Advances in Autism Research
compiled by Teresa Binstock for
Autism Research Institute
April 2008
Nutrients and mitochondria
Would supoptimal, intra-body nutritional status affect mitochondria function? Numerous citations indicate the answer is Yes.
A few of the cites are free online. Several mention CoQ10, one focuses upon vitamin A, others mention antioxidants. These abstracts - in conjunction with citations linking nutritional status and immunity - suggest another question: Via genetic and/or aquired tendencies toward depletion of nutrients, would illness or recent illness create transient mitochondria dysfunction (MtD)?
This type of MtD would different from genetic mitochondria disorder and - it is suggested - might put a child experiencing a vaccination incident at increased risk (albeit transient risk) of a disease progression (regression; development of autism symtoms) akin to what has been described for Hannah Poling (US HHS concession 2007; Poling et al 2006, J Child Neurology).
A related issue: had most children who regressed subsequent to vaccination incidents been lab-tested (prior to their vaccination and prior to their vaccination-time illness), many and perhaps most of those children may NOT have generated lab signs consistent with MtD. Furthermore, several months or a year or more into their regression into autism symptoms, many and perhaps most such children (had they they been tested) may not have generated lab signs consistent with MtD. Nonetheless, the citations herein suggest that some children who were sick or recently sick at the time of a vaccination incident may have had transient MtD at the time of vaccine injection(s), due to impaired intra-body nutrient status which had been induced by the child's illness. Furthermore, lab-data documention of transient MtD at the time of vaccination might be virtually impossible to obtain retrospectively.
A bottom line is suggested. An illnesses during or soon prior to a vaccination incident is likely, at least in some children, to impair immunity, to impair detoxification, and to impair mitochondria function.
1: The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview
Liu J.
Neurochem Res. 2008 Jan;33(1):194-203.
We have identified a group of nutrients that can directly or indirectly protect mitochondria from oxidative damage and improve mitochondrial function and named them "mitochondrial nutrients". The direct protection includes preventing the generation of oxidants, scavenging free radicals or inhibiting oxidant reactivity, and elevating cofactors of defective mitochondrial enzymes with increased Michaelis-Menten constant to stimulate enzyme activity, and also protect enzymes from further oxidation, and the indirect protection includes repairing oxidative damage by enhancing antioxidant defense systems either through activation of phase 2 enzymes or through increase in mitochondrial biogenesis. In this review, we take alpha-lipoic acid (LA) as an example of mitochondrial nutrients by summarizing the protective effects and possible mechanisms of LA and its derivatives on age-associated cognitive and mitochondrial dysfunction of the brain. LA and its derivatives improve the age-associated decline of memory, improve mitochondrial structure and function, inhibit the age-associated increase of oxidative damage, elevate the levels of antioxidants, and restore the activity of key enzymes. In addition, co-administration of LA with other mitochondrial nutrients, such as acetyl-L: -carnitine and coenzyme Q10, appears more effective in improving cognitive dysfunction and reducing oxidative mitochondrial dysfunction. Therefore, administrating mitochondrial nutrients, such as LA and its derivatives in combination with other mitochondrial nutrients to aged people and patients suffering from neurodegenerative diseases, may be an effective strategy for improving mitochondrial and cognitive dysfunction.
PMID: 17605107
2: Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management
Kidd PM.
Altern Med Rev. 2005 Dec;10(4):268-93.
Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan.
PMID: 16366737
3: Reducing mitochondrial decay with mitochondrial nutrients to delay and treat cognitive dysfunction, Alzheimer's disease, and Parkinson's disease
Liu J, Ames BN.
Nutr Neurosci. 2005 Apr;8(2):67-89.
