Mitochondria as promising targets for nutritional interventions aiming to improve performance and longevity of sows.

DOI: 10.1111/jpn.12160

REVIEW ARTICLE

Mitochondria as promising targets for nutritional interventions aiming to improve performance and longevity of sows J. Lapointe Dairy and Swine R & D Centre, Agriculture and Agri-Food Canada, Sherbrooke, QC, Canada

Summary Genetic selection and management changes during the last decades have significantly increased the average litter size of sows. However, this recent success has not correlated with an extension of longevity and reduction in replacement rate. Longevity or lifetime production of sows is determined by a combination of environmental and genetic factors. Nutrition is an environmental factor of importance, and it has long been appreciated that animals fed with specific diets may perform differently. The advent of modern science revealed that this is partly due to the ability of nutrients to act as signalling molecules that, through appropriate intracellular sensing mechanisms, can control gene expression and modulate cell functions. Based on this concept, nutrigenomics studies now aim to show that not only are certain nutrients essential for general health, but also that specific quantities of precise nutrients are necessary during critical periods of energy deficiency and oxidative stress such as gestation and lactation to ensure long-term productivity. The toxic molecules at the origin of oxidative stress, free radicals, are mainly generated as normal by-products of aerobic energy production by mitochondria. In all cells, mitochondria are dynamic organelles that are mainly known as the primary energy-generating system. Thus, when metabolic demands are elevated as it is for hyperprolific sows, mitochondria are heavily solicited for answering all energetic needs, and substantive amounts of free radicals are generated. As a result, optimal conditions in term of antioxidant protection and metabolic substrates availability are required to support mitochondrial function in these animals. This article discusses how performance and longevity of sows are linked to mitochondrial function and oxidative stress and reviews the major natural nutrients known for their antioxidant and/or energetic properties that are susceptible to impact mitochondria and likely improved sows productivity. Keywords mitochondria, nutrigenomics, oxidative stress, energy metabolism, sows nutrition, longevity r o ^me Lapointe, Dairy and Swine R & D Centre, Agriculture and Agri-Food Canada, Sherbrooke, QC J1M 0C8, Canada. Correspondence Je Tel: 819 780 7219; Fax: 514 564 5507; E-mail: [email protected] Reproduced with the permission of the Minister of Agriculture and Agri-Food Canada. Received: 23 July 2013; accepted: 5 December 2013

Introduction It is clearly recognized that breeding herd productivity is one of the major factors that determines pork industry profitability in combination with feed efficiency. Indeed, large litters of healthy piglets delivered by highly productive sows that breed regularly with minimal culling rate provide the best scenario for long-term economic survivability of producers. The productivity of sows is generally determined by a combination of environmental and genetic factors. In this optic, genetic selection and management changes during the last decades have increased the average litter size of sows in many countries (Fox-

croft, 2012). Thus, the producers aim to conserve these genetically selected proliferative sows for as many parities as possible in order to maximize their production and enhance their benefits (Lucia et al., 2000). The longevity or lifetime production of a sow is normally defined as the number of pigs weaned per sow per lifetime, and it was established that a sow must produce at least 4–6 litters for optimal economics (Serenius and Stalder, 2004; RodriguezZas et al., 2006). Unfortunately, the recent success that was obtained in term of increasing litter size has not correlated with an extension of reproductive sow longevity and reduction in replacement rate. Indeed, it has been

© 2014 Her Majesty the Queen in Right of Canada Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH

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Mitochondrial nutrients for improving sows longevity

estimated that as many as 40–50% of sows are culled annually with over one-third of these removals attributed to reproduction problems (Rodriguez-Zas et al., 2003). Moreover, roughly half of these culls attributed to reproduction failure are associated with first parity sow or replacement gilts (Engblom et al., 2008). Reproductive problems are indeed frequent in such animals, and therefore, the number of non-productive days before first farrowing or within the period from first to second farrowing increases, which considerably influences the fertility of herd. Considering that the maintenance of the proper number of females in each breeding group depends upon the introduction of replacement gilts, it is crucial for producers that those animals reproduce efficiently and there is thus an increased economic demand for gilts with greater reproductive potential, resistance and longevity (Onteru et al., 2011). It is also well known that litter size generally increases with each parity beyond the second litter before starting to drastically decline after six parities (Quesnel et al., 2008). The exact causes of poor longevity and high replacement rate are complex and far to be fully characterized (Serenius et al., 2006). While it is relatively straightforward to identify the nature of the physiological failure which leads to the removal of a sow from the herd (specific diseases, irregular or repeated oestrous cycle, anovulation, abortions, preterm labour, small litter, low birth weight, lactation problems, locomotion…), identification of the underlying biological and molecular reasons for the occurrence of these events continues to be more challenging. The future success of pig farms is now largely relying on a better understanding of those processes as well as on the development of new strategies aiming to enhance the reproductive potential, health and longevity of sows. The main objectives of this review article are to describe how the mitochondria could be related to the poor longevity of reproductive sows, by putting the emphasis on energy requirements and oxidative stress, and to explain how innovative targeted nutrigenomics approaches specifically designed to support mitochondrial function could maximize sow’s lifetime production.

