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Diabetes and Nutrition: The Mitochondrial Part^{1 ,2}

Department of Foods and Nutrition, University of Georgia, Athens, GA 30602

	ABSTRACT

TOP ABSTRACT INTRODUCTION Aberrations in metabolic control... Metabolic control exerted by... OXPHOS structure and function Mitochondrial DNA Mitochondrial DNA transcription Other factors that influence... Perspectives REFERENCES

 
Diabetes mellitus is the most common genetic disease in the Western world today. It is the phenotype for >150 genotypes. Each of these genotypes is characterized by impaired glucose tolerance and impaired control of intermediary metabolism. There are many strains of mice and rats that can be used to study diabetes in its various forms. One of these is the BHE/Cdb rat, which mimics the human phenotype with a mutation in the mitochondrial (mt) DNA. The result of such mutation is a loss in metabolic control with respect to the role of the mitochondria in this control. This review addresses those aspects of control that are exerted by mt oxidative phosphorylation (OXPHOS). Diet can have both genomic and nongenomic effects on OXPHOS. The type of dietary fat influences the fluidity of the mt membranes and hence, mt function. The dietary fat effect depends on the genetic background of the consumer. Diabetes-prone BHE/Cdb rats with base substitutions in the mt ATPase 6 gene are more likely to be influenced by the diet effect on mt membrane fluidity than are normal rats. Vitamin A also affects mt function through an effect on mt gene expression. BHE/Cdb rats have a greater need for vitamin A than normal rats and supplemental vitamin A appears to influence OXPHOS.

KEY WORDS: • mtDNA • mtATPase 6 • membrane fluidity • oxidative phosphorylation • BHE/Cdb rats

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Aberrations in metabolic control... Metabolic control exerted by... OXPHOS structure and function Mitochondrial DNA Mitochondrial DNA transcription Other factors that influence... Perspectives REFERENCES

 
One of the common degenerative diseases afflicting people in the world today is diabetes mellitus. Current estimates of the prevalence of diabetes in the United States and Canada reveal that one person in 14 either has or will develop the disease (Diabetes Surveillance 1997 ). As many as 60% of the adult population of certain groups (Pima Indians, for example) have the disease. People with diabetes mellitus have five times the risk of having heart disease as people without diabetes. More than 60% of people with end-stage renal disease are people with diabetes. Diabetes is the leading cause of blindness in the United States. Diabetes mellitus is among the top 10 causes of death either directly or indirectly, yet our understanding of its pathophysiology and management is incomplete. The role of diet and lifestyle choices is an important area of research because these choices can affect the time course and severity of the disease. Diabetes in its many forms could truly be a disease that results from an interaction among diet, lifestyle and genetics.

Diabetes mellitus is a collection of genetic diseases with the common phenotype of impaired glucose tolerance. More than 150 mutations with the diabetes phenotype have been identified (Alcolado and Thomas 1995 , Awata et al. 1997 , Becker 1999 , Bell et al. 1993 , Chiu et al. 1993 , Gerbitz et al. 1996 , Mathews and Berdanier 1998 , Vanheim and Rotter 1992 ). One of the interesting aspects of this disease is that twice as many people have the genotype as have the phenotype. This suggests that factors in addition to genetics must influence the phenotypic expression of the diabetes genotype.

As a clinical condition, diabetes mellitus is divided into two types on the basis of the management required to control glucose homeostasis. Type 1 or insulin-dependent diabetes mellitus, is diabetes that requires daily insulin replacement therapy in addition to diet and activity management. People with type 1 diabetes comprise about 10% of the total population with diabetes. Their disease is due to pancreatic failure either through an autoimmune or viral attack of the cells in the pancreas (Becker 1999 ). This disease frequently develops in young children and also has far more serious complications than type 2 diabetes. Renal disease, blindness, gangrene, heart disease and other degenerative conditions are not uncommon in people with this form of diabetes.

Type 2 diabetes mellitus used to be called noninsulin-dependent diabetes mellitus because hormone replacement was not used to manage glucose homeostasis. Obesity or excess fat stores frequently accompany or precede the disease. It occurs in the mature rather than the young person. The disease can be managed using diet, exercise and sometimes glucose-lowering drugs. Weight loss by those with excess fat stores can be beneficial. As persons with this type of diabetes age, they sometimes require insulin replacement, but their disease is still classified as a type 2 diabetes. The list of mutations that phenotype as type 2 diabetes is quite large and includes mutations in the genes for the glucose carriers, the insulin molecule, the insulin receptor and the insulin release mechanism (Awata et al. 1997 , Bell et al. 1996, Chiu et al. 1993 , Kahn and Halban 1997 , Matschinsky et al. 1993, Stoffel et al. 1992 , Velho et al. 1997 ). Mutations in genes that encode some of the enzymes required for glucose metabolism as well as mutations in the genes that encode components of the food intake regulatory system can also phenotype as diabetes. People with type 2 diabetes comprise 90% of the population with the disease. Cardiovascular disease is not an uncommon secondary feature of this disease.