Mitochondrial decay due to oxidative damage is a contributor to brain aging and age-related neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). One type of mitochondrial decay is oxidative modification of key mitochondrial enzymes. Enzyme dysfunction, that is due to poor binding of substrates and coenzymes may be ameliorated by supplementing adequate levels of substrates or coenzyme precursors. Such supplementation with mitochondrial nutrients (mt-nutrients) may be useful to prevent or delay mitochondrial decay, thus prevent or treat AD and PD. In the present review, we survey the literature to identify mt-nutrients that can (1) protect mitochondrial enzymes and/or stimulate enzyme activity by elevating levels of substrates and cofactors; (2) induce phase-2 enzymes to enhance antioxidant defenses; (3) scavenge free radicals and prevent oxidant production in mitochondria, and (4) repair mitochondrial membrane. Then, we discuss the relationships among mt-nutrient deficiency, mitochondrial decay, and cognitive dysfunction, and summarize available evidence suggesting an effect of mt-nutrient supplementation on AD and PD. It appears that greater effects might be obtained by longer-term administration of combinations of mt-nutrients. Thus, optimal doses of combinations of mt-nutrients to delay and repair mitochondrial decay could be a strategy for preventing and treating cognitive dysfunction, including AD and PD.
PMID: 16053240
4: Nutritional cofactor treatment in mitochondrial disorders
Marriage B, Clandinin MT, Glerum DM.
J Am Diet Assoc. 2003 Aug;103(8):1029-38.
Mitochondrial disorders are degenerative diseases characterized by a decrease in the ability of mitochondria to supply cellular energy requirements. Substantial progress has been made in defining the specific biochemical defects and underlying molecular mechanisms, but limited information is available about the development and evaluation of effective treatment approaches. The goal of nutritional cofactor therapy is to increase mitochondrial adenosine 5'-triphosphate production and slow or arrest the progression of clinical symptoms. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of antioxidants, electron transfer mediators (which bypass the defective site), and enzyme cofactors. Metabolic therapies that have been reported to produce a positive effect include Coenzyme Q(10) (ubiquinone); other antioxidants such as ascorbic acid, vitamin E, and lipoic acid; riboflavin; thiamin; niacin; vitamin K (phylloquinone and menadione); creatine; and carnitine. A literature review of the use of these supplements in mitochondrial disorders is presented.
PMID: 12891154
5: Lifestyle and nutrition, caloric restriction, mitochondrial health and hormones: scientific interventions for anti-aging
Vitetta L, Anton B.
Clin Interv Aging. 2007;2(4):537-43.
Aging is a universal process to all life forms. The most current and widely accepted definition for aging in humans is that there is a progressive loss of function and energy production that is accompanied by decreasing fertility and increasing mortality with advancing age. The most obvious and commonly recognised consequence of aging and energy decline is a decrease in skeletal muscle function which affects every aspect of human life from the ability to play games, walk and run to chew, swallow and digest food. There is hence a recognised overall decline of an individuals' fitness for the environment that they occupy. In Westenised countries this decline is gradual and the signs become mostly noticeable after the 5th decade of life and henceforth, where the individual slowly progresses to death over the next three to four decades. Given that the aging process is slow and gradual, it presents with opportunities and options that may ameliorate and improve the overall functional capacity of the organism. Small changes in function may be more amenable and likely to further slow down and possibly reverse some of the deleterious effects of aging, rather, than when the incremental changes are large. This overall effect may then translate into a significant compression of the deleterious aspects of human aging with a resultant increase in human life expectancy.
PMID: 18225453
6: Nutritional and exercise-based therapies in the treatment of mitochondrial disease
Mahoney DJ, Parise G, Tarnopolsky MA.
Curr Opin Clin Nutr Metab Care. 2002 Nov;5(6):619-29.
