DALE SEXO A TUS MITOCONDRIAS. CICLALAS DE INVIERNO A OTOÑO. VIVIRAS MIL AÑOS. COMO UNA PANTERA NEGRA. NO HAGAS DIETA. VIVE PALEO.

Annu Rev Genet. 2005; 39: 359. doi:  10.1146/annurev.genet.39.110304.095751

PMCID: PMC2821041

NIHMSID: NIHMS5688

SEGUNA TU GENETICA, TUS MITOCONDRIAS NECESITAN TEMPORADAS DE SOLO GRASA Y PROTEINAS. LA KETOADAPTACION PRODUCE ATP SIN TANTOS RADICALES LIBRES COMO LA PRODUCCION DE ENERGIA A PARTIR DE LAS CARBODROGAS.
NO HAGAS DIETA. VIVE PALEO.

A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

Mitochondrial Defects in Diabetes

mtDNA tRNA^Ile mutation at np 4291 (T > C) that causes hypertension, hyperc-holesterolemia, and hypomagnesemia (renal ductal convoluted tubule defect).

MITOCHONDRIAL ADAPTATION AND EVOLUTIONARY MEDICINE

The Interplay between Environment and Energetics

These considerations indicate that mitochondria lie at the intersection between environmental factors such as calories and cold and the human capacity to energetically cope with the environmental challenges in different regions of the globe. Our ancient ancestors had to be able to adapt to two classes of environmental changes: (a) short term changes in calories and climate associated with seasonal variation and (b) long term changes in the nature of calories and average annual temperatures defined by the latitude and geographic zone in which they lived.

The need to adapt energetically to seasonal changes is a challenge common to all mammals, including aboriginal human populations. For populations that lived in the colder temperate and arctic zones, people needed to be able to uncouple mitochondrial OXPHOS in both BAT and muscle by induction of the UCPs. However, in industrial societies, most individuals avoid cold stress through central heating. Similarly, most ancient populations had to accumulate plant carbohydrate calories and store them as fat during the plant growing season and then to efficiently use the stored fat calories to sustain their cellular energetics when the plants were dormant. This season variation in caloric availability was metabolically managed via the insulin signaling network that coordinately integrated the energy-utilization, energy-storage, and energy-homeostasis tissues, through the hormonal signals of the energy-sensing tissues, the pancreatic α and β cells. This was accomplished by cueing the energy-sensing tissues to serum glucose concentration that oscillated based on the availability of plant carbohydrate calories. When plant calories were abundant, blood sugar was high, insulin was secreted, mitochondrial OXPHOS and its attendant antioxidant defenses were down-regulated in the energy-utilization tissues, and the excess carbohydrate calories were stored as fat in energy-storage tissues. When plant calories declined at the end of the growing season, blood sugar levels declined, resulting in decreased insulin secretion and increased glucagon secretion. These hormonal changes up-regulated mitochondrial OXPHOS and the attendant antioxidant defenses in the energy-utilization tissues, mobilized the stored fats in the energy-storage tissues for use as mitochondrial fuel, and activated glucose synthesis in the energy-homeostasis liver to sustain minimal blood sugar levels.

This energetic system worked well for out ancestors who lived in an environment of periodic carbohydrate surplus and deficiency. However, in today’s developed societies, technology provides us with unlimited dietary calories including carbohydrates throughout the year. As a result, our energy signaling system remains continuously in the high carbohydrate state. Consequently, mitochondrial OXPHOS and its attendant antioxidant defenses are chronically down-regulated. At the same time, our sedentary life style means that we do not turnover ATP through sustained physical activity. Therefore, the excess of caloric reducing equivalents in our diet leads to fat accumulation and obesity and keeps the mitochondrial electron carriers of our down-regulated ETC fully reduced. This results in chronically increased mitochondrial ROS production, which damages the mitochondria and mtDNAs. The reduced mitochondrial energy output and the increased oxidative stress sensitize the mtPTP to activation, driving post-mitotic cells into premature apoptosis. The resulting loss of post-mitotic cells results in the tissue-specific symptoms associated with aging and the age-related diseases.