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Reproductive sows are known to have high energetic demands associated with growth and energy utilization during critical periods such as gestation and lactation, which may have an impact on reproductive and litter trait performances (Willis et al., 2003). Given

the increase in litter size that was recently observed, hyperprolific aged sows and first parity gilts frequently fail to satisfy their energetic nutrient requirements even if voluntary feed intake usually increases along with litter size (Quesnel et al., 2007). As a consequence, sows nursing large litters lose generally more body weight during lactation than sows nursing smaller litters. Thus, to adequately fulfil their cellular energetic needs throughout gestation and lactation processes, hyperprolific sows completely rely on the maintenance of functional mitochondria. In all cells, mitochondria are remarkably dynamic organelles that participate in diverse cellular processes. They are implicated in calcium and nitrogen homeostasis, signal transduction, apoptosis (programmed cell death) and synthesis of numerous essential biochemical components such as haem, steroid hormones and bile acids but are mainly known as the primary energy-generating system. Mitochondria are located at the interface between the environmental calorie supply and the energy requirements of each organ. Indeed, in response to energy demands, various substrates such as carbohydrates, proteins and fatty acids are metabolized via several pathways including glycolysis, b-oxidation, the tricarboxylic acid (TCA) cycle and electron transport through the respiratory chain to ultimately drive energy production by oxidative phosphorylation (OXPHOS) in the form of adenosine-5′triphosphate (ATP) (Green and Tzagoloff, 1966). As seen in Fig. 1, the OXPHOS process involves the action of the five multiprotein complexes of the mitochondrial respiratory chain embedded into the inner membrane. The reduced form of nicotinamide adenine dinucleotide (NADH) generated by the TCA cycle is initially oxidized by complex I. As the electrons from NADH are passed to the first mobile electron acceptor, oxidized coenzyme Q10 (CoQ10) or ubiquinone, the energy is converted by the movement of protons from the mitochondrial matrix towards the intermembrane space. CoQ10 can also accept electrons from complex II which have been donated by the reduced form of flavin adenine dinucleotide (FADH2), another product of the TCA cycle. CoQ10 then passes electrons to complex III. Electrons are then transferred to the second mobile element in the respiratory chain, cytochrome c, which reduces complex IV that will ultimately drive the reduction of molecular oxygen to form water. This final dissipation of the redox energy at the level of complex IV is also associated with a final ejection of protons from the matrix. The passage of protons into the intermembrane

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Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH

Understanding the links between energy requirements, mitochondria and longevity


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Matrix

TCA cycle NAD+

ATP

H+

NADH

FAD+ FADH2

C

I III

II

V

IV

CoQ ROS succinate

ROS

H+

ROS

H+

O2

H+

H2O

ADP Pi

ATP

malate glutamate pyruvate

Intermembrane space Fig. 1 Schematic representation of the mitochondrial electron transport chain and oxidative phosphorylation (OXPHOS) system of energy production. TCA cycle, tricarboxylic acid cycle; I–V, mitochondrial complexes I–V; CoQ, coenzyme Q or ubiquinone; (c), cytochrome C; H+, protons; Pi, phosphate; ADP, adenosine diphosphate; ATP, adenosine triphosphate; ROS, reactive oxygen species; O2, oxygen; H2O, water; NAD, nicotinamide adenine dinucleotide oxidized or reduced (NADH); FAD, flavin adenine dinucleotide oxidized or reduced (FADH2).

space results in an electrochemical potential that eventually drives the phosphorylation of adenosine diphosphate (ADP) to ATP through complex V or ATP synthase when protons re-enter the matrix. The ATP is then transferred out of the mitochondria by the adenine nucleotide translocase complex and the energy became available for all cellular processes (Fig. 1). Given their central roles in energy metabolism, mitochondria are directly involved in many reproductive processes in mammals (El Shourbagy, 2006). Indeed, mitochondria are important determinants of normal mammalian oogenesis, fertilization, embryo development, implantation and lactation in many species including pigs (El Shourbagy, 2006; Dumollard et al., 2007; Van Blerkom and Davis, 2007). Significant correlation between expression levels of mitochondrial proteins implicated in energy metabolism and productivity has been recently observed in pigs (Grubbs et al., 2013). Thus, when metabolic demands are elevated as they are for gestating and lactating modern sows, the mitochondrial respiratory chain is heavily solicited for answering all energetic needs by generating large amount of ATP. The physiological state of an animal deter-

mines the nutrient requirements and energetic efficiency of mitochondrial function. Numerous factors such as high metabolic activity and hypoxia can significantly affect substrate utilization and activities of key mitochondrial enzymes mainly via increased oxidative stress conditions as it will be discussed in the following section. It is also well known that the rate of energy production by mitochondria is tightly related to the ageing process. Many studies conducted in a wide variety of species have clearly demonstrated that levels of ATP produced by mitochondria significantly decline with ageing (Harman, 1972; Conley et al., 2007). This decline in mitochondrial energy production eventually leads to cellular dysfunction, physiological disabilities and loss of performance usually associated with ageing. The ageing process is also known to impair mitochondrial turnover by reducing the rate of production of new mitochondria (biogenesis) and to affect clearance of dysfunctional mitochondria (mitophagy) in reproductive as well as non-reproductive tissues (Bentov et al., 2011). This reinforces the concept that mitochondria are complex and dynamic organelles that are highly responsive to physiological and cellular stresses.