PURPOSE OF REVIEW: This review will critically summarize the nutritional and exercise-based interventions that have been used to treat mitochondrial disease, with a focus on the biochemical or molecular rationale for their use as well as recent advances in the field. RECENT FINDINGS: Many nutritional-based treatment strategies have been used in an attempt to target energy impairment and its sequelae. Recently, coenzyme Q10, idebenone and triacylglycerol have been shown to bypass defective respiratory enzymes or scavenge free radicals, whereas creatine monohydrate has provided an alternative energy source. Thiamine has been used to decrease lactate levels and increase flux through aerobic metabolism, and riboflavin has been used as a precursor to complexes I and II. Several therapies employing various antioxidants in combination with other supplements have been effective at targeting several of the final common pathways of mitochondrial disease. Miscellaneous supplements, such as L-arginine and uridine, have also had recent success. However, although positive responses have been reported with these agents, many reports have shown no benefit, and there is widespread disparity in the literature. An alternative approach to treatment is exercise training. Both resistance and endurance exercise training have had positive outcomes in patients with mitochondrial disease, although several questions remain to be answered. SUMMARY: There is no currently recognized treatment for mitochondrial disease. Future clinical trials are needed, as well as research into the potential for in-vitro screening of various compounds within affected cells from patients. Until this time, an accurate diagnosis will facilitate treatment on a case-by-case basis.
PMID: 12394637
7: Mitochondrial gene expression in diabetes mellitus: effect of nutrition
Berdanier CD.
Nutr Rev. 2001 Mar;59(3 Pt 1):61-70.
Diabetes mellitus is a collection of genetic diseases that share a common phenotype: glucose intolerance. The genetic origins of this disease are being widely investigated. An estimated 0.19% of the population with diabetes has the disorder owing to one or more mutations in the mitochondrial genome. Diet can affect the expression of the genome as well as the function of its gene products. The antioxidant nutrients serve to protect this very vulnerable genome from oxidative damage. These nutrients may affect mitochondrial DNA transcription and nutrients that affect membrane fluidity affect the function of the gene products.
PMID: 11330623
8: Nutrient supply and mitochondrial function
Aw TY, Jones DP.
Annu Rev Nutr. 1989;9:229-51.
PMID: 2669872
9: Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer's disease
Atamna H, Frey WH 2nd.
Mitochondrion. 2007 Sep;7(5):297-310. Epub 2007 Jun 13.
Several studies have demonstrated aberrations in the Electron Transport Complexes (ETC) and Krebs (TCA) cycle in Alzheimer's disease (AD) brain. Optimal activity of these key metabolic pathways depends on several redox active centers and metabolites including heme, coenzyme Q, iron-sulfur, vitamins, minerals, and micronutrients. Disturbed heme metabolism leads to increased aberrations in the ETC (loss of complex IV), dimerization of APP, free radical production, markers of oxidative damage, and ultimately cell death all of which represent key cytopathologies in AD. The mechanism of mitochondrial dysfunction in AD is controversial. The observations that Abeta is found both in the cells and in the mitochondria and that Abeta binds with heme may provide clues to this mechanism. Mitochondrial Abeta may interfere with key metabolites or metabolic pathways in a manner that overwhelms the mitochondrial mechanisms of repair. Identifying the molecular mechanism for how Abeta interferes with mitochondria and that explains the established key cytopathologies in AD may also suggest molecular targets for therapeutic interventions. Below we review recent studies describing the possible role of Abeta in altered energy production through heme metabolism. We further discuss how protecting mitochondria could confer resistance to oxidative and environmental insults. Therapies targeted at protecting mitochondria may improve the clinical outcome of AD patients.
PMID: 17625988
10: Mitochondrial oxidative stress and inflammation: an slalom to obesity and insulin resistance
Martínez JA.
J Physiol Biochem. 2006 Dec;62(4):303-6.
