino acids on mitochondria function, a high-protein diet has been shown to promote a higher rate of fatty acid oxidation than a high-carbohydrate counterpart Raben et al.
Nonetheless, despite the evidence from in vitro and animal models, the effect of amino acid supplementation and high-protein diets on human skeletal muscle mitochondrial function remains elusive. Thus, future research is required to better understand the synergistic actions of all amino acids on muscle mitochondrial function and insulin resistance, as well as shed the light on the molecular mechanisms through which they exert their effects. Bioactive compounds are commonly referred to as a non-nutritive compounds that are present in very small quantities in foods but do have tremendous potential to produce significant improvements in human health Naumovski, ; Christenson et al.
Furthermore, the use of food bioactive derivatives, predominately from plant-based products, has long been described as particularly favourable as it provides a relatively easy and affordable method to incorporate nutraceuticals in the diet.
The health promoting effect of these bioactive molecules also extends to mitochondria and may represent a valuable nutritional tool to prevent or mitigate the metabolic aberrations underpinning mitochondrial dysfunction.
In this regard, the bioactives, which have been most widely described for their effect on mitochondria dys function, include, but are not limited to, Coenzyme Q10, resveratrol and quercetin.
Contrarily to the other bioactives described in this section, CoQ10 is particularly abundant in animal food products. Besides its role as an electron transporter from complex I and II to complex III, CoQ10 is also a potent antioxidant, which protects cells from oxidative damage. Thus, ubiquinone supplementation can positively modulate mitochondria function by supporting electron transport in the ETC on one hand and prevent mitochondrial oxidative damage on the other Shen and Pierce, Furthermore, there is a close relationship between mitochondria dynamics and CoQ10, with MTF2 being required for the synthesis of CoQ10 and ubiquinone itself being able to rescue the reduction in respiratory function resulting from MTF2 deficiency Mourier et al.
Of note, CoQ10 deficiency has been observed in individuals with T2DM, and considering the role of mitochondrial dysfunction in the pathogenesis of insulin resistance and oxidative stress, it can be speculated that CoQ10 supplementation may improve glycaemic control via a direct effect on mitochondrial function Shen and Pierce, Quercetin is a polyphenol, which belongs to the class of flavonoids and is particularly abundant in apples, onions, peppers, berries and leafy green vegetables.
Furthermore, quercetin can stimulate mitochondria oxidative metabolism by directly decreasing ATP:AMP ratio, which in turn results in the activation of AMPK and its downstream catabolic pathways Dorta et al.
Finally, despite quercetin being able to modulate pivotal pathways involved in mitochondria biogenesis and oxidative metabolism in rodents Davis et al. Despite the initial interest towards this bioactive molecules primarily focused on its putative role in increasing longevity, resveratrol has emerged in the recent years for its beneficial effects on metabolic health due to its ability to modulate mitochondria function and biogenesis and oxidative metabolism Christenson et al.
Furthermore, resveratrol has been shown to counteract the deleterious effect of a high-fat diet on metabolic and mitochondria health in rats.
While a high-fat diet induced insulin resistance, downregulated SIRT1 and SIRT3, inhibited mitochondria biogenesis and decreased mtDNA, resveratrol countered high-fat diet-induced metabolic deterioration with a mechanisms which relayed albeit in part, on its beneficial effects on mitochondrial health and function Haohao et al.
Remarkably, the effect of resveratrol was confirmed in the first-degree relatives of type 2 diabetic individuals with resveratrol increasing mitochondrial respiration on octanoyl-carnitine de Ligt et al. Besides the aforementioned compounds, other food-derived bioactives have been described as potential regulator of mitochondrial function.
The bioactives described thus far only represent a portion of the food bioactive molecules being described as positive modulator of mitochondrial function and biogenesis, a more comprehensive list of food bioactive derivatives able to increase mitochondrial function has been reviewed elsewhere Serrano et al. Thus, food bioactive derivatives can, not only improve mitochondrial function by directly scavenging ROS and protecting mitochondria from oxidative damage, but also activate intracellular signalling pathways known to modulate mitochondria function and biogenesis including AMPK, SIRT1 and NRF-1, which renders these molecules an attractive nutritional tool in metabolic health.