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High energy production is associated with mitochondrial oxidative stress Reactive oxygen species generation by mitochondria

Reactive oxygen species (ROS), including free radicals, are mainly generated as normal by-products of aerobic respiration and energy metabolism by mitochondria (Fig. 1). The reaction of oxygen reduction during mitochondrial electron transport is the main source of the superoxide radical (O2• ), which cannot cross most biological membranes but can attack mitochondrial iron–sulphur-containing proteins to release ferrous iron (Fe2+) and ultimately lead to the formation of highly reactive hydroxyl radical (•OH). However, most superoxide is efficiently converted into hydrogen peroxide (H2O2) and O2 by mitochondrial superoxide dismutases (SODs). Importantly, because H2O2 is relatively stable and membrane permeable, it can diffuse out of the mitochondria into the cytoplasm (Veal et al., 2007). ROS can thus inflict serious damage to both mitochondrial and cytoplasmic macromolecules, such as lipids, nucleic acids and proteins. Polyunsaturated fatty acids are one of the most sensitive oxidation targets for ROS because once lipid peroxidation is initiated, a damaging chain reaction takes place (Niki, 2009). DNA bases are also very susceptible to ROS attack, and oxidation of DNA bases is believed to cause mutations and deletions in both nuclear and mitochondrial genomes (Fraga et al., 1990). Almost all amino acid residues in a protein can be oxidized by ROS, with these modifications leading to losses of function (Ugarte et al., 2010). Due to their localization, mitochondrial enzymes are particularly vulnerable to be altered by ROS, which leads to mitochondrial dysfunction and increases oxidative pressure during stressful conditions. Consequently, mitochondrial energetic efficiency is compromised, and cellular demands are not fulfilled when physiological state is characterized by high energy requirements. Exposure to ROS appears to be unavoidable for cells living in an aerobic environment, and ROS toxicity is controlled by a complex network of non-enzymatic and enzymatic antioxidants, including the superoxide dismutases (SODs), the glutathione peroxidases (GPxs), the thioredoxin reductases (TRxs), the peroxiredoxins (PRxs), catalase and glutathione (GSH) (Yu, 1994; Flohe, 2010). Therefore, oxidative stress can be defined as any imbalance between the production and the detoxification of ROS. However, the toxicity of ROS is only one aspect of their action in living cells as ROS originating from mitochondria and other cellular sites can also modulate the function of various signalling pathways. In fact under physiological as well as stress conditions, 4

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the transient generation of ROS, within boundaries, appears to be essential to maintain cellular homeostasis. As second messengers, mitochondrial ROS have notably been implicated in cycle progression (Burhans and Heintz, 2009), inflammation (Hultqvist et al., 2009), apoptosis (Circu and Aw, 2010), cell survival (Groeger et al., 2009) and reproduction (Agarwal et al., 2006). Consequences of mitochondrial ROS production on reproductive performance and longevity

Reproductive performance, susceptibility to diseases and longevity could all be largely affected by the actions of ROS in mammals (Agarwal et al., 2006). Similar to other physiological processes, a minimal amount of ROS is crucial to achieve good reproduction performance either in males or females. In females, this implication is broad and is related to almost all reproductive events including cyclic luteal and endometrial changes, follicular development, ovulation, fertilization, embryogenesis, implantation, placental differentiation and labour (Fujii et al., 2005; Agarwal et al., 2008). On the other side, oxidative stress has increasingly emerged as a likely promoter of several diseases as well as reproductive disorders, such as anovulation, spontaneous abortions, abnormal embryonic development, foetal growth restriction, preterm labour and low birth weight (Al-Gubory et al., 2010). The links between oxidative stress, female health and development of adverse reproductive outcomes constitute important issues in animal sciences and especially for sows. However, although reproductive dysfunction and decreased longevity of sows are actual problems that seriously affect the pig industry, studies related to the characterization of those links and the development of specific strategies to improve the situation in swine remain scarce and knowledge is largely limited. Ageing has been associated with increases in the levels of endogenous oxidative stress and decreases in antioxidant defences, leading to a wide range of oxidative damage in major cell structures. Studies evaluating the links between ageing and mitochondria in various tissues have confirmed an age-dependent decrease in energy production associated with increased ROS generation thus identifying these organelles as crucial determinants of ageing (Balaban et al., 2005). Age-related decline in female fertility is a well-documented phenomenon which in most species like swine occurs long before death. Ovarian dysfunction accounts for most of this loss of reproductive function and is characterized by declines in ovarian Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH

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follicle numbers and in oocyte quality (Lim and Luderer, 2011). Several studies now suggest that mitochondrial oxidative stress may play a role in the age-related decline in ovarian function in some species but almost nothing is known in sows (Navarro et al., 2005; Ramalho-Santos et al., 2009). A better understanding of the cellular and molecular mechanisms underlying reproductive decline in sows with particular attention to mitochondria and oxidative stress should lay the foundations for the development of specific interventions to extend sows longevity. Modulation of mitochondrial function by ‘mitochondrial nutrients’ As mentioned earlier, mitochondrial energy production is tightly associated with ROS production, and hyperprolific sows should handle substantive ROS amounts that are susceptible to induce oxidative damage and likely perturb reproductive processes, increase their vulnerability to various diseases and decrease their longevity (Jansen and Burton, 2004; Pieczenik and Neustadt, 2007). As a result, their mitochondria require optimal conditions in terms of antioxidant protection and metabolic substrates availability to ensure reproductive success, health and long-term productivity. Such aim to optimize mitochondrial function could be seen as ambitious and relatively complex but these organelles are known to be quite sensitive to the quantity and variety of nutrients provided in diet. Variation in protein content has a major effect on mitochondrial number and also specifically affects activities of numerous mitochondrial enzymes. Specific change in carbohydrate component of the diet has a large effect on enzymes involved in energy metabolism, especially those related to triglyceride synthesis, and can affect mitochondrial function through changes in phospholipid composition (Wander and Berdanier, 1985). Accordingly, several vitamin and mineral deficiencies can result in aberrant expression of mitochondrial proteins and have a deleterious effect on mitochondrial structure, biogenesis and function (Aw and Jones, 1989). These particular phenotypes can be frequently reversed by nutrient repletion, which suggests that nutritional supplementation may be useful to support mitochondrial function in stressful conditions. Interestingly, increasing evidence now suggests that targeting mitochondria with specific nutrients from natural sources, now termed mitochondrial nutrients, could efficiently prevent and ameliorate various conditions associated with mitochondrial dysfunction. Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH


Several drugs and molecules are also continuously characterized for their positive actions on mitochondria (Gruber et al., 2013), but this review will strictly focus on natural nutrients which have greater potential of being used in sow’s diet in the near future. Recent studies have shown that targeted nutritional interventions with mitochondrial nutrients can be beneficial in preventing and improving mitochondrial function mainly by stimulating mitochondrial energy production, enhancing mitochondrial metabolism (biogenesis and degradation) as well as by alleviating oxidative stress. Those nutrients could exert their function either directly by being actively implicated in specific mitochondrial biochemical pathways or indirectly by enhancing the expression of genes encoding proteins involved in mitochondrial biology (Baltzer et al., 2010). In other terms, mitochondrial nutrients could be incorporated and being immediately active in mitochondria or having delayed nutrigenomic effects on the endogenous system (Fig. 2). The following sections will be dedicated to the enumeration and basic description of the mitochondrial actions of the most recognized mitochondrial nutrients that are susceptible of being of interest for the elaboration of nutritional strategies for reproductive sows. Particular emphasis will be placed on their potential to serve as alternative energy sources, enhance mitochondrial antioxidant defence system, induce mitochondrial biogenesis or improve mitochondrial function by acting as cofactors in biochemical processes (Fig. 3). Types of mitochondrial nutrients and modes of action Energy enhancers

Creatine is a guanidino compound found ubiquitously in mammalian cells. Creatine is synthesized endogenously by the liver, kidney and pancreas from the amino acids arginine, glycine and methionine and is supplied exogenously via the diet. Creatine is transported into tissues via a sodium-dependent creatine transporter and is actively incorporated in mitochondria (Wyss and Kaddurah-Daouk, 2000). The aim for using creatine as mitochondrial nutrient is to act as an energy-boosting compound by increasing creatine/ phosphocreatine stores and consequently preventing ATP depletion. The creatine/phosphocreatine system functions as a spatial energy buffer between the cytosol and mitochondria, and variation in this ratio has been shown to be related to mitochondrial dysfunction (Tarnopolsky, 2008). L-carnitine and its acetyl derivative (Acetyl-L-carnitine; ALCAR) transport long-chain fatty acids into mitochondria for b-oxidation and production. Carni5


Endogenous antioxidants

Mitochondria

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Mitochondrial nutrients

ROS Mitochondrial oxidative damage

ATP

tine may also play a role in membrane stabilization by modifying the physiological properties of mitochondrial membranes (Carter et al., 1995). Endogenous carnitine is normally synthesized in the liver and kidneys from the amino acids lysine and methionine. Carnitine homeostasis is usually maintained by the acquisition of carnitine from dietary sources (animal proteins). Tissue concentrations of carnitine in animals decrease with ageing (Maccari et al., 1990), which affects the integrity of mitochondrial membranes and may be associated with mitochondrial decay. Several studies showed that ALCAR supplementation elevates activities of mitochondrial enzymes, increases antioxidant potential and improves mitochondrial function (Calvani et al., 1992; Hagen et al., 1998).

Cellular oxidative damage

Fig. 2 Synergistic actions of mitochondrial nutrients on oxidative stress conditions. Mitochondrial nutrients could exert their antioxidant function either directly by neutralizing mitochondrial-generated ROS or indirectly by enhancing the expression of endogenous genes encoding proteins involved in mitochondrial antioxidant defences (nutrigenomics). ATP, adenosine triphosphate; ROS, reactive oxygen species.