Mitochondria, in addition to energy transformation, play a role in important metabolic tasks such as apoptosis, cellular proliferation, heme/steroid synthesis as well as in the cellular redox state regulation. The mitochondrial phosphorylation process is very efficient, but a small percentage of electrons may prematurely reduce oxygen forming toxic free radicals potentially impairing the mitochondria function. Furthermore, under certain conditions, protons can reenter the mitochondrial matrix through different uncoupling proteins (UCPs), affecting the control of free radicals production by mitochondria. Disorders of the mitochondrial electron transport chain, overgeneration of reactive oxygen species (ROS) and lipoperoxides or impairments in antioxidant defenses have been reported in situations of obesity and type-2 diabetes. On the other hand, obesity has been associated to a low degree pro-inflammatory state, in which impairments in the oxidative stress and antioxidant mechanism could be involved. Indeed, reactive oxygen species have been attributed a causal role in multiple forms of insulin resistance. The scientific evidence highlights the importance of investigating the relationships between oxidative stress and inflammation with obesity/diabetes onset and underlines the need to study in mitochondria from different tissues, the interactions of such factors either as a cause or consequence of obesity and insulin resistance.
PMID: 17615956
11: Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function
Nicolson GL.
J Cell Biochem. 2007 Apr 15;100(6):1352-69.
Metabolic syndrome consists of a cluster of metabolic conditions, such as hypertriglyceridemia, hyper-low-density lipoproteins, hypo-high-density lipoproteins, insulin resistance, abnormal glucose tolerance and hypertension, that-in combination with genetic susceptibility and abdominal obesity-are risk factors for type 2 diabetes, vascular inflammation, atherosclerosis, and renal, liver and heart disease. One of the defects in metabolic syndrome and its associated diseases is excess cellular oxidative stress (mediated by reactive oxygen and nitrogen species, ROS/RNS) and oxidative damage to mitochondrial components, resulting in reduced efficiency of the electron transport chain. Recent evidence indicates that reduced mitochondrial function caused by ROS/RNS membrane oxidation is related to fatigue, a common complaint of MS patients. Lipid replacement therapy (LRT) administered as a nutritional supplement with antioxidants can prevent excess oxidative membrane damage, restore mitochondrial and other cellular membrane functions and reduce fatigue. Recent clinical trials have shown the benefit of LRT plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue. Thus LRT plus antioxidant supplements should be considered for metabolic syndrome patients who suffer to various degrees from fatigue.
PMID: 17243117
12: Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders
Mancuso C et al.
Front Biosci. 2007 Jan 1;12:1107-23.
Protein conformational diseases, such as Alzheimer's, Parkinson's and Huntington's, affect a large portion of aging population. The pathogenic dysfunctional aggregation of proteins in non-native conformations is associated with metabolic derangements and excessive production of reactive oxygen species. Reduction of cellular expression and activity of antioxidant proteins result in increased oxidative stress. Free-radicals derived from mitochondrial dysfunction and from the cyclooxygenase enzyme activity play a role in oxidative damage of brain. Cyclooxygenase also mediates in neuro-inflammation by the production of pro-inflammatory prostaglandins which contribute to brain injury. The pathogenic role of cyclooxygenase has been demonstrated in Alzheimer and Parkinson diseases. The brain responses to detect and control diverse forms of stress are accomplished by a complex network of "longevity assurance processes" integrated to the expression of genes termed vitagenes. Heat shock proteins are a highly conserved system responsible for the preservation and repair of correct protein conformation. Heme oxygenase-1, a inducible and redox-regulated enzyme, is currently considered as having an important role in cellular antioxidant defense. A neuroprotective effect, due to its heme degrading activity, and tissue-specific pro-oxidant effects, due to its products CO and free iron, are under debate. There is a current interest in dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiology of Alzheimer disease, with a chronic inflammatory response, brain injury and beta-amyloid associated pathology. Curcumin and ferulic acid, two powerful antioxidants, the first from the curry spice turmeric and the second a major constituent of fruit and vegetables, have emerged as strong inducers of the heat shock response. Food supplementation with curcumin and ferulic acid is considered a nutritional approach to reduce oxidative damage and amyloid pathology in Alzheimer disease.