Obesity and diabetes together have been termed diabesity. In some of the phenotypes, the development of obesity and diabetes is concurrent. Sometimes the obesity precedes diabetes and weight loss will normalize glucose homeostasis. In other forms, renal disease and diabetes development occur concurrently. The same may also be true for heart disease and diabetes. Likely there are common genetic threads that can explain these developments.

As mentioned, diabetes is a genetic disease. Its transmission varies depending on the mutation involved. In animal models (mice, rats), transmission can be dominant, recessive, sex-linked or maternal. It is suspected that as much variation in transmission will be found in the human population as well. What is known is that in the human population, the inheritance of type 1 diabetes is less strong than that for type 2. Studies of twins have shown that if one twin develops type 1 diabetes, the other twin has a 60% chance of developing the disease. In contrast, with type 2 diabetes, if one twin develops diabetes, the other has a 100% chance of developing the disease (Newman et al. 1987 , Vanheim and Rotter 1992 ). The only exception to this is when the diabetes is due to mutation in the mitochondrial (mt)³genome. Mitochondrial diabetes is inherited as a maternal trait because the mtDNA comes from the mother (Giles et al. 1980 ). Very little mtDNA is contributed by the father because the mitochondria in the sperm are located in the tail. At fertilization, the sperm mt disappears. In twins, the lack of concordance results from the uneven division of the mitochondria at meiosis in the fertilized egg, which subdivides into identical twins; one twin might develop mt diabetes, whereas the other might not. The phenotype depends on how many mutated mitochondria are present (Alcolado and Alcolado 1991 , Alcolado et al. 1994 , Alcolado and Thomas 1995 , Gerbitz et al. 1996 , Isshiki 1997 ). Mitochondrial diabetes accounts for 10% of the type 2 population (Gerbitz et al. 1995 and 1996 , Ghosh and Schork 1996 , Maassen and Kadowaki 1996 , Mathews and Berdanier 1998 , Wallace 1989 and 1992 ). It is due to one or more base substitutions in the mt genome and is characterized by a fatty liver, aberrant mt function, aberrant metabolic control and sometimes sensory losses. People with mt diabetes are seldom obese. They might have slightly less than normal muscle mass and slightly more fat mass but do not have a large excess of fat. Mutations in the mt genome may result in acute lethal disease that has the secondary feature of elevated lactate levels and impaired glucose homeostasis. Whether the individual develops this acute condition or diabetes (or both) depends on the degree of heteroplasmy (the proportion of mutated to nonmutated DNA copies in the mitochondria); this is termed the gene dosage effect. Cells differ in the number of mitochondria. Each mitochondrion has 8–10 copies of the genome. Heteroplasmy occurs when some of the copies are mutated and some are not.

There are many animal analogs of human diabetes. Monkeys, rabbits, gerbils, desert animals, hamsters, and laboratory mice and rats have been used to study the disease (Goto and Kanazawa 1991 , Shafrir 1991 ). Each of them has a particular genetic signature that allows researchers to study the disease as it appears in humans. All of the forms of diabetes are characterized by aberrations in metabolic control. Some are quite subtle, whereas others are more obvious. As mentioned, the prevalence of diabetes genotypes is greater than that of diabetes phenotypes. The question that arises is how this could occur. The observation that fat store reduction could improve glucose utilization suggests that nutrition and exercise could determine whether the phenotype would be expressed. Thus, one could think of diabetes, especially type 2 diabetes, as a disease that arises as a response to an interaction among diet, exercise and the genetic background of the individual. With this in mind then, one could suggest that if one knew his or her genotype, one could choose appropriate foods and activities that would delay the development of diabetes and its complications. Unfortunately, the technology is not yet available to screen people for the many mutations that phenotype as diabetes.

Food choice influences metabolic control; this in turn has long-lasting effects on glucose homeostasis. In this review on metabolic control and diabetes, the focus has been placed on the role of the mitochondrial genome in determining the response to diet variables. The review summarizes work with BHE/Cdb rats, which have a mitochondrial mutation in a place similar to one that occurs in the human (Mathews et al. 1995 ). Both species have aberrant metabolic control, aberrant mt function, impaired glucose homeostasis and elevated blood lactate levels. Neither is obese. In both species, the diabetic trait is maternally inherited (Gebhart et al. 1996 , Gerbitz et al. 1996 , Kadowaki et al. 1993, Mathews et al. 1999 , Reardon et al. 1992 , van den Ouweland et al. 1992, Velho et al. 1996 ).