B vitamins are especially important for supporting mitochondrial function because they directly act either as cofactors for mitochondrial enzymes or as precursors of important cofactors (Fig. 3). It is well recognized that B vitamins play essential roles in mitochondrial aerobic respiration and energy production. Furthermore, mitochondrial integrity and function are compromised by dietary deficiency of many B vitamins (Depeint et al., 2006b). Thiamin (vitamin B1) plays a central role in the generation of energy by mitochondria. Thiamin occurs as free thiamin or in its phosphorylated forms. Thiamin pyrophosphate (TPP) is a required coenzyme for the mitochondrial enzymes pyruvate, alpha-ketoglutarate and branched-chain ketoacid dehydrogenases, which all play critical roles in mitochondrial energy

production. It has been reported that TPP is rapidly taken up by mitochondria and that the transfer occurs via a TPP/thiamin antiporter (Barile et al., 1990). Riboflavin (vitamin B2) is a water-soluble vitamin that is the major component of the flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which function as redox cofactors in both complexes I and II of the respiratory chain. Riboflavin also plays a role in the activity of pyruvate, alphaketoglutarate and branched-chain ketoacid dehydrogenases. FAD is also the coenzyme of glutathione reductase which recycles oxidized glutathione (GSSG) to its reduced form GSH (Depeint et al., 2006b). Therefore, it is possible that riboflavin supports mitochondrial function by modulating electron transport chain and improving antioxidant defences. Nicotinamide, the amide form of niacin or nicotinic acid (vitamin B3), is a precursor for both nicotinamide adenine dinucleotide (NAD/NADH) and nicotinamide adenine dinucleotide phosphate (NADP/NADPH). The major role of NADH is to transfer electrons from metabolite intermediates to the respiratory chain. Complex I accepts electrons from NADH and passes them to coenzyme Q. NAD is also implicated in the activity of key enzymes of the TCA cycle such as pyruvate and alpha-ketoglutarate dehydrogenases (PDH and KGDH). It also appears that NADH and NADPH have antioxidant properties and that NAD should further serve as substrate of poly (ADP-ribose) polymerase, which is involved in the nuclear and mitochondrial DNA repair mechanism (Kirsch and De Groot, 2001). High doses of nicotinic acid can raise NAD/NADP levels in both mitochondria and cytoplasm (Ames et al., 2002).

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B vitamins


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Matrix

B5

CoA

B1

PDH

B3

B8

B6 B2

Carboxylases

Citrate S. BC-KADH

α -KGDH

TCA cycle B3

NAC

α -LA

Succinyl-CoA

Se

A

Mn Cu

B6

Antioxidants

ROS

NADH NAD+

C

(SODs, GPxs, GSH…)

B12

FAD+ FADH2

ATP

B2 Inner membrane

II

I

CoQ

III

C

IV

V

Cardiolipin Creatine Kinase

Outer membrane

E Cytosol

CoQ10

Creatine

ALCAR

PUFAs

Fig. 3 Mitochondrial targets and modes of action of mitochondrial nutrients. TCA cycle, tricarboxylic acid cycle; I–V, mitochondrial complexes I–V; NAD, nicotinamide adenine dinucleotide oxidized or reduced (NADH); FAD, flavin adenine dinucleotide oxidized or reduced (FADH2); Citrate S., citrate synthase; CoA, coenzyme A; PDH, pyruvate dehydrogenase; a-KGDH, alpha-ketoglutarate dehydrogenase; BC-KADH, branched-chain ketoacid dehydrogenase, SODs, superoxide dismutases, GPxs, glutathione peroxidases; GSH, glutathione; ROS, reactive oxygen species; CoQ, coenzyme Q or ubiquinone; (c), cytochrome C; B1–B12, B vitamins; E, vitamin E; C, vitamin C; alpha-LA, alpha-lipoic acid; NAC, N-acetylcysteine; Se, selenium; Mn, manganese; Cu; copper; ALCAR, acetyl-L-carnitine; PUFAs, polyunsaturated fatty acids.

Pantothenic acid (vitamin B5) is involved in the oxidation of fatty acids and carbohydrates. Pantothenic acid is the precursor of coenzyme A (CoA), a molecule essential for many mitochondrial enzymatic reactions. CoA functions as an acyl group carrier and carbonyl-activating group which is essential in the mitochondria for mitochondrial enzymes PDH and KGDH of the TCA cycle as well as for the b-fatty acid oxidation pathway (Atamna, 2004). Pantothenic acid also protects mitochondrial constituents from oxidative damage by increasing both CoA and GSH levels and enhancing glutathione peroxidase activity (Wojtczak and Slyshenkov, 2003). Vitamin B6 is converted to pyridoxal 5′-phosphate (PLP), a coenzyme required for the metabolism of amino acids and lipids. PLP is also directly involved in haem synthesis, and a large number of PLPdependent reactions in cells are carried out within the mitochondria. This vitamin is involved in gluta-