 ... The importance of mitochondrial defects in β cell insulin secretion deficiency has been confirmed in two mouse models. In the first, the mitochondrial transcription factor Tfam was inactivated in the pancreatic β cells. This resulted in increased blood glucose in both fasting and nonfasting states, and the progressive decline in β cell mass by apoptosis (201). In the second, the ATP-dependent K⁺-channel (K_ATP) affinity for ATP was reduced, resulting in a severe reduction in serum insulin, severe hyperglycemic with hypoinsulinemia, and elevated D-3-hydroxybutyrate levels (102). These models demonstrate that mitochondrial ATP production is critical in the signaling system of the β cell to permit insulin release (238). Thus pancreatic β cell mitochondrial defects are important in both glucose sensing through glucokinase and insulin release through the K_ATP channel.

For our hunter-gather ancestors, the primary variation in available dietary calories was due to the cyclic growing seasons of edible plants caused by either warm versus cold or wet versus dry seasons. During the growing season, plants convert the Sun’s energy into glucose, which the plants store as starch. When humans and animals ingest these plant tissues the concentration of glucose in their blood rises. Hence, serum glucose is the metabolic surrogate for monitoring plant calorie abundance.

When plant calories are abundant and consumed, the elevated serum glucose is detected by the energy-sensing pancreatic β cells, which respond by secreting insulin into the blood stream. The insulin signal then informs the energy-utilizing heart and muscle tissues to down-regulate mitochondrial energy utilization, since food-seeking behavior is less pressing. It also informs the energy-storing WAT and BAT tissues to store the excess calories as fat for when the season changes and plant calories again become limiting. When plant calories do become limited, insulin secretion declines and the pancreatic α cells secrete glucagon. These low blood sugar hormonal signals inform the energy-utilization tissues to up-regulate the mitochondrial OXPHOS system, thus enhancing food-seeking capacity. They also mobilize the energy-storage tissues to transfer the stored triglycerides into the blood to fuel the increased mitochondria OXPHOS. Furthermore, low blood glucose stimulates the energy-homeostasis tissue, liver, to synthesis glucose to maintain the basal level of blood sugar, which is particularly critical for brain metabolism. The molecular basis of this primeval system for adapting to energy fluctuation can now be partially understood through recent discoveries pertaining to the transcriptional regulation of mitochondrial gene expression.

 In the β cells, the excessive mitochondria ROS inhibits mitochondrial ATP production, eventually leading to a decline in insulin secretion due to inadequate ATP for glucokinase and a low ATP/ADP ratio that cannot activate the K_ATP channel. The resulting high glucose but reduced serum insulin is termed insulin-independent diabetes. Continued calorie overload in the pancreatic β cells and associated mitochondrial ROS production ultimately activates the β cell mtPTP, resulting in β cell death by apoptosis, producing insulin-dependent diabetes.

High carbohydrate diets stimulate insulin secretion that phosphorylates the FOXOs, removing them from the nucleus. This down-regulates the cellular stress-response pathways including the mitochondrial and cytosolic antioxidant defenses and reduces the transcription of PGC-1α, thus down-regulating mitochondrial OXPHOS. Additionally, the high NADH/NAD⁺ ratio inhibits SIRT1 leaving the forkhead transcription factors acetylated and out of the nucleus. The suppression of SIRT1 also permits p53 to become acetylated and fully active, increasing the expression of BAX and the activation of p66^Shc. BAX binds to the mitochondrial outer membrane and activates the mtPTP to initiate apoptosis. The activated mitochondrial component of p66^shc increases mitochondrial ROS production and stimulates cytochrome c release and apoptosis. This destructive trend is partially countered by the ROS-mediated stimulation of the interaction of SIRT1 with the forkheads, enhancing the deacetylation of forkheads and their import into the nucleus to activate the antioxidant and stress response systems. However, continued caloric overload counters this protective effect. In the end, high calorie diets lead to the down-regulation of mitochondrial OXPHOS and antioxidant and stress response defenses, increasing mitochondrial ROPS production and the accumulation of oxidative damage to the mitochondria and mtDNA, leading to cell death.

Gene. 1999 Sep 30;238(1):211-30.

Mitochondrial DNA variation in human evolution and disease.

Wallace DC, Brown MD, Lott MT.

Source

Center for Molecular Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Abstract

Analysis of mitochondrial DNA (mtDNA) variation has permitted the reconstruction of the ancient migrations of women. This has provided evidence that our species arose in Africa about 150000 years before present (YBP), migrated out of Africa into Asia about 60000 to 70000 YBP and into Europe about 40000 to 50000 YBP, and migrated from Asia and possibly Europe to the Americas about 20000 to 30000 YBP. Although much of the mtDNA variation that exists in modern populations may be selectively neutral, studies of the mildly deleterious mtDNA mutations causing Leber's hereditary optic neuropathy (LHON) have demonstrated that some continent-specific mtDNA lineages are more prone to manifest the clinical symptoms of LHON than others. Hence, all mtDNA lineages are not equal, which may provide insights into the extreme environments that were encountered by our ancient ancestor, and which may be of great importance in understanding the pathophysiology of mitochondrial disease.