	Aberrations in metabolic control due to mtDNA mutation

TOP ABSTRACT INTRODUCTION Aberrations in metabolic control... Metabolic control exerted by... OXPHOS structure and function Mitochondrial DNA Mitochondrial DNA transcription Other factors that influence... Perspectives REFERENCES

 
Metabolic regulation is defined as the sum of all those processes and reactions designed to provide a continuous supply of substrates for the maintenance of life. It includes both catabolic and anabolic processes and both energy-consuming and energy-producing reaction sequences. Living organisms must interdigitate these pathways so that they can survive in times of energy deficits and surpluses. Central to this interdigitation or control is the provision of the high energy compound, ATP. ATP can be produced via substrate phosphorylation but most of it is synthesized in the mitochondria. It is synthesized by the F₁F_oATPase. Working together, the respiratory chain and the ATPase comprise the process called oxidative phosphorylation (OXPHOS). The F₁F₀ATPase of OXPHOS captures the energy released through the synthesis of water by the respiratory chain and uses it to make the high energy bond of ATP. This ATPase joins inorganic phosphate (Pi) to ADP using the energy generated by the respiratory chain.

The activity of OXPHOS is controlled by a number of factors (Boyer 1989 , Brown et al. 1990 , Brown 1992 , Davis and Davis-Van Thienen 1984 , Owen and Wilson 1971 ). Among the more important rate controllers is the provision of ADP, Pi and reducing equivalents. Reducing equivalents are available within the mitochondrial compartment as products of fatty acid oxidation as well as the oxidation of other metabolites. The oxidation of amino acids and glucose in the cytosol provides reducing equivalents; these are transported into the mitochondrial compartment by one of several shuttle systems. The glycophosphate shuttle, the malate-aspartate shuttle and the malate-citrate shuttle are important systems for this reducing equivalent transfer.

In fact, respiration itself is not controlled by the reducing equivalent transfer but rather by the phosphorylation state of the mitochondrial compartment. That is, the influx of ADP will stimulate the respiratory chain and in turn will stimulate ATP synthesis. Thus, the influx of ADP is a rate controller for OXPHOS. The adenine nucleotide transporter serves to exchange ADP for ATP. This transporter is located in the inner mt membrane. Also important is the H⁺/Pi symporter and the Pi/OH^- antiporter that provide the needed Pi. There is, in addition, a creatine phosphate shuttle located in the outer mt membrane. All of these influence the availability of ADP and Pi for phosphorylation to ATP by the F₁F₀ATPase.

OXPHOS is also influenced by the metabolic state of the animal, which in turn is nutritionally responsive (Berdanier 1993 ). Starving animals or those in a catabolic state have increased rates of fatty acid oxidation as well as decreased rates of anabolic metabolism. This changes the metabolic mixture of fuels being metabolized, thus altering the flow and source of reducing equivalents available to the respiratory chain. Less ATP is synthesized and less is used in the cytosol to support anabolic processes. The composition of the diet can also influence OXPHOS (Kim and Berdanier 1998 ). Diets that alter the anabolic/catabolic processes will affect OXPHOS. For example, a protein-deficient diet in which there is ample carbohydrate but little fat and protein will mean that glycolysis is stimulated as is lipogenesis and fatty acid oxidation and yet, because of the protein deficiency, little protein synthesis (compared with well-nourished individuals) will occur. ATP synthesis will rise initially but then fall as the protein status deteriorates.

The type and amount of dietary fat will also affect OXPHOS. Diets containing polyunsaturated fatty acids (PUFA) will improve the efficiency with which the mitochondria synthesize ATP. That is, these diets will increase the ease with which the energy liberated by the respiratory chain can be captured in the high energy bond of ATP.

	Metabolic control exerted by the mitochondria

TOP ABSTRACT INTRODUCTION Aberrations in metabolic control... Metabolic control exerted by... OXPHOS structure and function Mitochondrial DNA Mitochondrial DNA transcription Other factors that influence... Perspectives REFERENCES

 
The synthesis of ATP and the ratio of ATP to ADP and ATP to ADP + AMP (the phosphorylation state) have metabolic control properties. A number of enzymes are activated or inactivated depending on the phosphorylation state of the compartment in which they exist. In general, when the phosphorylation state of the cytosol is high, lipogenesis as well as other anabolic reaction pathways are active. When the phosphorylation state is low, catabolic pathways are active. Hence, actively respiring ATP-synthesizing mitochondria are associated with cells that have active ongoing metabolic pathways. Any pathway that requires substantial ATP for its function will, of necessity, be less active should there be a shortfall of ATP. An example would be protein synthesis. If there is a shortfall of ATP, then protein synthesis will not be as active as when such a shortfall does not exist. Thus, the malnourished child grows poorly because the child does not consume enough food to provide the substrates for oxidation that in turn provide the reducing equivalents to make water and generate ATP. This, in addition to a shortage of amino acids required to synthesize new protein, creates a shortfall of ATP and protein synthesis is reduced.

