Mitochondrial Dysfunction and Lipid Homeostasis - IngentaConnect.com

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Current Drug Metabolism, 2012, 13, 1388-1400

Mitochondrial Dysfunction and Lipid Homeostasis Joseph Vamecq1,2,3#, Anne-Frédérique Dessein2, Monique Fontaine2, Gilbert Briand2,4, Nicole Porchet2, Norbert Latruffe5, Pierre Andreolotti5 and Mustapha Cherkaoui-Malki5 1

Inserm Lab Ext and 2Department of Biochemistry and Molecular Biology, Laboratory of Hormonology, Metabolism-Nutrition & Oncology (HMNO), Center of Biology and Pathology Pierre-Marie Degand (CBP), CHRU Lille, 59037 Lille, France; 3Department of the Dean, Faculty of Medicine and Pharmacy, University of Mons-UMons, Mons, Belgium; 4Mass Spectrometry Application Laboratory, University of Lille 2, 59045 Lille, France; 5Inserm, UMR 866, Dijon F-21000 and Université de Bourgogne, Centre de Recherche-Biochimie Métabolique et Nutritionnelle (LBMN), GDR CNRS 2583, Dijon F-21000, France Abstract: This review is aimed at illustrating that mitochondrial dysfunction and altered lipid homeostasis may concur in a variety of pathogenesis states, being either contributive or consecutive to primary disease events. Underlying mechanisms for this concurrence are far from being the exhaustive elements taking place in disease development. They may however complicate, contribute or cause the disease. In the first part of the review, physiological roles of mitochondria in coordinating lipid metabolism and in controlling reactive oxygen species (ROS), ATP and calcium levels are briefly presented. In a second part, clues for how mitochondria-driven alterations in lipid metabolism may induce toxicity are discussed. In the third part, it is illustrated how mitochondrial dysfunction and lipid homeostasis disruption may be associated (i) to complicate type 1 diabetes (pancreatic -cell mitochondrial dysfunction in ATP yield induces reduced insulin secretion and hence disruption of glucose and lipid metabolism), (ii) to contribute to type 2 diabetes and other insulin resistant states (mitochondrial impairment may induce adipocyte dysfunction with subsequent increase in circulating free fatty acids and their abnormal deposit in non adipose tissues (pancreatic ß-cells, skeletal muscle and liver) which results in lipotoxicity and mitochondrial dysfunction), (iii) to offer new clues in our understanding of how the brain controls feeding supply and energy expenditure, (iv) to promote cancer development notably via fatty acid oxidation/synthesis imbalance (in favor of synthesis) further strengthened in some cancers by a lipogenetic benefit induced by a HER2/fatty acid synthase cross-talk, and (v) to favor cardiovascular disorders by impacting heart function and arterial wall integrity.

Keywords: ATP, calcium, ceramides, fatty acids, lipotoxicity, metabolic syndrome,mitochondria, reactive oxygen species. INTRODUCTION Recently, our knowledge about the role of mitochondria in cell physiology and in human diseases has literally exploded. Among others, mitochondria control cell apoptosis by endogenous route, regulate free radical generation, calcium and ATP levels, provide cells and tissues with preconditioning protection, govern cell metabolic redox status and energy supply, participate in a large panel of biochemical pathways. A dysfunction of the mitochondrial activity may therefore affect a myriad of cell and body tasks. In addition to a brief account for the role of mitochondria in controlling the metabolism of lipids and how lipids may be quantitatively or qualitatively altered by endogenous oxidant species, ATP and calcium levels, this review will provide the reader with a snapshot of how pathogenesis conditions including types 1 and 2 diabetes, obesity, cancer, heart disease, metabolic syndrome and atherosclerosis associate mitochondrial dysfunction and disrupted lipid homeostasis.

*Address correspondence to this author at the Inserm & HMNO, CBP, CHRU Lille, 59037 Lille, France; Tel/Fax: + 33 320 445694; E-mail: [email protected]

here briefly accounted for. Presented pathways need to be further integrated with signaling routes regulating liver metabolism during these states. For a detailed presentation of these signaling events (notably insulin or glucagon-driven regulations), the reader may be referred to the recent review of Fritsche et al. [1]. In the postabsorptive period, the hepatocyte is supplied with large amounts of glucose (Fig. 1) and is under influence of increased insulin levels. Glucose is oxidized in cytosol to pyruvate to yield ATP (2 ATP produced from 1 glucose); and mitochondrial oxidations intervene to complete glucose oxidation by metabolizing pyruvate to acetyl-CoA via pyruvate dehydrogenase (activated by insulin) and by further oxidation of acetyl-CoA in the Krebs’cycle. The metabolic energy produced in the form of reduced cofactors (NADH + H+, FADH2) is recovered in the final form of ATP via the respiratory chain OXPHOS complexes with a net result of about 34 ATP generated by mitochondria during glucose oxidation. In the postabsorptive period, energy supply is in excess and the major part of intramitochondrial acetyl-CoA instead of being oxidized for energy production is transferred to the cytosol for anabolic purposes (fatty acid and cholesterol syntheses). This transfer is performed by citrate as a shuttle form between mitochondrial matrix and cytosol. Citrate is intramitochondrially formed from condensation of acetylCoA with oxaloacetate and may escape the matrix via a specific mitochondrial inner membrane carrier SLC25A1 (citrate carrier) [2]. This carrier exchanges one molecule of citrate with one molecule of malate which results in the import of oxaloacetate previously exported in the form of citrate. Oxaloacetate is actually released from citrate by cytosolic ATP citrate lyase which also acts in finalizing the transfer of acetyl-CoA from mitochondrial matrix to cytosol. Cytoplasmic acetyl-CoA is used for fatty acid synthesis and for cholesterol biosynthesis. Malonyl-CoA the product of acetyl-CoA carboxylase is a physiological inhibitor of CPT1, the enzyme catalyzing the rate limiting step in mitochondrial long-chain fatty acid oxidation [3,4]. Its action leads to a disruption of mito-

© 2012 Bentham Science Publishers

THE PHYSIOLOGICAL ROLE OF MITOCHONDRIA IN LIPID METABOLISM, ATP, CALCIUM AND REACTIVE OXYGEN SPECIES (ROS), CONCENTRATIONS Catalysis and Coordination Roles of Liver Mitochondria in the Intermediary Metabolism Mitochondria play a key role in metabolism and may impact lipid homeostasis diversely, depending on the tissue. In this respect, a clear view of how a mitochondrial metabolic dysfunction may alter lipid homeostasis in a tissue requires a preliminary account for mitochondrial metabolism in its interdependency within the entire cell metabolism. In liver, mitochondrial metabolism takes place in cell function in a way dependent on the nutritional state. Liver metabolic flux orientations during the fed and starved states are