thione (GSH) biosynthesis from homocysteine in the maintenance of an adequate GSH/GSSG ratio and is thus implicated in the control of mitochondrial oxidative stress (Kannan, 2004; Maranesi et al., 2004). Interestingly, it was shown that PLP can easily be imported within the different compartments of the mitochondria by an energy-independent mechanism (Lui et al., 1982). Biotin (vitamin B8) plays a major role in the metabolism of lipids, proteins and carbohydrates. Biotin is a recognized coenzyme for five mitochondrial carboxylases and is essential for growth, development and normal mitochondrial function (Depeint et al., 2006b). It has also been suggested that biotin can enhance mitochondrial biogenesis thorough guanylate cyclase activation (Vesely, 1982; Nisoli et al., 2003). Once in the cell, dietary-supplemented biotin distributes mostly to the mitochondria and cytosol fractions.


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Folates (vitamin B9) function as a family of cofactors that carry one-carbon (C1) units required for the synthesis of thymidylate, purines and methionine. Folates are also required for other methylation reactions. Almost fifty percentage of cellular folates are located in the mitochondria, and it is generally thought that mitochondrial folates are required for the initiation of mitochondrial protein synthesis (Depeint et al., 2006a). High-dose folates supplementation can also decrease oxidative stress parameters, while folates deprivation promotes mitochondrial oxidative damage (Huang et al., 2004; Chang et al., 2007). Cobalamin (vitamin B12) is also involved in one-carbon transfer pathways. In mitochondria, adenosylcobalamin is required for the synthesis of succinyl-CoA, an important intermediate of the TCA cycle. Cobalamin deficiency has been shown to cause mitochondrial dysfunction as a result of inhibition of the TCA cycle, but effect of vitamin B12 supplementation on mitochondrial function remains to be clarified (Toyoshima et al., 1996). Other vitamins

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dietary levels of all-rac-a-tocopheryl acetate (Lauridsen and Jensen, 2012). Trace minerals

Copper (Cu) acts as a cofactor for many mitochondrial enzymes playing key roles in energy metabolism and antioxidant defences such as cytochrome C oxidase (complex IV) and copper–zinc superoxide dismutase (CuZnSOD or SOD1) respectively. Copper deficiency is associated with mitochondrial dysfunction and oxidative stress (Liu and Ames, 2005). Manganese (Mn) is an essential component of several mitochondrial enzymes, notably the manganese superoxide dismutase (MnSOD or SOD2). MnSOD is the main mitochondrial antioxidant against superoxide and is exclusively located in the mitochondrial matrix (Zelko et al., 2002). Selenium (Se) is a mineral that participates in the synthesis of selenoproteins with strong antioxidant properties, such as glutathione peroxidases (GPxs) and thioredoxin reductases (TRxs). It is also well known that cellular Se level is tightly related to mitochondrial antioxidant potential and protects against mitochondrial dysfunction (Dursun et al., 2011). Iron (Fe) plays an essential role in the maintenance of mitochondria, through its two major functional forms which are haem and iron–sulphur clusters. Both ironbased cofactors are formed and utilized in the mitochondria and are important for normal assembly and for optimal activity of the electron transfer complexes. Abnormal homeostasis of iron is linked to mitochondrial cytochrome C oxidase disassembly, loss of mitochondrial DNA integrity, mitochondrial dysfunction and increased oxidative stress (Liu and Ames, 2005).

Vitamin A and carotenoids are well-known effective antioxidants. Dietary beta-carotene is efficiently incorporated by mitochondria and participates in protection of mitochondrial DNA and cytochrome c from ageing-associated oxidative insults (Liu and Ames, 2005). It has also recently been described that retinol (common dietary form of vitamin A) was a key regulator of mitochondrial function in vitro (Acin-Perez et al., 2010). Vitamin C (ascorbic acid) is a water-soluble vitamin which has been used in mitochondrial disorders for its antioxidant properties. Indeed, ascorbate can become oxidized (dehydroascorbate) and can be reduced back to ascorbate through endogenous antioxidant enzymes and GSH. In addition to its function as an antioxidant, vitamin C is a cofactor for collagen hydroxylation and is implicated in the endogenous biosynthesis of carnitine (Liu and Ames, 2005). Vitamin E is a lipid-soluble antioxidant and refers to four tocopherols and four tocotrienols with a-tocopherol having the greatest biological activity. Tocopherols are important naturally occurring lipophilic antioxidants, which accumulate in cellular membranes, and are particularly abundant in mitochondrial membranes. The main function of vitamin E is to scavenge mitochondrial ROS and to inhibit lipid peroxidation, which helps to maintain membrane integrity (Marriage et al., 2003). Several evidences indicate that it is possible to enrich mitochondria of various animal models with vitamin E using supranutritional