PMID:

10570998

[PubMed - indexed for MEDLINE]

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Diabetologia. 1995 Feb;38(2):193-200.

Diabetes mellitus carrying a mutation in the mitochondrial tRNA(Leu(UUR)) gene.

Kishimoto M, Hashiramoto M, Araki S, Ishida Y, Kazumi T, Kanda E, Kasuga M.

Source

Second Department of Internal Medicine, Kobe University, School of Medicine, Japan.

Abstract

We screened 214 Japanese NIDDM (non-insulin-dependent) diabetic patients with a family history of diabetes for mutations in the mitochondrial tRNA(Leu(UUR)) gene using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Six patients were identified as having an A to G transition at position 3243 (3243 mutation), but no patients were detected with a T to C transition at position 3271, in the mitochondrial tRNA(Leu(UUR)) gene. These two mutations were not present in 85 healthy control subjects. It was disclosed that the patients' mothers were also affected by diabetes mellitus in five of the six cases. In these six affected patients, the 3243 mutation shows variable phenotypes, such as the degree of multiple organ involvement, intrafamilial and interfamilial differences in disease characteristics, and the degree of the involvement of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) phenotype. Endocrinological examinations revealed that those diabetic patients with the 3243 mutation show not only beta-cell dysfunction, but also a defect in alpha-cell function, which is considered characteristic of diabetes with the 3243 mutation. When compared with 50 selected diabetic control subjects without the 3243 mutation, whose mothers, but not fathers, were found to have diabetes, it was established statistically that those with the 3243 mutation possess the following clinical characteristics; 1) the age of diabetes onset is lower, 2) they have lean body constitutions, and 3) they are more likely to be treated with insulin than control subjects. We suggest that diabetes with the 3243 mutation possesses phenotypes distinct from those in common forms of diabetes.

Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S172-7. Epub 2007 Apr 23.

Genetic factors related to mitochondrial function and risk of diabetes mellitus.

Cho YM, Park KS, Lee HK.

Source

Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-744, Korea.

Abstract

Mitochondria are the intracellular organelles responsible for the generation of ATP by the process of oxidative phosphorylation (OXPHOS) and have their own DNA containing genes for 13 subunits of OXPHOS and 2 rRNAs and 22 tRNAs for their protein synthesis machinery. Since mitochondrial DNA (mtDNA) has limited coding capacity, nuclear genes make a major contribution to mitochondrial architecture, metabolic systems and biogenesis. Nowadays, there is a growing body of evidence that the mitochondrial dysfunction plays a crucial role in the pathogenesis of type 2 diabetes. In this review, we showed that mtDNA copy number in peripheral blood cells is associated with various pathophysiological characteristics of type 2 diabetes such as insulin resistance and insulin secretory defect. In addition, peripheral blood mtDNA copy number is a risk factor for the development of type 2 diabetes. Common polymorphisms in mtDNA and nuclear genes regulating mitochondrial function might be associated with type 2 diabetes. Elucidation of genetic factors regulating mitochondrial function would be of help to understand how mitochondrial dysfunction is linked to the pathogenesis of type 2 diabetes.

Altern Med Rev. 2002 Apr;7(2):94-111.

Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment.

Lamson DW, Plaza SM.

Source

Bastyr University, Kenmore, WA, USA. davisl@seanet.com

Abstract

A growing body of evidence has demonstrated a link between various disturbances in mitochondrial functioning and type 2 diabetes. This review focuses on a range of mitochondrial factors important in the pathogenesis of this disease. The mitochondrion is an integral part of the insulin system found in the islet cells of the pancreas. Because of the systemic complexity of mitochondrial functioning in terms of tissue and energetic thresholds, details of structure and function are reviewed. The expression of type 2 diabetes can be ascribed to a number of qualitative or quantitative changes in the mitochondria. Qualitative changes refer to genetic disturbances in mitochondrial DNA (mtDNA). Heteroplasmic as well as homoplasmic mutations of mtDNA can lead to the development of a number of genetic disorders that express the phenotype of type 2 diabetes. Quantitative decreases in mtDNA copy number have also been linked to the pathogenesis of diabetes. The study of the relationship of mtDNA to type 2 diabetes has revealed the influence of the mitochondria on nuclear-encoded glucose transporters and the influence of nuclear encoded uncoupling proteins on the mitochondria. This basic research into the pathogenesis of diabetes has led to the awareness of natural therapeutics (such as coenzyme Q10) that increase mitochondrial functioning and avoidance of trans-fatty acids that decrease mitochondrial functioning.

Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78. Epub 2006 Feb 20.

Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress.

Rolo AP, Palmeira CM.

Source

Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal.

Abstract

Hyperglycemia resulting from uncontrolled glucose regulation is widely recognized as the causal link between diabetes and diabetic complications. Four major molecular mechanisms have been implicated in hyperglycemia-induced tissue damage: activation of protein kinase C (PKC) isoforms via de novo synthesis of the lipid second messenger diacylglycerol (DAG), increased hexosamine pathway flux, increased advanced glycation end product (AGE) formation, and increased polyol pathway flux. Hyperglycemia-induced overproduction of superoxide is the causal link between high glucose and the pathways responsible for hyperglycemic damage. In fact, diabetes is typically accompanied by increased production of free radicals and/or impaired antioxidant defense capabilities, indicating a central contribution for reactive oxygen species (ROS) in the onset, progression, and pathological consequences of diabetes. Besides oxidative stress, a growing body of evidence has demonstrated a link between various disturbances in mitochondrial functioning and type 2 diabetes. Mutations in mitochondrial DNA (mtDNA) and decreases in mtDNA copy number have been linked to the pathogenesis of type 2 diabetes. The study of the relationship of mtDNA to type 2 diabetes has revealed the influence of the mitochondria on nuclear-encoded glucose transporters, glucose-stimulated insulin secretion, and nuclear-encoded uncoupling proteins (UCPs) in beta-cell glucose toxicity. This review focuses on a range of mitochondrial factors important in the pathogenesis of diabetes. We review the published literature regarding the direct effects of hyperglycemia on mitochondrial function and suggest the possibility of regulation of mitochondrial function at a transcriptional level in response to hyperglycemia. The main goal of this review is to include a fresh consideration of pathways involved in hyperglycemia-induced diabetic complications.

PMID:

16490224

[PubMed - indexed for MEDLINE]

Toxicol Appl Pharmacol. 2007 Dec 1;225(2):214-20. Epub 2007 Aug 7.

Hyperglycemia decreases mitochondrial function: the regulatory role of mitochondrial biogenesis.

Palmeira CM, Rolo AP, Berthiaume J, Bjork JA, Wallace KB.

Source

Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal. palmeira@ci.uc.pt

Abstract

Increased generation of reactive oxygen species (ROS) is implicated in "glucose toxicity" in diabetes. However, little is known about the action of glucose on the expression of transcription factors in hepatocytes, especially those involved in mitochondrial DNA (mtDNA) replication and transcription. Since mitochondrial functional capacity is dynamically regulated, we hypothesized that stressful conditions of hyperglycemia induce adaptations in the transcriptional control of cellular energy metabolism, including inhibition of mitochondrial biogenesis and oxidative metabolism. Cell viability, mitochondrial respiration, ROS generation and oxidized proteins were determined in HepG2 cells cultured in the presence of either 5.5 mM (control) or 30 mM glucose (high glucose) for 48 h, 96 h and 7 days. Additionally, mtDNA abundance, plasminogen activator inhibitor-1 (PAI-1), mitochondrial transcription factor A (TFAM) and nuclear respiratory factor-1 (NRF-1) transcripts were evaluated by real time PCR. High glucose induced a progressive increase in ROS generation and accumulation of oxidized proteins, with no changes in cell viability. Increased expression of PAI-1 was observed as early as 96 h of exposure to high glucose. After 7 days in hyperglycemia, HepG2 cells exhibited inhibited uncoupled respiration and decreased MitoTracker Red fluorescence associated with a 25% decrease in mtDNA and 16% decrease in TFAM transcripts. These results indicate that glucose may regulate mtDNA copy number by modulating the transcriptional activity of TFAM in response to hyperglycemia-induced ROS production. The decrease of mtDNA content and inhibition of mitochondrial function may be pathogenic hallmarks in the altered metabolic status associated with diabetes.

PMID:

17761203

[PubMed - indexed for MEDLINE]