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Fig. (1). The metabolic role of liver mitochondria in the fed state in regulating intermediary metabolism by linking glycolysis (A), fatty acid synthesis (B), fatty acid oxidation (C) and esterification (D). This figure highlights the need for an intact liver mitochondrial function in the normal regulation and working of the intermediary metabolism and in whole body management of energetic substrates. The high glycolysis-driven NADPH production also represents a key event in the general hepatic orientation towards anabolic tasks. Recent developments have further emphasized the crucial role of lipins in controlling the fatty acid oxidation/esterification balance. Abbreviations are : G3P, glycerol-3-phosphate; DHAP, dihydroxyacetone phosphate; cG3PD, cytosolic glycerol-3phosphate dehydrogenase; mG3PD, mitochondrial glycerol-3-phosphate dehydrogenase; micGPAT, microsomal glycerol-3-phosphate acyltransferase; mitGPAT, mitochondrial glycerol-3-phosphate acyltransferase; ACS, acyl-CoA synthetase; CPT1, carnitine palmitoyltransferase type 1; PDH, pyruvate dehydrogenase; CS, citrate synthase; CL citrate lyase; cMDH, cytosolic malate dehydrogenase; mMDH, mitochondrial malate dehydrogenase; FASN, fatty acid synthase; PyC, pyruvate carrier; CIC, citrate carrier; AGPAT, acylglycerolphosphate acyltransferase; TAG, triacylglycerol; PL, phospholipids; PC, phosphatidyl-choline; PE, phosphatidyl-ethanolamine; VLDL, very low density lipoproteins; LPA, lysophosphatidic acid; PA, phosphatidic acid; LCFA, long-chain fatty acid; LCFA-CoA, long-chain fatty acyl-CoA; LCFA-Cn, long-chain fatty acyl-carnitine.

chondrial fatty acid oxidation, an event which prevents a futile cycle in which fatty acids synthesized de novo from acetyl-CoA and malonyl-CoA would be broken down locally by mitochondria. Fatty acids are in these conditions directed towards incorporation into glycerolipids, condensing with glycerol-3P originating from glucose to form a lysophosphatic acid which after addition of a second fatty acid gives rise to phosphatidic acid. The latter is hydrolyzed by lipin (s) and resulting diacylglycerol is further converted to triglycerides or to phospholipids [5]. Triglycerides add to the apolipoprotein B100 during protein synthesis in the ER lumen through the action of the MTTP (microsomal triglyceride transfer protein) to contribute to the synthesis of liver VLDL [6]. So, during the postabsorptive period one may conclude that mitochondrial matrix metabolism coordinates glucose oxidation to fatty acid synthesis and physiologically disrupted fatty acid oxidation favors phospholipid and triglyceride incorporation of formed fatty acids. These pathways are regulated by metabolic cross talks and also by gene expression modulation in response to the hormonal context and to regulatory metabolites (for a review, see [1]). Upon starvation, liver metabolism is shifted towards fatty acid oxidation as a net result of increased blood supply in fatty acids previously released from adipocytes (Fig. 2). Fasting fatty acids offer to liver a source of energetic substrates alternative to glucose which, like insulin, is lower in starved than in the fed state [7]. Malonyl-CoA is consequently reduced not longing dam to CPT1 activity and fatty acid oxidation. In parallel, liver ensures gluconeogenesis from glycerol released during lipolysis, from proteolysis-driven supply in gluconeogenic amino acids and from lactate produced by extrahepatic tissues in the scope of the Cori cycle [7]. Liver mitochondrial fatty acid oxidation provides reduced cofactors

(NADH + H+) which via the malate-aspartate shuttle are transferred to cytosol and orientate glyceraldehyde-3P dehydrogenase reaction towards glucose formation further released in blood stream to be used by extrahepatic tissues. Liver mitochondria generate ketone bodies which also represent energetic substrates for extrahepatic oxidation. Mitochondria contribution to lipid homeostasis occurs in most tissues other than liver. In these tissues, mitochondrial metabolism also works as depicted for liver, without local gluconeogenesis (intestine and kidney keeping, however, some gluconeogenic capacity) and without ketone body formation (astrocytes and kidney being however able, like liver, to produce ketones). In addition, extrahepatic mitochondria equipped with ketolysis enzymes can oxidize ketone bodies to yield energy [8]. Extrahepatic tissues also display the capacity to synthesize fatty acids and cholesterol and to form triglycerides and phospholipids. Role of Mitochondria in Sterol Metabolism Mitochondria are also involved in cholesterol metabolism, especially in diverse conversions of cholesterol leading to the synthesis of pregnenolone, aldosterone, cortisol and 1,25-dihydroxyvitamin D3 [9, 10]. Mitochondria are also involved in bile acid synthesis, catalyzing C27-hydroxylation of cholesterol [9,10]. These hydroxylations are performed by members of mitochondrial cytochrome P450scc [9.10]. The formation of pregnenolone from cholesterol represents the rate-limiting step in steroid hormone biosynthesis. This metabolic step occurs at the level of mitochondrial inner membrane, and interestingly, supply of cholesterol alimenting this reaction involves a cholesterol binding protein located to the mitochondrial outer membrane and capable of transferring

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Fig. (2). The hub role in the starved state of liver mitochondria in the control of the organism energy dispatching and balance. This figure highlights the need for a normal liver mitochondrial function for converting, in the starved state, local and extrahepatic metabolites into glucose and ketone bodies two types of energetic substrates readily-oxidizable by extrahepatic tissues. Abbreviations are : ACS, acyl-CoA synthetase; CPT1, carnitine palmitoyltransferase type 1; CACT, carnitine acylcarnitine translocase; CPT2, carnitine palmitoyltransferase type 2; LCFA, long-chain fatty acid; LCFA-CoA, long-chain fatty acyl-CoA; LCFA-Cn, long-chain fatty acyl-carnitine; -ox, -oxidation; glng aas, gluconeogenic amino acids; OA, oxaloacetate; PEP, phosphoenol-pyruvate; 2PG, 2phosphoglycerate; 3PG, 3-phosphoglycerate; 1.3 BisPG, 1.3-bisphosphoglycerate; GA-3P, glyceraldehyde-3-phosphate; DHAP, dihydroxyacetone phosphate; F16BisP, fructose-1,6,-bisphosphate; F6P, fructose-6-phosphate; G6P, glucose-6-phosphate.