Another example is the large requirement for ATP to support work. As muscles contract, ATP is needed. Fortunately, muscle fibers have large numbers of mitochondria that provide these contracting fibers with ATP. Should a shortfall of ATP synthesis occur, the individual fibers will fail to contract and subsequently deteriorate. Such is the case in diseases due to mutations in the mt genome that phenotype as myopathy, not only of the heart muscle but the skeletal muscle as well. In this example, there are mutations in the genome that result in an aberrant gene product, which in turn is an essential protein for OXPHOS. OXPHOS is impaired because one or more of the subunits of the respiratory chain or the F₁F₀ATPase are aberrant in function and thus insufficient amounts of ATP are made. Just as base substitutions and deletions in the nuclear genome can result in disease, so too does this occur in the mt genome. The list of diseases that are the result of mtDNA mutation is small compared with those of nuclear origin. Included in this list is type 2 diabetes mellitus as well as a number of diseases that are characterized by losses in central nervous system (CNS) function, structural defects in the skeletal and cardiac muscle, and sensory losses (hearing and vision). These losses can be explained by the dependence of the involved cells on ATP production. For example, the CNS requires substantial ATP for the transmission of impulses along the neural pathways. If mitochondrial function is markedly impaired through a mtDNA mutation affecting OXPHOS, ATP production will be reduced. Hence, the phenotypic features of such a mutation will include neural degeneration and losses in metabolic control. Elevated lactate levels are usually indicative of such losses. Glycolysis slows down and the end product of glycolysis, pyruvate, is converted to lactate. The redox state of the cytosol rises and mitochondrial ATP synthesizing efficiency falls. As mentioned, type 2 diabetes mellitus can result from mtDNA mutation (Alcolado and Thomas 1995 , Gerbitz et al. 1996 , Mathews and Berdanier 1998 , Matschinsky 1996 , Wallace 1992 ). In addition to the impairment in glucose metabolism due to an impairment in mt metabolism, islet cells require significant amounts of ATP for insulin synthesis and release (Malaisse 1992 ). Impaired mt metabolism thus affects the responsiveness of the insulin-producing cells to a glucose stimulus (Liang et al. 1994 , Matschinsky 1996 ). Thus, individuals with mt gene mutations or nuclear mutations that affect the structure and function of the components of OXPHOS will phenotype as diabetes. Because the initial problem is subtle, the initial diagnosis is type 2 diabetes; with age and subsequent deterioration in islet cell function, however, the disease may progress such that insulin replacement is required for the management of glucose homeostasis. Unfortunately, because of the mt problem, glucose homeostasis cannot be fully normalized. Elevated lactate levels as well as some of the secondary features of diabetes (e.g., renal disease or blindness) may still develop because the basic problem resides with OXPHOS rather than simply the production of insulin.

	OXPHOS structure and function

TOP ABSTRACT INTRODUCTION Aberrations in metabolic control... Metabolic control exerted by... OXPHOS structure and function Mitochondrial DNA Mitochondrial DNA transcription Other factors that influence... Perspectives REFERENCES

 
Over the years, the various components of OXPHOS have been isolated and studied intensively. Their assembly within the inner mt membrane and matrix has been described and modeled (Capaldi 1982 , Engelbrecht and Junge 1997 , Pedersen 1996 , Schwerzmann and Pedersen 1986 , Thomas et al. 1992 , and others). One such model is shown in Figure 1 . OXPHOS is comprised of five complexes. Four of these contain subunits encoded by the mt genome. Complex I consists of all of the NAD-linked reactions of the respiratory chain. Seven of its subunits are encoded by mtDNA. It is linked to Complex II by an iron-sulfur center. Complex II consists of all of the FAD-linked reactions that donate electrons to the respiratory chain via ubiquinone. Reducing equivalents can enter the respiratory chain through either Complex I or II. These complexes are linked to the next complex (Complex III) by another iron-sulfur center. Complex III consists of cytochrome b562, b566 and is linked by an iron-sulfur group to cytochrome C₁ for electron transfer. Three of its subunits are encoded by the mt genome. Complex IV consists of the cytochromes a to a₃. One of these proteins is encoded by the mt DNA.

View larger version (48K): [in this window] [in a new window]   Figure 1. Representation of the arrangement of the respiratory chain and the F1F0ATPase of the oxidative phosphorylation (OXPHOS) system. The mitochondrially encoded subunits are shown in ???. This system is embedded in the inner mitochondrial membrane with the F1 portion of the ATPase projecting out into the matrix.