PMID: 17127365
13: Role of mitochondrial oxidative stress to explain the different longevity between genders: protective effect of estrogens
Viña J et al.
Free Radic Res. 2006 Dec;40(12):1359-65.
Females live longer than males. Work from our laboratory has shown that this may be due to the up-regulation of longevity-associated genes by estrogens. Estrogens bind to the estrogen receptors and subsequently activate the mitogen activated protein kinase and nuclear factor kappa B signalling pathways, resulting in an up-regulation of antioxidant enzymes.Estrogen administration, however, has serious undesirable effects and of course, cannot be administered to males because of its powerful feminizing effects. Thus, we tested the effect of genistein, a phytoestrogen of high nutritional importance whose structure is similar to estradiol, on the regulation of the expression of antioxidant, longevity-related genes and consequently on oxidant levels in mammary gland tumour cells in culture. Phytoestrogens mimic the protective effect of oestradiol using the same signalling pathway.The critical importance of up-regulating antioxidant genes, by hormonal and dietary manipulations, to increase longevity is discussed.
PMID: 17090425
14: Targeting antioxidants to mitochondria by conjugation to lipophilic cations
Murphy MP, Smith RA.
Annu Rev Pharmacol Toxicol. 2007;47:629-56.
Mitochondrial oxidative damage contributes to a range of degenerative diseases. Consequently, the selective inhibition of mitochondrial oxidative damage is a promising therapeutic strategy. One way to do this is to invent antioxidants that are selectively accumulated into mitochondria within patients. Such mitochondria-targeted antioxidants have been developed by conjugating the lipophilic triphenylphosphonium cation to an antioxidant moiety, such as ubiquinol or alpha-tocopherol. These compounds pass easily through all biological membranes, including the blood-brain barrier, and into muscle cells and thus reach those tissues most affected by mitochondrial oxidative damage. Furthermore, because of their positive charge they are accumulated several-hundredfold within mitochondria driven by the membrane potential, enhancing the protection of mitochondria from oxidative damage. These compounds protect mitochondria from damage following oral delivery and may therefore form the basis for mitochondria-protective therapies. Here we review the background and work to date on this class of mitochondria-targeted antioxidants.
PMID: 17014364
15: Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways
Depeint F et al.
Chem Biol Interact. 2006 Oct 27;163(1-2):113-32.
The B vitamins are water-soluble vitamins that are required as coenzymes for reactions essential for cellular function. This review focuses on the essential role of vitamins in maintaining the one-carbon transfer cycles. Folate and choline are believed to be central methyl donors required for mitochondrial protein and nucleic acid synthesis through their active forms, 5-methyltetrahydrofolate and betaine, respectively. Cobalamin (B12) may assist methyltetrahydrofolate in the synthesis of methionine, a cysteine source for glutathione biosynthesis. Pyridoxal, pyridoxine and pyridoxamine (B6) seem to be involved in the regeneration of tetrahydrofolate into the active methyl-bearing form and in glutathione biosynthesis from homocysteine. Other roles of these vitamins that are relevant to mitochondrial functions will also be discussed. However these roles for B vitamins in cell function are mostly theoretically based and still require verification at the cellular level. For instance it is still not known what B vitamins are depleted by xenobiotic toxins or which cellular targets, metabolic pathways or molecular toxic mechanisms are prevented by B vitamins. This review covers the current state of knowledge and suggests where this research field is heading so as to better understand the role vitamin Bs play in cellular function and intermediary metabolism as well as molecular, cellular and clinical consequences of vitamin deficiency. The current experimental and clinical evidence that supplementation alleviates deficiency symptoms as well as the effectiveness of vitamins as antioxidants will also be reviewed.
PMID: 16814759
16: Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism
Depeint F et al.
Chem Biol Interact. 2006 Oct 27;163(1-2):94-112.