However, studies investigating the effect of food bioactive derivatives on mitochondrial biology remain limited, and further investigation is warranted to identify novel food-derived molecules, also used in combination, which may be able to improve mitochondrial function and ameliorate metabolic health. Mitochondrial dysfunction has been widely described as a metabolic defect associated with insulin resistance and T2DM.
Mitochondrial function is regulated at different levels, which include mitochondrial biogenesis, post-translational modification of mitochondrial protein, mitochondrial dynamics and supercomplexes formation with all these processes appearing to be dysregulated in type 2 diabetic individuals. However, whether these mitochondrial defects represent a cause or a consequence of insulin resistance in skeletal muscle remains to be fully elucidated.
Nonetheless, independently on whether mitochondrial dysfunction represents a primary defect in the pathogenesis of insulin resistance, increasing mitochondrial function represents a promising approach to enhance insulin sensitivity. Indeed, athletes in light of their higher mitochondrial oxidative capacity relative to sedentary individuals appear to be protected, albeit in part, from lipid induced insulin resistance, confirming that interventions aimed at increasing mitochondrial function i.
However, exercise is not the only lifestyle intervention able to positively modulate mitochondrial function. Despite these advances in understanding the role of nutrition in mitochondrial function, dietary patterns and combination of nutrients and food bioactives able to restore mitochondrial oxidative capacity are still to be identified as it remains to be elucidated as to whether their putative effect on mitochondrial function translates into improved metabolic health.
All authors participated in the conception, design, writing and editing of this review article. All authors read and approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Also, in sperm cells, the mitochondria are spiraled in the midpiece and provide energy for tail motion. The mtDNA holds the instructions for a number of proteins and other cellular support equipment across 37 genes. The human genome stored in the nuclei of our cells contains around 3.
However, the child always receives their mtDNA from their mother. Because of this, mtDNA has proven very useful for tracing genetic lines. For instance, mtDNA analyses have concluded that humans may have originated in Africa relatively recently, around , years ago, descended from a common ancestor, known as mitochondrial Eve.
Although the best-known role of mitochondria is energy production, they carry out other important tasks as well. In fact, only about 3 percent of the genes needed to make a mitochondrion go into its energy production equipment.
The vast majority are involved in other jobs that are specific to the cell type where they are found. ATP, a complex organic chemical found in all forms of life, is often referred to as the molecular unit of currency because it powers metabolic processes. Most ATP is produced in mitochondria through a series of reactions, known as the citric acid cycle or the Krebs cycle.
Mitochondria convert chemical energy from the food we eat into an energy form that the cell can use. This process is called oxidative phosphorylation. In molecules of ATP, energy is stored in the form of chemical bonds.
When these chemical bonds are broken, the energy can be used. Cell death, also called apoptosis, is an essential part of life. As cells become old or broken, they are cleared away and destroyed. Mitochondria help decide which cells are destroyed.
Mitochondria release cytochrome C, which activates caspase, one of the chief enzymes involved in destroying cells during apoptosis. Because certain diseases, such as cancer , involve a breakdown in normal apoptosis, mitochondria are thought to play a role in the disease.
Calcium is vital for a number of cellular processes. For instance, releasing calcium back into a cell can initiate the release of a neurotransmitter from a nerve cell or hormones from endocrine cells.
Calcium is also necessary for muscle function, fertilization, and blood clotting, among other things. Because calcium is so critical, the cell regulates it tightly. Mitochondria play a part in this by quickly absorbing calcium ions and holding them until they are needed. Other roles for calcium in the cell include regulating cellular metabolism, steroid synthesis , and hormone signaling.
That energy is produced by having chemicals within the cell go through pathways, in other words, be converted. And the process of that conversion produces energy in the form of ATP, because the phosphate is a high-energy bond and provides energy for other reactions within the cell. So the mitochondria's purpose is to produce that energy. Some different cells have different amounts of mitochondria because they need more energy.
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