The proteins in the F₀ are largely hydrophobic. The F₀ consists not only of subunit a and b but also includes parts of the stalk as listed above. Subunit a of the F₀ is encoded by the mt genome. This genome also encodes the A6L (F₆) subunit. These are referred to as the mtATPase 6 and 8 gene products, respectively.

As the F₁F₀ATPase catalyzes the synthesis of ATP, it moves or rotates around its stalk (Cross and Duncan 1996 , Pedersen 1996 ). The motion of the F₀ may be impeded by a relatively less fluid membrane; conversely, it may be enhanced by a very fluid membrane. Hence its activity is dependent on the fluidity of the membrane in which it rotates. This is the basis for the effect of dietary fat on OXPHOS. The lipids of the inner mt membrane provide the environment for the F₀ATPase, and these lipids are affected by the composition of the fat in the diet.

The movement of the F₀ can be constrained not only by the fluidity of the lipid that surrounds it but also by its genetically determined conformation. In diabetes-prone BHE/Cdb rats, there are two base substitutions in the mtATPase 6 gene that encodes the F₀ subunit a (Mathews et al. 1995 , Herrnstad, personal communication). One of these is at bp 8204 and affects the proton channel, reducing the efficiency with which the F₀ can capture the energy of the respiratory change and transmit it to the F₁ for ATP synthesis. The other base substitution occurs at bp 8289 and changes the amino acid sequence at position 129 in the protein structure. Using molecular modeling techniques, one would predict that the 8289 mutation would change the amino acid loop to a pleated sheet (Garnier et al. 1978 ). This change in protein structure would probably confer a degree of rigidity to this portion of the molecule. Because molecular mobility is essential to ATPase function, this small change in protein structure could have effects on function given a change in the fluidity of the lipid environment. Indeed, such has been observed (Kim and Berdanier 1998 ). When diabetes-prone BHE/Cdb rats were compared with Sprague-Dawley rats without ATPase base substitutions, there was a marked change in mitochondrial function when these two groups were fed hydrogenated coconut oil. Other groups of rats were fed either corn oil or menhaden oil. The coconut oil produced a less fluid inner mitochondrial membrane; when combined with the mitochondrial mutation, OXPHOS efficiency was reduced. Shown in Figures 2 and 3 are the results of this study. Note the loss in respiratory control (the ratio of state 3 respiration to state 4 respiration) in rats fed the hydrogenated coconut oil. There were also diet and strain differences in the transition temperatures as well as OXPHOS. The Arhennius plots (Fig. 3) show that break points occurred in the temperature-dependent succinate-supported state 3 respiration and that these breakpoints were determined not only by the saturation of the dietary fat but also by the strain of rat.

View larger version (25K): [in this window] [in a new window]   Figure 2. Succinate-supported respiration by isolated hepatic mitochondria from BHE/Cdb and Sprague-Dawley (SD) rats fed 6% corn oil (CO), menhaden oil (MO) or hydrogenated coconut oil (HCO). State 3 and state 4 respiration = nmol oxygen consumed/(mg mitochondrial protein · min). Respiratory control ratio (RC) = state 3 respiration rate/state 4 respiration rate; this is a measure of the quality of the mitochondrial preparation. Data are from Kim and Berdanier (1998) .

View larger version (16K): [in this window] [in a new window]   Figure 3. Arrhenius plots of the temperature dependence of succinate-supported state 3 respiration. Mitochondria were from BHE/Cdb and Sprague-Dawley rats fed 6% menhaden oil, corn oil or hydrogenated coconut oil. This figure is used with permission from Kim and Berdanier (1998) .

	Mitochondrial DNA

TOP ABSTRACT INTRODUCTION Aberrations in metabolic control... Metabolic control exerted by... OXPHOS structure and function Mitochondrial DNA Mitochondrial DNA transcription Other factors that influence... Perspectives REFERENCES

 
In contrast to the nuclear genome, the mt genome has been completely sequenced and mapped for a number of species (Anderson et al. 1981 , Britten and Kohne 1968 , Cantatore and Attardi 1980 , Gadaleta et al. 1989 , Monnat and Reay 1986 , Walker et al. 1987a and 1987b ). Although the nuclear genome is linear, the mt genome is circular. The mt genome encodes 13 of the 78 proteins that comprise OXPHOS. This genome has some unique characteristics that stem from its origin as a component of early single-cell organisms. Shown in Figure 4 is the human mtDNA with each of the components labeled. Species differ in the number of bases that comprise this DNA, but the map of this genome is consistent from species to species. The size of the genome in rats is 16,298 bp, whereas in humans it is 16,569 bp. The mt DNA encodes 22 tRNAs, 2 ribosomal RNAs and 13 structural genes. These include seven subunits of Complex I (ND1-ND5 + ND4L), one unit of Complex II (cyt b), three units of Complex IV (CO I-IV) and two units of Complex V, the F₁F₀ATPase (ATPase 6 and 8). Approximately 6% of the bases are noncoding. Of these, 97% are located in the two controller regions, the 30-bp origin of replication for the light strand (O_L) and the 898-bp unit called the displacement loop or D-loop.