local cholesterol from cytosolic or vesicle origin (protein or vesiclebound) to the mitochondrial inner membrane [11, 12]. This mitochondrial protein is steroidogenic acute regulatory protein (StAR) and, in a scenario in which it picks up cholesterol from a cytosolic cholesterol binding protein, StarD4, is able to drive towards steroidogenesis the cytosolic cholesterol resulting from endogenous synthesis, hydrolysis of cholesteryl esters and/or cell uptake via LDL and scavengers receptors [11,12]. The crucial role of mitochondrial StAR is supported experimentally by its stimulating action on steroidogenesis and pathophysiologically by its deficiency in lipoid congenital adrenal hypertrophy in which disrupted steroidogenesis is associated with intracellular accumulation of cholesterol [11,12]. Role of Mitochondria in ATP Production and Cell Calcium Homeostasis Mitochondria are generators of ATP and play an active role in the manner by which cells govern their subcellular contents in calcium. Like ROS, ATP and calcium repartition in cells are modified upon mitochondrial dysfunction, and may also contribute to disrupt lipid homeostasis. Mitochondria contribute to calcium homeostasis, and hence, play a key role in cell life. The mitochondrial handling of calcium is involved in energy generation needed for performing cell tasks. It buffers variations in cytosolic calcium concentrations and influence apoptotic/pro-apoptotic status of the cell. In this respect, interconnections of mitochondria with the endoplasmic reticulum are considered below in the text. Generation and Breakdown of Reactive Oxygen Species (ROS) Lipid homeostasis requires adequate regulation and catalysis of lipid metabolic pathways. It also requires adequate removal and

replacement of altered lipids. A major source of lipid alterations is represented by reactive oxygen species (ROS). ROS may directly affect lipids notably via lipid peroxidation. The role of mitochondria in membrane lipid oxidation essentially involves either induction or repair of free radical damages. An important site of free radical formation is the mitochondrial respiratory chain [8,13]. Superoxide anion may be generated at the level of respiratory chain, essentially but not exclusively by complexes I and III, through electron leakage and by a single electron reduction of oxygen. Physiologically; mitochondrial ROS generation concerns a few percent of the total cell oxygen content. An increase in ROS levels may have harmful consequences for integrity of membrane phospholipids, proteins and DNA through notably the harmful effects of the hydroxyle radical which is generated by Fenton’s chemistry from hydrogen peroxide in the presence of transition metal ions in the reduced stage such as ferrous and cuprous ions (Fig. 3). Fenton’s chemistry and hence hydroxyle radical formation may be exacerbated by the amount of iron recovered in the mitochondrial matrix and/or Fe/S cluster that could release iron after oxidative stress Products and intermediates of the single electron reduction of oxygen (oxidative stress) may in turn interact with players of the nitrosative stress, superoxide anion radical reacting for instance with nitric oxide (another radical) to form peroxinitrite which, though being not a radical, is highly reactive and harmful towards cell components [14]. To face oxidative attacks, mitochondria contain their own mechanisms of defenses against ROS, including membrane enrichment in vitamin E, dolichol and ubiquinone, and organelle content in soluble reduced glutathione, glutathione peroxidase(s) and glutathione reductase [15-17]. Ascorbic acid and lipoic acid are also recovered in mitochondria. Mitochondria contain su-



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Fig. (3). Products and intermediates of the single electron reduction of oxygen. Molecular oxygen (O2 on the figure designs triplet oxygen, the symbol of which is 3O2) may be reduced one electron by one electron to form water (outspread horizontal gray box). This molecular oxygen to water conversion differs from that physiologically catalyzed by cytochrome c oxidase complex IV which transfers 4 protons and 4 electrons on one molecule of O2 to form 2 molecules of H2O. In turn, triplet molecular oxygen (O2) may also generate singlet oxygen (O2* on the figure designs singlet oxygen, the symbol of which is 1O2) for instance in the presence of a photo-sensitizer and light. The reduction one electron by one electron of molecular oxygen to water (outspread horizontal gray box) generates intermediates which are reactive oxygen species. This pathway may be here commented as follow. The first step, O2 to O2.- reduction, is not thermodynamically favored in contrast to the other steps of the depicted pathway; this energetic barrier is a natural protection against the toxicity of oxygen. Note also that O2 itself is a bi-radical, the relative stability of this radical towards non-radicals holds in the fact that the two unpaired electrons have the same spin preventing their pairing in the absence of external energy (this pairing occurs when energy is supplied and results in the formation of the highly reactive singlet oxygen formation). O2.- is a radical more reactive than molecular oxygen O2, it may act as an oxidant but also as a reducer (conversion back to molecular oxygen O2 is thermodynamically favored). The latter reducing behavior when expressed towards transition metal in the oxidized form leads to a reduced transition metal which in the presence of hydrogen peroxide (H2O2) promotes Fenton’s chemistry responsible for the formation of hydroxyle radical (OH•) which is a strong oxidant and instantaneously highly reactive. Hydrogen peroxide is, like superoxide, a moderate oxidant.

peroxide dismutases (SODs), a manganese SOD located in the mitochondrial matrix (SOD2) and a cupro-zinc SOD (SOD1) located in the mitochondrial intermembrane space [18, 19]. Mitochondria possess a phospholipid hydroperoxide glutathione peroxidase which contributes to the local repair of oxidatively altered membrane phospholipids and may protect ATP generation under oxidative injury [17, 20]. Thioredoxin and thioredoxin reductase are also found in mitochondria [21]. These organelles further contain peroxyredoxins (PRXs) 3 and 5 [22]. PRX 3 is located exclusively in mitochondria whereas PRX 5 is also located in other cell compartments such as the peroxisome [22]. There are at least six mammalian PRXs; PRXs 1,2 and 6 are cytosolic and PRX resides in the endoplasmic reticulum [22]. In contrast to glutathione peroxidase, a cysteine instead of selenocysteine is involved in catalysis of peroxidase activity by PRXs (for additional details, see [22]). Prx 3 usually manages the bulk of the hydrogen peroxide generated in the mitochondrial matrix, and hence, represents an important line of antioxidant defense towards intramitochondrially-generated hydro-