Coenzyme Q10 (CoQ10) or ubiquinone (UQ) is a bioactive lipid which is principally known for its function as an electron carrier from complexes I and II to complex III in the mitochondrial respiratory chain. In its reduced form (ubiquinol), CoQ10 can act as an antioxidant and protects mitochondrial lipids, proteins and DNA from oxidative damage. It is also recognized for its anti-apoptotic as well as anti-inflammatory properties and is now extensively used as a nutritional supplement (Bentinger et al., 2010). Dietary-supplemented UQ is actively incorporated in mitochondrial membrane where it can reverse mitochondrial dysfunction, alleviate oxidative stress conditions and improve cellular function in various conditions (Bhagavan and Chopra, 2006; Lapointe et al., 2012). Alpha-lipoic acid (a-LA) is a coenzyme found naturally in mitochondria and involved in energy

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Antioxidants

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metabolism. The reduced form of a-LA, dihydrolipoic acid, is a powerful mitochondrial antioxidant. It reduces vitamins C and E, recycles CoQ10, raises intracellular glutathione and ascorbic acid levels, chelates iron and copper and activates key enzymatic antioxidants (Packer et al., 1995). Animal studies with a-LA supplementation have resulted in decreased oxidative damage, reduced oxidant formation and improved mitochondrial function (Hagen et al., 1999). N-acetylcysteine (NAC), the N-acetyl derivative of the amino acid cysteine, is also recognized as an efficient nutrient with antioxidant properties. It was found to increase glutathione pool and its related enzymatic antioxidant system (Schiff et al., 2011).


Mitochondrial nutrients can thus perform a variety of beneficial effects on mitochondrial function such as prevention of oxidative stress by limiting oxidant production or scavenging free radicals. These nutrients also enhance mitochondrial metabolism by promoting the degradation of dysfunctional mitochondria and increasing mitochondrial biogenesis. They further stimulate mitochondrial enzyme activity and energy production by elevating substrate and cofactor levels. However, even if each of the previously listed mitochondrial nutrients has promising properties and was shown to support mitochondrial function, some combinations may possess unique functions and be more efficient than the individual nutrients. Such nutritional interventions based on specific combination of mitochondrial nutrients have been frequently tested in attempt to maximize their potential and to simultaneously act on several mitochondrial parameters. Most of the time, synergistic effects were indeed observed between mitochondrial nutrients. Several

studies thus indicate that the antioxidant and/or the energetic potential of CoQ10 could be more efficient when acting with either a-tocopherol, a-lipoic acid, PUFAs or carnitine (Marriage et al., 2003; Rodriguez et al., 2007; Quiles et al., 2010). Similarly, it was shown that a combination of a-lipoic acid and ALCAR significantly improves mitochondrial function and stimulate mitochondrial biogenesis in aged animals, while treatments with either a-lipoic acid or ALCAR alone had only very slight effect on the same parameters (Tarnopolsky, 2008). This strong synergistic effect suggests that these two nutrients complement each other’s functions in mitochondrial biogenesis (Shen et al., 2008). In the same vein, it is now recognized that most of the reactions required for the antioxidant action of organic selenium in mitochondria are vitamin B6 dependent (Beilstein and Whanger, 1989). A unique targeted nutritional intervention containing alipoic acid, ALCAR, biotin and niacin was further shown to be effective in improving mitochondrial function and decreasing mitochondrial oxidative damage in mammals (Hao et al., 2009). Combination of mitochondrial nutrients could also influence tissue distribution and concentration following dietary supplementation. Indeed, deposition of vitamin E within cellular and mitochondrial membranes was found to be enhanced by other mitochondrial nutrients such as copper, CoQ10 and vitamin C (Lauridsen and Jensen, 2005, 2012). There are only few examples but it is now reasonable to advance that combination of mitochondrial nutrients could be the most effective strategy to support mitochondrial function and promote longevity. Particular attention should also be paid to dosage determination when elaborating a nutritional intervention with mitochondrial nutrients due to the fact that some of those nutrients are toxic at high concentrations and that desired actions should be missed at low levels. High intake of specific nutrients such as niacin could indeed pose a risk for mitochondrial homeostasis, and it was demonstrated that b-carotene breakdown products may have potential side effects and impair mitochondrial functions (Siems et al., 2005; Depeint et al., 2006b). Iron could also act as a strong pro-oxidant via the Fenton’s reaction and induce oxidative damage. Accordingly, as it is now widely accepted that low amounts of particular ROS are essential for many cellular functions, mitochondrial nutrients with strong antioxidant properties could likely compromise some physiological processes at high dose (Hekimi et al., 2011). Finally, the fact that ROS generation by mitochondria increases with ageing process should be carefully take in consideration


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Polyunsaturated fatty acids (PUFAs)