View larger version (62K): [in this window] [in a new window]   Figure 4. The human mitochondrial (mt) genome with the various structural genes indicated.

Structural genes are located on both strands of the DNA. The heavy strand is the main coding strand. In this strand are the codes for 2 rRNAs, 14 tRNAs and 12 structural genes. The light strand codes for 8 tRNAs and one of the NADH dehydrogenase subunits (ND6). There is great economy in the mt DNA in that there are very few noncoding bases outside of the D-loop. In fact, there is some overlapping of bases. In six instances, there are genes that share coding nucleotides. In half of these, the bases are not really shared. They are used by genes in the light and heavy strands such that the shared bases are on the 3' ends of both genes. In the other half of the shared bases, the shared bases are actually shifts in the reading frames to allow the same nucleotides to code for two different proteins. The genes that share nucleotides include the ATPase 6 and 8 genes. These genes share 52 bp. The ND4 and ND4L genes share 7 bp; the ND 5 and ND6 genes share 31 bp. Other base pair share partners are the tRNA^ser(agn) and tRNA^leu, which share 1 bp, tRNA^ser(unc) and COI share 4 bp and tRNA^gln and tRNA^ile share 3 bp.

The initiator codon of each reading frame (AUG, AUA, AUU or AUC) follows immediately after the 3' termination sequence of its upstream neighbor. In a few instances, there are only a few bases that separate the initiation codon from the termination codon. In other instances, there are no bases to separate the two codons. Most reading frames lack termination codons and code a T or TA only after the last sense codon. Completion of the termination codon occurs at the time of RNA processing by polyadenylation. Transfer removal from the primary transcripts causes the production of both tRNA species themselves as well as mature mRNAs.

	Mitochondrial DNA transcription

TOP ABSTRACT INTRODUCTION Aberrations in metabolic control... Metabolic control exerted by... OXPHOS structure and function Mitochondrial DNA Mitochondrial DNA transcription Other factors that influence... Perspectives REFERENCES

 
Transcription of the mtDNA is symmetrical and is initiated within the D-loop (Aloni and Attardi 1971 , Cantatore and Attardi 1980 , Montoya et al. 1982 and 1983 , Walberg and Clayton 1983 ). The light strand moves clockwise, whereas the heavy strand moves counterclockwise. The heavy strand is transcribed as two polycistrons. There are three promoters of transcription and two widely spaced origins of replication, one for each strand (Bogenhagen et al. 1984 , Chang and Clayton 1984 , 1986a and 1986b , Chang et al. 1986 , Hixson and Clayton 1985 , Topper and Clayton 1989 . Light-strand transcription is 2–3 times greater than heavy-strand transcription, but the half-lives of the transcripts are significantly shorter than those of the heavy-strand transcripts. There are two main promoters that function independently (one for each strand) and these are separated by 90 nucleotides. There is a third promoter coupled with a transcription termination factor located downstream from the 16S rRNA in the tRNA^leu(uur) (Chang and Clayton 1984 , Chang et al. 1986 , Hixson and Clayton 1985 ).

Nuclear encoded proteins are essential to mt gene expression. The regulation of transcription by nuclear encoded proteins is only now being explored. The mt transcription factor A (mtTFA) as well as the mt transcription termination factor (mtTERF) have been known for some time (Fisher and Clayton 1985 and 1988 , Fisher et al. 1987, Kruse et al. 1989 ). Initiation of transcription involves mtTFA, whereas termination on the heavy strand involves mtTERF. There is also a nonselective RNA polymerase that may be involved. In vitro studies have shown that mtTFA binds to the promoter regions in each strand. It also binds to a region in between the two conserved sequence blocks and condenses, unwinds and bends the DNA (Fisher et al. 1992 ). In addition, in vitro, more mtTFA is required to promote heavy-strand transcription than light-strand transcription, suggesting that low levels of mtTFA may result in the activation of the light strand and be involved in replication (Larsson et al. 1994 , Poulton et al. 1994 ). This is supported by the observation that mtTFA protein levels are correlated with mtDNA copy number (Larsson et al. 1998 , Montoya et al. 1997 ).