gen peroxide and hence modulates hydrogen peroxide-driven signaling pathways including apoptosis [22]. Like ROS, RNS (reactive nitrosative species) may be of mitochondrial origin, may be scavenged by and may target the mitochondrion. Mechanisms by which mitochondria generate nitric oxide ( NO) are not completely elucidated. Though a specific isoform of nitric oxide synthase (NOS) has been described in mitochondria and to be distinct from endothelial, neuronal and inducible NOS, the existence of mitochondrial NOS [23, 24] still remains a matter of debate. On the other hand, mitochondria can synthesize NO through a pathway independent on oxygen and on NOS (enzymes which requires arginine and oxygen). This other pathway for NO formation works under hypoxic or anoxic conditions and solicits the mitochondrial respiratory chain, reducing NO2- to NO [25, 26]. This mitochondrial nitrite reductase activity is catalyzed by cyctochrome c oxidase [25, 26]. Interestingly, in the presence of oxygen, NO may interact competitively with oxygen for binding to cytochrome c oxidase, inhibiting the oxidase activity and contribut


ing to the NO /cytochrome c oxidase signaling pathway. The oxygen sensitive binding of NO to the heme of cytochrome c oxidase modulates (i) respiratory chain-driven formation of hydrogen peroxide and subsequent signaling generated by the peroxide and (ii) oxygen consumption and hence oxygen gradients notably in liver and heart. Imbalances in the levels of NO and hydrogen peroxide levels lead to mitochondrial dysfunction through formation of excess peroxinitrite and subsequent irreversible alterations of proteins [26]. As it is highlighted by the study of pathophysiological states, relationships existing between mitochondria and oxidant species may be reciprocal: mitochondrial dysfunction may lead to disrupted ROS and RNS homeostasis and, inversely, increased ROS and RNS may induce mitochondrial dysfunction.

THE MITOCHONDRIAL-DRIVEN LIPID HOMEOSTASIS DISRUPTIVE EVENTS AND LIPOTOXICITY Fatty Acid Metabolism-initiated Lipotoxicity As mentioned above, mitochondria play a key role in the clearance of fatty acids through -oxidative breakdown and resulting energy production. The functional or physical inhibition of CPT1 through regulatory processes, substrate overflow, synthetic inhibitors, or reduced availability in L-carnitine leads to an imbalance in fat oxidation/fat synthesis status in favor of fat synthesis. Impairment of mitochondrial fatty acid oxidation resulting from the alteration of a step downstream to CPT1 may also favor fat synthesis versus oxidation. The rise in intracellular levels of fatty acids, secondary to lipid homeostasis disruption, represents a toxic condition for the cell which involves different mechanisms including ROS production, peroxidized lipids, ceramide and DAG signaling [27, 28]. Interestingly, triglyceride formation may exhibit in some but not all circumstances a cytoprotective effect through removal of fatty acids and their CoA esters. Lipid-binding proteins are necessary for optimal cell lipid metabolism and lipid homeostasis. Along with vesicle-mediated lipid transfer (lipoprotein uptake, for instance), they play a key role in cellular and subcellular lipid uptake and trafficking. Cytosolic and mitochondrial sterol-binding proteins have been evoked above. Fatty acid binding proteins (FABP) exist in the form of various tissue-specific isoforms including notably liver, heart, brain, intestinal, adipocyte and keratinocyte as well as additional specific isoforms for the binding of retinoate, retinol and also, like sterolbinding proteins, bile acids [29]. The FABP/fatty acid complex impacts positively the diverse utilizations of fatty acids by cells such as uptake, oxidation, esterification and involvement in cell signaling (for instance, PPAR and HNF activation and subsequent regulation of target genes) [29]. Fatty acyl-CoA binding proteins (ACBP) have been also described and reviewed in detail along with their role in metabolism and signaling. ACBP present with high affinity towards fatty acyl-CoA and play a key role in acylCoA trafficking and subcellular pools [30-32]. ACBP contribute with FABP to maintain cytosolic concentration of fatty acyl-CoAs in the nanomolar range. ACBP/fatty acyl-CoA complexes have been further proposed to be the regulators of many cell functions [30]. Finally, an interesting function of ACBP in mitochondrial metabolism is the binding of the product of the acyl-CoA synthetase located to the mitochondrial outer membrane. This binding removes the product of the synthetase (free acyl-CoA), and then alleviates product inhibition of this enzyme, allowing the reaction to occur at high rates [32]. FABP and ACBP may be involved in PPAR, notably PPAR, activation in the same time as these proteins may be up-regulated by this and other nuclear receptors [30, 32]. Free Radical- and Hyperglycaemia-complicated Lipotoxicity The nature of the fat plays as important a role as the abundance of fat. As explained earlier, ROS may alter the quality of fats and a

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physiological source of the oxidant species is the mitochondrial respiratory chain. In conditions in which mitochondrial electron transfer chain is impaired, the amount of increase in levels of ROS may exceed the capacity of local antioxidant defenses leading to an increased steady state concentration of ROS and increased risk for lipid alterations. Besides a direct oxidative damage of macromolecules, the increase of ROS disrupts physiological oxidant-based signaling further disturbing adaptation of cells to oxidative stress and contributing to exacerbate pre-existing lipid homeostasis imbalance. The toxicity of fatty acids may be also worsened by hyperglycaemia and in this case is referred to as “gluco-lipotoxicity” or “glucolipoxia” [33]. As explained elsewhere in the text and as illustrated in (Fig. 1) for liver in the fed state, substantial glucose utilization inhibits fatty acid oxidation through increased levels of malonyl-CoA and this leads to the accumulation of acyl-CoA thioesters and the stimulation of their further metabolic handling to synthesize fatty acid esters in the form of cholesteryl esters and ester glycerolipids that include as mentioned above lipids such as ceramides which represent important signal molecules favoring for instance cell apoptosis. Gluco-lipotoxicity classically applies to non adipose tissues. The limit of expandability rather than lipotoxicity per se is a preferred terminology to account for the fat accumulation in adipocytes which represent cells physiologically involved in fat storage. Interconnections between the Endoplasmic Reticulum and Mitochondria Like endoplasmic reticulum (ER), mitochondria may organize into a network within the cell. Each of these two, ER and mitochondria, networks contributes to cell homeostasis and under stress conditions plays a key role in regulating cell fate. Recently, close contacts between ER and mitochondria have received a particular attention indicating that they were more than the proximity of two organelles and were actually the result of elaborated communications between the two subcellular compartments, involving macromolecular complexes at contact sites and highlighting the concept of mitochondrial-associated ER membranes (MAM) [34-36]. MAM have been described as ER microdomains resistant to detergents and are involved notably in the metabolism of glucose and lipids (phospholipid, sphingolipid, ganglioside, cholesterol, fatty acids) as well as in cellular calcium homeostasis and signaling [34-36]. In fact, MAM are considered as connecting physically, metabolically, signally and functionally ER and mitochondria. These interorganelle connecting structures explain why changes in mitochondrial biogenesis or why a mitochondrial dysfunction may trigger ER stress, especially through mitochondrial (i) excess ROS production (the unfolded protein response which takes place in ER stress may be triggered by changes in the redox sate) and (ii) altered calcium uptake. Mitochondrial changes in calcium uptake induce alterations in neighboring ER calcium channels IP3R (insositol, 1.4.5triphosphate receptor) and RyR (ryanodine receptor) activities which are allosterically regulated by calcium ions and which control release of calcium by ER [34-36]. Lipid Homeostasis and Impairment of Mitochondria Morphology and Function The importance of lipid metabolism for intracellular and mitochondrial membrane fusion/fission processes has been recently reviewed by Furt and Moreau [37]. These authors particularly stressed the lipids involved in mitochondrial membrane fusion/fission, and discussed the fact that these events, regulated by the balance between of numerous fusion and fission proteins, are also lipid-assisted processes [37]. A complicate network of metabolic and translocative events interesting complex lipids such as cardiolipins occurs within and between mitochondrial membranes to regulate the delivery of fusiogenic lipids to different fusion sites