Fatty acids are important regulators of mitochondrial structure and function through their roles as oxidative substrates, inhibitors of carbohydrate oxidation, ligands for nuclear receptors that regulate the expression of mitochondrial proteins and structural components in mitochondrial membranes (Stanley et al., 2012). There is growing evidence that long-chain PUFAs from dietary sources are rapidly incorporated in mitochondria and have beneficial effects on mitochondrial fatty acid composition, mitochondrial function and resistance to stress (Al-Gubory, 2012; Eckert et al., 2013). Combination, dosage and timing are crucial parameters to consider when using mitochondrial nutrients


in the design of nutritional diet with mitochondrial nutrients. As a result, young gilts should perhaps not be supplemented with the same nutrient combination as older sows. Using mitochondrial nutrients to enhance performance and longevity of reproductive sows Despite their promising energetic and antioxidant properties, mitochondrial nutrients have not yet been frequently used to optimize performance of reproductive sows. Accordingly, data related to their effects on mitochondrial function and mitochondrial oxidative stress parameters in pigs are very limited. It was reported that dietary supplementation of gilts with organic selenium increases expression of enzymatic antioxidant (GPx) in corpus luteum and enhances embryo development (Fortier et al., 2011). Another study indicates that nutritional supplementation of pigs with CoQ10 renders their hearts more resistant to ischaemia–reperfusion injury, probably by limiting mitochondrial oxidative stress (Maulik et al., 2000). It was also demonstrated that L-carnitine had beneficial effects on the average foetal weight at day 70 of gestation as well as on mean birth weight of piglets in both gilts and sows (Eder et al., 2001; Brown et al., 2008). A recent study revealed that feeding sows a diet enriched in n-3 polyunsaturated fatty acids from fish source before and during lactation increases litter size at the subsequent farrowing (Smits et al., 2011). Furthermore, beneficial effects of a-lipoic acid supplementation during late gestation and lactation on antioxidant potential and performance of sows and their nursing piglets have been evaluated. Results from this study indicate that this mitochondrial nutrient increases enzymatic antioxidant activity and reduces oxidative damage in plasma from treated sows at day 21 of lactation. Alpha-lipoic acid supplementation also increased the birth weight of piglets as well as their weight gains between days 1 and

References Acin-Perez, R.; Hoyos, B.; Zhao, F.; Vinogradov, V.; Fischman, D. A.; Harris, R. A.; Leitges, M.; Wongsiriroj, N.; Blaner, W. S.; Manfredi, G.; Hammerling, U., 2010: Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis. FASEB Journal 24, 627–636. Agarwal, A.; Gupta, S.; Sikka, S., 2006: The role of free radicals and antioxidants

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21 compared with piglets from control-fed sows (Bai et al., 2011). Interestingly, a study conducted with newborn piglets has revealed that dietary folic acid supplementation enhanced mRNA expression levels of genes involved in mitochondrial biogenesis and antioxidant defences (Liu et al., 2012). Conclusion and future perspectives Studies investigating the impacts of mitochondrialtargeted nutrients in different animal models have demonstrated relevant benefits in many organ systems via their ability to improve mitochondrial function and decrease oxidative damage. Of particular interest, the promising results obtained with defined combinations of nutrients with complementary and synergistic effects now provide great expectations for preventing and treating physiological problems associated with mitochondrial dysfunction such as reproductive decline, susceptibility to diseases and poor longevity. The impact of many mitochondrial nutrients on mitochondrial function is yet to be fully appreciated in pigs, but the benefits shown in supplementation of those nutrients in other animals as well as in vitro experiments encourage further studies. Therefore, the future directions should include the use of modern technology of nutrigenomics to identify novel combinations of precise mitochondrial nutrients for optimal effects on mitochondrial energy metabolism, oxidative stress, biogenesis and ageing. Investigating the mechanisms of action of mitochondrial nutrients at the cellular and molecular levels should also greatly help in the elaboration and the fine tuning of such nutritional interventions. While more research is definitely needed to investigate the safety and efficacy of mitochondrial nutrients in improving performance and longevity of sows, this could represent a promising area of interests for producers looking for long-term productivity and profitability of their herds.

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NARRATIVE AND META-ANALYTIC REVIEW OF INTERVENTIONS AIMING TO IMPROVE MATERNAL-CHILD ATTACHMENT SECURITY.

Foundations Aiming To Improve Children's Health.

Exploiting mitochondria as targets for the development of new antifungals.

Phenotypic and genetic variation in longevity of Polish Landrace sows.

Mitochondria as therapeutic targets for cancer stem cells.

A systematic review of interventions aiming to improve involvement in physical activity among adults with intellectual disability.

Cell cycle proteins as promising targets in cancer therapy.

Interventions to Improve Late Life.

ROCK and Rho: Promising therapeutic targets to ameliorate pulmonary fibrosis.

Confinement of sows for different periods during lactation: effects on behaviour and lesions of sows and performance of piglets.

Fucoxanthin: A Promising Medicinal and Nutritional Ingredient.

Aiming to improve the quality of primary mental health care: developing an intervention for underserved communities.

Autophagy of mitochondria: a promising therapeutic target for neurodegenerative disease.

Introduction. Nutritional triggers to adaptation and performance.

STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy.

Inhibitor of Apoptosis Proteins: Promising Targets for Cancer Therapy.

siRNA as a tool to improve the treatment of brain diseases: Mechanism, targets and delivery.

Universal Stress Proteins as New Targets for Environmental and Therapeutic Interventions of Schistosomiasis.

Nutritional considerations for ultraendurance performance.

The role of mitochondria in longevity and healthspan.

General practitioners' preferences for interventions to improve guideline adherence.

Exosomes: From Garbage Bins to Promising Therapeutic Targets.

Interventions to Improve Infant Safe Sleep Practices.

Interventions to improve adolescent vaccination coverage.