Transgenic technology has provided us with further evidence for the role of mtTFA in transcription and replication (Larsson et al. 1998 , Montoya et al. 1997 ). First, overexpression of mtDNA in HeLa cell mitochondria has been shown to increase transcription. Second, heterozygous m-mTFA (also called tfam) knockout mice were shown to have reduced mtDNA copy number in heart, kidney and liver, reduced mitochondrial transcription in these tissues and reduced OXPHOS. If the gene was completely absent, this absence was lethal. Thus, there are no homozygous knockout mice. The tissue response in the heterozygous mice was not identical. Although respiratory chain activity was reduced, there was no reduction in the amount of ATPase 8 gene product (F₀ subunit F₆) and no reduction in cytochrome c oxidase subunit II in all of the tissues examined. These observations, together with the results of the in vitro cell studies, support the concept that the mtTFA is essential for mitochondrial replication primed from the light-strand promoter, but is not solely responsible for regulating heavy-strand transcription. It is altogether likely that mt transcription depends on other transcription factors as well.

Nuclear hormone receptors may directly regulate mitochondrial transcription. Figure 5 shows where putative glucocorticoid (GRE), vitamin D (VDRE), thyroid (TRE) and retinoic acid (RARE) response elements have been found in the D-loop (Demonacos et al. 1996 ). The presence of these response elements suggests that the essential nutrients, vitamin D and vitamin A, might play a role in mitochondrial gene expression. Preliminary studies in our laboratories have shown this to be true with respect to vitamin A (Everts and Berdanier 1999 ). We have found retinoic acid receptors in the mitochondrial compartment (unpublished observations) and have also shown that increasing the vitamin A content of the diet to three times the NRC recommended amount improved the OXPHOS activity of BHE/Cdb rats (Everts and Berdanier 1999 ). A dose-response feeding study revealed that BHE/Cdb rats required significantly more vitamin A than do normal rats. An earlier longevity study using whole egg as the source of fat and protein also provided this same amount of vitamin A, and this study showed that gluconeogenesis was downregulated and impaired glucose tolerance delayed (Berdanier et al. 1998 ). Here is another example of a nutrient affecting mitochondrial activity; in this instance, however, the effect is a genomic one. That is, retinoic acid appears to affect the expression of the ATPase 6 gene product as well as some of the other gene products with the net result of an improved OXPHOS function and metabolic control.

View larger version (27K): [in this window] [in a new window]   Figure 5. Putative glucocorticoid (GRE), vitamin A (RARE), thyroid hormone (TRE) and vitamin D (VDRE) response elements found in the D-loop of the mitochondrial (mt) genome.

	Other factors that influence OXPHOS

TOP ABSTRACT INTRODUCTION Aberrations in metabolic control... Metabolic control exerted by... OXPHOS structure and function Mitochondrial DNA Mitochondrial DNA transcription Other factors that influence... Perspectives REFERENCES

 
As discussed above, genetics and dietary factors can influence mt function. However, these are not the only factors that can affect mt metabolism. Several reports in the literature have shown that mt metabolism decreases with age (Berdanier and McNamara 1980 , Wei and Kao 1996 ). OXPHOS efficiency as well as respiratory chain activity declines. The reasons for this decline include the hypothesis that age-related increases in saturated fatty acids in the inner mt membrane affect its fluidity and OXPHOS efficiency. However, another school of thought concerns the possibility that there are accumulated mutations in the mtDNA with age, resulting from free radical–induced damage (Corral-Debrinski et al. 1991 , Eimon et al. 1996 , Hagen et al. 1997 , Kao et al. 1997 , Lee et al. 1997 Loft et al. 1994 , Shigenaga et al. 1994 , Wei 1992 and 1998 , Wei and Kao 1996 , Yakes and Van Houten 1997 , Yen et al. 1991 , 1992 , Zhang et al. 1998 ). Mitochondria use 90% of all oxygen used by the cell. These organelles are the most important sources of superoxides; because of their proximity, they are also the most likely targets of attack. Free radicals not only attack nearby fatty acids but also nearby DNA, as well as nearby proteins. As a side note, it should be mentioned that mtDNA is naked. That is, it has no protective histone coat. It also has limited repair capability. Some of the free radicals are generated in the intermembrane space and some in the matrix (Byrne et al. 1999 , Chance et al. 1979 , Dawson et al. 1993 , Gores et al. 1989 , Nieminen et al. 1997 ). When generated in the inner membrane space, they can migrate to the matrix readily. There they are scavenged not only by the superoxide dismutase (SOD) but also by cytochrome c. In addition, SOD can migrate to the inner membrane space for the purpose of scavenging superoxides. Although all of these reactions serve to minimize free radical damage, some damage does occur. Clearly, the evidence of an age-related increase in damage as well as a decrease in OXPHOS efficiency suggests that this damage is cumulative. Possibly one of the reasons this occurs is that deleted mtDNA can replicate itself faster than can DNA of normal length. Thus, there is not only the random damage inflicted by the free radicals but also the fact that this shorter DNA replicates more quickly. Because mtDNA turns over more quickly than do the cells that contain it, these two events together can explain in part the age-related increase in mtDNA deletion mutation.