[37]. So, any disruption in the metabolism and transfer of these fusiogenic lipids may inevitably trigger mitochondrial dysfunction, and hence, can affect cell and whole body physiology. PATHOPHYSIOLOGICAL STATES ASSOCIATING MITOCHONDRIAL DYSFUNCTION AND LIPID HOMEOSTASIS IMBALANCE As a general rule, pathological states represent cross-roads of intricate pathogenesis events. These events may be identified without necessarily stating the exact chronological order in which they take place in the pathogenesis process. Disruption of homeostatic states corresponds to disruption of physiological homeostatic feedback loops. The altered regulatory loop may either recover spontaneously (homeostasis) or may lead to a new state (allostasis) represented here by the pathological state. The onset of the latter state may be favored by the concurrence of “vicious circles” (i.e. when consequences of a causal factor, instead of attenuating, exacerbate the intensity of the initiating factor). Whether mitochondrial dysfunction is a cause or a consequence of disrupting lipid homeostasis is not always obvious in the pathophysiological states mentioned below. This review attempts to illustrate in a non exhaustive way that these pathologies may involve mitochondrial dysfunction and lipid homeostasis imbalance. Type 1 Diabetes (Insulinopenic, Juvenile) Type 1 diabetic patients may present with mitochondrial alterations in pancreatic ß-cells along with deficient insulin secretion, apoptosis and reduced cell mass in the context of autoimmune destruction of ß-cells [38,39]. Mitochondrial oxidative metabolism is a major producer of ATP which controls insulin secretion via ATPsensitive potassium channels. The activity of these channels couples the cell metabolism to cellular tasks ([40] and references therein). When ATP is high, ATP-sensitive potassium channels are inhibited and cannot hyperpolarize plasma membrane. Local membrane voltage-dependent calcium channels may then work inducing entry of calcium in pancreatic -cells and subsequent stimulation of insulin secretion. When ATP is low, for instance as a result of limited supply in energetic substrates (due to large gap between meals) or in turn as a result of impaired mitochondrial function, ATP-sensitive potassium channels are stimulated and hyperpolarize the cell membrane, leading to inhibition of calcium entry via the voltagedependent calcium channels, and hence to inhibition of insulin secretion. Failure to secrete insulin leads to altered glucose utilization and lipogenesis. Type 2 Diabetes (Insulin Resistant, Adult) It has been recently stressed that mitochondrial dysfunction in skeletal muscle may represent one of the causes (and not the exclusive cause) of insulin resistance and type 2 diabetes ([28] and references therein). The mechanisms invoked are illustrated in (Fig. 4) and attribute a key role to fatty acid oxidation/esterification imbalance caused by defective mitochondrial oxidative capacity. In these mechanisms, a role is also attributed to ROS, the production of which would be increased by uncoupling properties of fatty acids and by reduction of UCP3 levels; desensitization of insulin signaling being the direct result of skeletal muscle accumulation of lipid intermediates secondarily to reduced mitochondrial oxidative capacity. Lipid peroxide formation (interaction of lipids and ROS) in the vicinity of mitochondria would further alter local macromolecules, generating or amplifying the mitochondrial dysfunction. Though UCP3 may favor proton gradient leakage, this function (i) requires its activation by ROS and (ii) would not be the sole and major function of this protein. Indeed, it is currently assumed that, besides its involvement in proton conductance, fatty acid transport and metabolism, efflux of mitochondrial ROS byproducts, glucose metabolism and calcium homeostasis, UCP3 is primarily aimed at organizing the first line of defense against mitochondrial ROS


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production [41,42]. Reduced levels of UCP3 mentioned above should be then considered as boosting the development of mitochondrial oxidative stress and dysfunction conditions [41,42]. This protein intervening also in the adjusting of mitochondrial calcium uptake [43], reduced levels of UCP3 should further disturb calcium homeostasis. Fatty acyl-CoA and diacylglycerol accumulating secondarily to deficient fatty acid oxidation have been also proposed to activate novel protein kinase C in skeletal muscle and hence a serine kinase cascade [44]. This activation leads to increased phosphorylation of insulin receptor substrate-1 (IRS-1) at critical sites that prevents its tyrosine phosphorylation by the insulin receptor which in turn inhibits phosphatidyl inositol 3-kinase with as a result suppression of insulin-stimulated glucose transport [44]. In type 2 diabetes, mitochondrial dysfunction may also prevent pancreatic ß-cells to sense properly glucose via changes in ATP level as described above for type 1 diabetes. This mitochondrial dysfunction may involve UCP2 in a scenario in which superoxide overproduced by mitochondrial electron chain promotes proton leak activity of UCP2 and hence loss of proton motive force and subsequent reduction of ATP formation that ultimately impacts KATP channel activity, cell membrane polarization, calcium uptake and insulin secretion by pancreatic ß-cells [44]. Mitochondrial dysfunction may also affect the adipocyte [45, 46]. Prior to present mechanisms by which adipocyte function may be affected by mitochondrial impairment, major features in the link existing between adipocyte dysfunction and insulin resistance are briefly developed (for extensive consideration, see [46]). Adipocyte dysfunction may lead to a defective capacity to store circulating free fatty acids and thereby to an increase in their levels. In this respect, it is now well documented that insulin resistance is linked to increased levels of circulating free fatty acids more than to increased body fat contents. Elevated circulating free fatty acids enhance the exposure of non-adipose tissues and hence predispose these tissues to lipotoxicity according to signaling involving notably fatty acid esters such as ceramides and diacylglycerol. Development of lipotoxicity in non-adipose tissues may impact negatively glucose uptake by these tissues according to mechanisms similar to those described just above for skeletal muscle. In this respect, skeletal muscle and liver are considered as the main two tissues which with adipose tissue physiologically remove glucose from blood in response to circulating insulin. Therefore, the increased exposure to fatty acids resulting in lipotoxicity and hence in reduced glucose uptake by these tissues creates the wake for permanent hyperglycaemia, the expression of which may be further worsened by impaired pancreatic ß-cell function. Regarding mitochondrial impairment and diabetes, Petersen [47] has provided evidence for age-associated decline in mitochondrial function as a cause in insulin resistance observed in the ederly. Mitochondrial dysfunction in pre-adipocytes has been shown to alter cell differentiation [48] inducing a less efficient adipocyte clearance of circulating glucose. In the mechanisms underlying these cell differentiation alterations, the ubiquitous transcription factor CREB plays a key role and its gene expression may be modulated by mitochondrial function/dysfunction [48]. Inhibitors/inhibition of mitochondrial OXPHOS are known to induce triglyceride accumulation in preadipocytes and to maintain the fibroblast phenotype, pre-adipocytes failing to differentiate into adipocytes and to acquire adipogenic markers [47, 48]. Interestingly, the lipodystrophy syndrome (peripheral lipoatrophy associated with visceral fat accumulation) caused by highly active antiretroviral therapy (HAART) appears to be attributed to adipocyte mitochondrial dysfunction and impaired fatty acid oxidation [49-51]. The drug-induced syndrome presents some analogies with the same phenotype developed by the older population, OXPHOS activity decreasing with ageing [47]. On the other hand, ROS also consecutive to mitochondrial dysfunction can inhibit adipogenesis and reduce both growth and multiplication of


FFA fat burning

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INSULIN RESISTANCE STATES (obesity, type 2 diabetes, metabolic syndrome)

Fig. (4). Role of mitochondrial dysfunction and cell lipid homeostasis disruption in insulin resistance of skeletal muscle. The mitochondrial dysfunction is associated with decreased oxidative capacity and increased ROS levels. The reduced mitochondrial oxidations shift the cell lipid homeostasis towards accumulation of fatty acids in their free (FFA, free fatty acids) or activated (FA-CoA, fatty acyl-CoA) forms. As a result fat esterification pathways are stimulated, enhancing fat storage and formation of lipid signaling compounds. On the other hand, the combined rise in fatty acids and ROS favors the production of peroxidized lipids which along with FFA and FA-CoA contribute to lipotoxicity which acts by aggravating the initial mitochondrial dysfunction. The increase of fat storage, particularly the enhancement of triglycerides impacts cell differentiation mechanisms and the increase in ceramides contributes to desensitize the cell to insulin signaling, inducing resistance to insulin and promoting the development of pathologies linked to insulin resistant states (obesity, type 2 diabetes, metabolic syndrome).

pre-adipocytes without necessarily inducing cell necrosis and death [52]. A recent study on the adipocyte as the specific cell type for storage of fat has provided elegant experimental support for a protective role of CPT1 against development of insulin resistance and inflammation [53]. This protection is mediated by a blunting of JNK signaling [53]. Obesity Obesity is a factor favoring the development of insulin resistance through chronic adipocyte inflammation and ectopic lipid deposition. The role of mitochondrial function and dysfunction in adipocyte differentiation has been evoked above. Mitochondrial dysfunction may alter differentiation of pre-adipocytes to adipocytes, altering lipid homeostasis via accumulation of triglycerides in pre-adipocytes. Mitochondrial dysfunction may also affect the mature adipocyte through increased ROS production, reduced mitochondrial biogenesis and ATP formation, impaired adipogenesis and production of inflammatory cytokines such as TNF [51, 54]. In this respect, TNF has been recently shown to cause mitochondrial dysfunction via alterations of mitochondrial dynamics characterized by increased levels of mitofusin protein mfn 1 and mitofission protein Drp1, and by morphological changes of mitochondria which were found to be smaller and more condensed than normal [54]. These effects of TNF are interesting owing to the fact that this cytokine was the first proinflammatory factor linking obesity, insulin resistance and adipocyte inflammation [54]. If excess TNF is associated with the insulin-resistant adipocyte, reduced production of adiponectin is observed in these conditions. These changes in the amount of adipokines inevitably impact crosstalk that adipo-

cyte normally develops with other tissues including skeletal muscle and liver, physiologically contributing to metabolism of fatty acids. The lowering in adiponectin leads to a removal of its antiinflammatory properties [55-58] and to a reduction of other effects of adiponectin, among which is activation of liver PPAR ([59] and references therein). These consequences compromise notably adipocyte insulin sensitivity and stimulation of liver fatty acid oxidation capacity physiologically coordinated to adipocyte metabolism, contributing to disrupt body lipid homeostasis. Another dimension of obesity and other insulin resistant states including the metabolic syndrome is the brain control of food intake and energy expenditure. Recent advances indicate that hypothalamic fatty acid metabolism and signaling might play a crucial role in the brain control of body energy balance [60-65]. Moreover the unique mitochondrial CPT1 C isoform which is restricted to brain appears to represent a target of cell malonyl-CoA which in the scope of a homeostatic loop reduces body glucose uptake and increases physical energy expenditure behavior [60-64]. When glucose supply is high, hypothalamic cells increase their contents in malonyl-CoA (via cytoplasmic glycolysis to pyruvate, mitochondrial oxidation of pyruvate to acetyl-CoA and transfer of mitochondrial to cyplasmic acetyl-CoA and subsequent carboxylation of cytoplasmic acetyl-CoA). Malonyl-CoA interacts with mitochondrial CPT1C and this interaction is supported to favor formation of mediators from hypothalamic origin acting as satiety factors (decrease in food intake) [62] and as physical expense stimulators (Fig. 5). A hypothalamic dysfunction of mitochondrial CPT1C role or sensitivity to malonyl-CoA might be involved in the development of obesity and other related disorders in which excess caloric supply and reduced energy expense take place.