Wei (1992 and 1998) and Wei and Kao (1996) reported an age-related increase in mtDNA mutation and linked this increase to an increase in mt lipoperoxides and mt manganese SOD activity. Whether free radical damage could account for the age-related diseases associated with mt malfunction has yet to be proven. There are so many mitochondria in each cell, with 8–10 copies of the genome in each mitochondrion, that a single free radical damage event would have very little effect on mt function as a whole. However, with time, this damage accumulates and it has been thought that this accumulated damage could explain the age-related decline in OXPHOS. Could this be related to the diabetes that develops in the elderly? We do not know. Studies on this aspect of mt metabolism and diabetes development are warranted.

One of the more common deletions occurs at bp 4977. Muscle, a tissue that has a longer turnover time than liver, shows a higher frequency of mt deletions at this location than does liver or testis (Wei and Kao 1996 ). Wallace and co-workers (Corral-Debrinski et al. 1991 ) reported that people dying of cardiovascular disease have more deletion mutations at this location than age- and sex-matched people dying from accidents or other nondegenerative causes. This location is very vulnerable because it is a region of direct repeats. For some reason, areas of direct repeats are more labile than regions without these repeats.

Diet can affect the formation of free radicals. Antioxidant vitamins as well as other nutrients have a protective effect with respect to free radical suppression. Vitamin E, ascorbic acid, and some of the minerals and carotenes serve in this capacity. In addition, the composition of the fat component of the diet will affect free radical generation. Diets rich in PUFA will result in larger amounts of free radicals in selected tissues. Some of these fatty acids will be incorporated into the mt membranes and, as discussed above, can be subject to free radical attack. Long-chain unsaturated fatty acids such as those found in marine oils increase the tissue content of peroxides (Wickwire et al. 1995 ). Studies with BHE/Cdb rats have shown beneficial effects of short-term feeding of menhaden oil vis à vis OXPHOS (Kim and Berdanier 1989 ) but with long-term feeding, the opposite effects have been shown (Berdanier et al. 1992 ). Aging in these rats appeared to be accelerated when the fish oil was fed. When beef tallow was fed, rats lived longer and were healthier compared with the fish oil–fed rats. In this instance, it would appear that short-term benefits (improved OXPHOS efficiency) were derived because of the diet effect on membrane fluidity. In contrast, the long-term result of decreased lifespan was due to accumulated free radical damage to vital tissues such as the kidneys, irrespective of the lipid effect on OXPHOS.

	Perspectives

TOP ABSTRACT INTRODUCTION Aberrations in metabolic control... Metabolic control exerted by... OXPHOS structure and function Mitochondrial DNA Mitochondrial DNA transcription Other factors that influence... Perspectives REFERENCES

 
This is a new era in research on the interaction of nutrients and genes. Although many nutrients have been shown to influence the expression of a wide variety of nuclear genes, few studies have been devoted to the study of nutrient effects on mt gene expression. Much has been learned about the mt genome, but its transcription and translation have not been well studied with respect to whether and how specific nutrients can affect these processes. We are gathering information about mt gene expression with respect to disease development. Initially, the list of mt genomic diseases was very short. It included those diseases that were acute and lethal. Now, however, with a better understanding of how mt activity is controlled and how its activity is related to some of the degenerative diseases such as diabetes and heart disease, we are gaining a new appreciation for the interactions that occur among genetics, diet and mitochondrial function.

	FOOTNOTES

 
¹ Presented at the symposium, Nutritional and Metabolic Diversity: Understanding the Basis of Biologic Variance in the Obesity/Diabetes/Cardiovascular Disease Connection, given at Experimental Biology 2000, April 15–19, 2000 in San Diego, CA. This symposium was sponsored by the American Society for Nutritional Sciences and was supported by an educational grant from Dairy Management, Incorporated. The proceedings of this conference are published as a supplement to The Journal of Nutrition. Guest editors for the supplement publication were Brian W. Tobin, Mercer University School of Medicine, Macon, GA and Gregory D. Miller, Dairy Management, Incorporated, Rosemont, IL.

² Supported by grants from U.S. Department of Agriculture, Mitokor, National Institutes of Health, the U.S. Poultry and Egg Board, USDC, The Cattlemans Association, The UGA Diabetes Research Fund, The Bly Fund and the Georgia Agricultural Experiment Station.

³ Abbreviations used: CNS, central nervous system; DHEA, dehydroepiandrosterone; GRE, glucocorticoid response element; LSP, light-strand transcription; mt, mitochondrial; mtTERF, mt transcription termination factor; mtTFA, mt transcription factor A; OXPHOS, oxidative phosphorylation; Pi, inorganic phosphate; PUFA, polyunsaturated fatty acids; RARE, retinoic acid response element; SOD, superoxide dismutase; T₃, triiodothyronine; TRE, thyroid response element; VDRE, vitamin D response element.

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