FASN


FATTY ACIDS

mitochondrial CPT1A and β-oxidation

1395

Fatty acid breakdown and local energy production

malonyl-CoA

mitochondrial CPT1C

cytoplasmic acetyl-CoA citrate

Ï FOOD INTAKE

unknow mechanisms

AMPK

PHYSICAL ENERGY EXPENSIVE BEHAVIOUR

ATP intramitochondrial acetyl-CoA pyruvate

pyruvate

GLUCOSE

Fig. (5). Role of mitochondrial dysfunction and cell lipid homeostasis disruption in the hippocampal control of food intake. Brain control of food intake is based on the function of a particular isoform of the carnitine palmitoyltransferase type 1. This enzyme and the two classical isoforms type 1A in liver and type 1B in muscle initiate mitochondrial fatty acid oxidation. CPT1A and B are inhibited by malonyl-CoA an intermediary in fatty acid synthesis (FASN) to avoid, as explained in the text, neo-formed fatty acids to be degraded locally. CPT1C is a protein specific of the brain which may concour with CPT1A in the mitochondrial outer membrane. Its essential role is upon interaction with malonyl-CoA to inhibit food intake. This is represented on the figure by an inhibition of malonyl-CoA of a putative role of this protein to increase, in the absence of malonyl-CoA, food intake. The physiological negative feed-back loop is the following : when the organism is supplied with glucose, hippocampal malonyl-CoA increases and interacts with (“inhibits” on the figure) CPT1C to reduce food intake. When systemic glucose lowers, the hippocampal cells form less malonyl-CoA and CPT1C in the form of CPT1C/malonyl-CoA complex decreases, alleviating the brain inhibition operated on food intake. Alterations of this regulatory loop are proposed to explain exaggerated and uncontrolled food intake and disruption of energy (and lipid metabolism) homeostasis via weight gain and insulin resistance. The function of CPT1C is linked to various signaling pathways. CPT1C/malonyl-CoA complex reduces neuropeptide Y (NPY) and agouti-related protein signaling, inducing a decrease in food intake, and increases proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) signaling, inducing an increase in energy expenditure (see references cited in the text).

Cancer Mitochondrial abnormalities including metabolic and genetic alterations may be numerous in the cancer cells [66-71] and a role of mit-DNA in metastasis is currently emerging [72]. Mitochondrial dysfunction may contribute to a disrupted balance between cell fatty acid oxidation and fatty acid synthesis. Whereas in some cancers, mitochondrial fatty acid oxidation is stimulated as a energysupplying source [73, 74], in some others, mitochondrial CPT1 activity is reduced and contributes to a fatty acid oxidation/synthesis imbalance state favoring fatty acid synthesis [75-77]. In fact, fatty acid synthesis is increased in many cancer cell lines, and the increased fatty acid synthase (FASN) capacity contributes to the tumoral cell development [78-81]. Increased fatty acid content represents a reservoir of precursors for signaling molecules that may promote cancer development. However as mentioned above, free fatty acids including those generated by FASN may be toxic for cells. To overcome fatty acids-driven lipotoxicity, cancer cells overexpress enzymes involved in triacylglycerol synthesis, a pathway which removes cellular fatty acids and stores them in a mobilizable and less toxic form. In this respect, a “lipogenetic benefit” has been supported to result from an unexpected cross-talk between the tyrosine kinase HER2 (human epidermal growth factor receptor) and FASN [82-88]. In cancer cells, this cross-talk is the basis for alleviating fatty acid-driven toxicity via coupling to triacylglycerol synthesis the free fatty acid formation [85, 89, 90] which by otherwise acts towards the increased aerobic glycolysis or Warburg’s effect as a pull metabolic pathway (the pull effect refers to the ability of a metabolic step or pathway to stimulate the step or pathway towards which it comes in continuation, the principle being similar to the favored displacement of the equilibrium of a chemical reaction towards the product when it is removed [for instance by evaporation or chelation] from the reaction medium). PPAR and PPAR-binding protein are in these conditions upregulated by overexpressed HER2 and activate the lipogenetic tria-

cylglycerol synthesis pathway [85, 89, 90] (Fig. 6). Very importantly, this collaboration between HER2 and FASN also takes place out of a pathological context and has physiological relevance in adipogenesis, i.e. proliferation and differentiation of adipocyte cell precursors [85, 91]. Cardiovascular Disorders In heart disease, mitochondrial dysfunction and lipid homeostasis imbalance in favor of either decreased (ischemic heart or hypertensive heart) or increased (diabetic heart) fat oxidation play a contributive role. Key actors in these scenarios include PPAR and PGC-1 which are both either up- or down-regulated [92-95]. Down-regulation of PPAR and PGC-1 induces a decrease in mitochondrial biogenesis and fatty acid oxidation in the ischemic/ hypertensive heart [92-95]. Energetic substrate utilization which normally rests on fatty acid oxidation is shifted towards glucose utilization. This metabolic adaptation may aggravate the heart performance and may lead to heart failure. In the diabetic heart, PPAR and PGC-1 are up-regulated leading to enhanced mitochondrial fatty acid oxidation and hence to increased oxygen consumption, a feature which may also increase the risk for heart failure [92, 93]. (Fig. 7) gives an illustrated and non-exhaustive account for how mitochondrial dysfunction and lipid homeostasis alterations may be involved in heart disease. Regarding atherosclerosis development, another concern of cardiovascular pathogenesis, arterial parietal macrophages may present with a mitochondrial dysfunction associated with lipid homeostasis imbalance in a way promoting disease and in which mitochondrial dysfunction may be responsible for excess ROS production, this oxidative stress promoting or being worsened by lipoprotein oxidation [96-103]. Oxidized LDL may up-regulate expression of scavenger receptors by macrophages; scavenger receptors, in contrast to the LDL receptor, are not regulated by intracellular cholesterol, and therefore, the expression of these receptors leads to


Vamecq et al.

+

Plasma membrane HER2

MAPK PI3'K/AKT

TRIGLYCERIDES

Ï FASN gene product expression

TRIACYLGLYCEROL SYNTHESIS

+

Ï HER2 gene product expression

Ï PPARγ gene product expression

+

SREBP1-C mTOR

FASN

FATTY ACIDS

ROS LIPOTOXICITY

mitochondrial CPT1A and β-oxidation

malonyl-CoA

ACC

Fatty acid breakdown and local energy production

cytoplasmic acetyl-CoA

ACL citrate down-regulatory mechanisms, gene mutations

intramitochondrial acetyl-CoA pyruvate

pyruvate

GLUCOSE

Fig. (6). Mitochondrial dysfunction, cell lipid homeostasis disruption and the lipogenetic advantage given by the HER-2/FASN cross-talk to cancer cells exhibiting the Warburg’s effect. Cancer cells developing the Warburg’s effect have often reduced mitochondrial oxidative activity. The sustained aerobic glycolysis in these cancer cells leads to stimulated fatty acid synthesis with increased steady-state concentrations of malonyl-CoA and increased activity of FASN (fatty acid synthase), the latter protein being considered as an oncoprotein. Another oncoprotein is the over expressed tyrosine kinase active plasma membrane HER2 receptor. These two oncoproteins are connected by a cross-talk in which one protein stimulates the function of the other and reciprocally. Fatty acids are lipotoxic and cancer cells develop to counteract the lipotoxicity linked to increased fatty acid synthesis versus reduced fatty acid breakdown a strategy devoted to remove the free fatty acids, and hence fatty acid-driven lipotoxicity and ROS production, in the storage form of triglycerides. Mechanisms developed for this purpose by the plasma membrane HER2 signaling involve the master adipogenic nuclear receptor PPAR.

Type 2 DIABETES

DECREASE

INCREASE

ABNORMAL MITOCHONDRIAL FUNCTION

SIGNALING WHICH LOWERS ORGANELLE BIOGENESIS AND FAT BURNING (L PPARα, PGC-1α)

ALTERED LIPID HOMEOSTASIS

DECREASED FATTY ACID BURNING ON STORAGE BALANCE

K fatty acid oxidation L glucose consumption

INCREASED FATTY ACID BURNING ON STORAGE BALANCE

SIGNALING WHICH FAVORS ORGANELLE BIOGENESIS AND FAT BURNING (K PPARα & PGC-1α)

ISCHEMIC/HYPERTENSIVE HEART

L fatty acid oxidation K glucose consumption

CARDIOMYOPATHY AND INCREASED RISK OF HEART FAILURE DUE TO INCREASED OXYGEN CONSUMPTION OR DECREASED HEART EFFICACY

Fig. (7). Mitochondrial dysfunction and cell lipid homeostasis disruption in the diseased heart. Enhanced (type 2 diabetes) and decreased (ischemia and hypertension) mitochondrial oxidative activity leads to disruption of cardiomyocyte lipid homeostasis characterized by increased fatty acid oxidation rates and shift from fatty acids to glucose utilization, respectively. Both conditions are detrimental for heart and increase the risk of heart failure (see additional comments and references in the text).



1397

Ï INFLAMMATORY and OXIDATIVE STATE

oxLDL OXYSTEROLS

LIPOTOXICITY CELL NECROSIS

ROS

ER stress AAs

mitochondrial dysfunction ÏFFA

ÏÏfree cholesterol FFA

FFA

VLDL

Fig. (8). Mitochondrial dysfunction and cell lipid homeostasis disruption in arterial wall macrophage. LDL in the oxidized form which is favored by an inflammatory/oxidative context is an inductor and ligand of scavenger receptors. The scavenger receptors in contrast to the LDL receptor are not regulated by intracellular cholesterol and then lead to a cellular scavenging of massive cholesterol quantities. Free fatty acids (FFA) are to a little extent generated by the macrophage incorporation of oxidized LDL (oxLDL) and adding to those released by local endothelial lipoprotein lipase action on VLDL also accumulate in cells. These enhanced lipid (free fatty acids and free cholesterol) species within the cell induce endoplasmic and mitochondrial stresses with abnormal oxysterol formation and rise in ROS which also strengthen lipotoxicity. The result is macrophage necrosis and hence an exacerbation of local inflammatory/oxidative stress which maintains and aggravates the formation of oxidized LDL, auto-maintaining an inflammatory/oxidative/lipotoxic vicious circle in the arterial wall further amplified by the recruitment of other resident and circulating inflammatory cells.

the accumulation of cholesterol by the cell without negative feedback loop regulation [104-108]. As a result, the cell content of free cholesterol dramatically enhances in a way triggering endoplasmic stress response and aggravating any pre-existing mitochondrial dysfunction. This may amplify ROS production and may sustain exposure of parietal macrophages and circulating elements to oxidative stress. Parietal macrophages may be exposed to excess fatty acids supplied by enhanced oxidized LDL internalization and metabolism but also resulting from the action of circulating lipoprotein lipase on VLDL. Excess intracellular cholesterol and resulting production of oxysterols (in abnormal quantities and qualities) along with excess intracellular fatty acids and ROS induce a state of lipotoxicity which up-regulates inflammatory cytokine production and causes macrophage cell necrosis [108-112]. Cell necrosis by itself strengthens the exposure to inflammatory and oxidative stress of surrounding cells and circulating lipoproteins, inducing a vicious circle (Fig. 8) promoting the development of atherosclerosis and atheromatic lesions.

diseases associating mitochondrial dysfunction and lipid homeostasis imbalance is represented by inborn errors affecting mitochondrial lipid metabolism for instance mitochondrial fatty acid oxidation. For a recent review on mitochondrial fatty acid oxidation disorders, the reader may be referred to the work of Houten and Wanders [113]. Beyond imbalance at the detriment of fat oxidation, these inborn disorders present with an increased risk of sudden death during metabolic attacks and hypoketotic hypoglycemia episodes, the prevention of which rests essentially on the avoidance of starvation. The aspects developed throughout this review are currently subject to careful study of additional pathological states notably neurological disorders; for instance, in Alzheimer’s disease, MAM dysfunction and lipid homeostasis have been recently reported to concur [114].

CONCLUSION This review has highlighted important diseases which in humans may involve mitochondrial dysfunction and altered lipid homeostasis as pathogenesis contributors and/or amplificatory factors. Underlying mechanisms contribute to complications in type 1 diabetes, type 2 diabetes and other insulin resistant states; to brain control of feeding supply and energy expenditure, to lipogenetic benefit of increased fatty acid synthase in cancer cells, and to disorders of heart function and arterial wall integrity. Another realm of

ACKNOWLEDGEMENT None declared.

CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.

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Received: April 28, 2011

Revised: July 7, 2011

Accepted: July 26, 2011

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