The B vitamins are water-soluble vitamins required as coenzymes for enzymes essential for cell function. This review focuses on their essential role in maintaining mitochondrial function and on how mitochondria are compromised by a deficiency of any B vitamin. Thiamin (B1) is essential for the oxidative decarboxylation of the multienzyme branched-chain ketoacid dehydrogenase complexes of the citric acid cycle. Riboflavin (B2) is required for the flavoenzymes of the respiratory chain, while NADH is synthesized from niacin (B3) and is required to supply protons for oxidative phosphorylation. Pantothenic acid (B5) is required for coenzyme A formation and is also essential for alpha-ketoglutarate and pyruvate dehydrogenase complexes as well as fatty acid oxidation. Biotin (B7) is the coenzyme of decarboxylases required for gluconeogenesis and fatty acid oxidation. Pyridoxal (B6), folate and cobalamin (B12) properties are reviewed elsewhere in this issue. The experimental animal and clinical evidence that vitamin B therapy alleviates B deficiency symptoms and prevents mitochondrial toxicity is also reviewed. The effectiveness of B vitamins as antioxidants preventing oxidative stress toxicity is also reviewed.
PMID: 16765926
17: Minireview: implication of mitochondria in insulin secretion and action
Wiederkehr A, Wollheim CB.
Endocrinology. 2006 Jun;147(6):2643-9.
Mitochondria are essential for intermediary metabolism as well as energy production in the cell. Their aerobic metabolism permits oxidation of glucose and fatty acids for the generation of ATP and other intermediates that are exchanged with the cytoplasm for various biosynthetic and secretory processes. In the pancreatic beta-cell, glucose carbons are quantitatively funneled to the mitochondria, where signals for the initiation and potentiation of insulin secretion are generated. After mitochondrial activation, the plasma membrane is depolarized with ensuing cytosolic calcium transients and exocytosis of insulin. Calcium also acts in a feed-forward manner on mitochondrial metabolism, which contributes to sustained second phase insulin secretion. Patients with mitochondrial diabetes and a corresponding mouse model display defective glucose-stimulated insulin secretion and reduced beta-cell mass, leading to overt diabetes. Normal mitochondrial activity appears to be equally important in the action of insulin on its target tissues. The development of insulin resistance may involve impairment of glucose oxidation after short exposure to increased levels of circulating free fatty acids. Insulin resistance in the elderly and in relatives of type 2 diabetic patients has also been associated with mitochondrial dysfunction. Both prevention and treatment of type 2 diabetes should focus on mitochondrial targets for the improvement of nutrient-stimulated insulin secretion and their utilization in peripheral tissues.
PMID: 16556766
18: Glutathionylation of mitochondrial proteins
Hurd TR et al.
Antioxid Redox Signal. 2005 Jul-Aug;7(7-8):999-1010.
Many proteins contain free thiols that can be modified by the reversible formation of mixed disulfides with low-molecular-weight thiols through a process called S-thiolation. As the majority of these modifications result from the interaction of protein thiols with the endogenous glutathione pool, protein glutathionylation is the predominant alteration. Protein glutathionylation is of significance both for defense against oxidative damage and in redox signaling. As mitochondria are at the heart of both oxidative damage and redox signaling within the cell, the glutathionylation of mitochondrial proteins is of particular importance. Here we review the mechanisms and physiological significance of the glutathionylation of mitochondrial thiol proteins.
PMID: 15998254
19: Hormonal regulation of mitochondrial energy production
Ritz P et al.
Curr Opin Clin Nutr Metab Care. 2005 Jul;8(4):415-8.
PURPOSE OF REVIEW: It had been thought for a long time that thyroid hormones were the only ones to regulate energy production within mitochondria. Recent findings show that other hormones (steroids, leptin, insulin) regulate the efficiency of mitochondrial adenosine triphosphate production. Furthermore, a mismatch between oxygen consumption and energy intake may not be sufficient to understand body weight regulation. It appears that the efficiency of adenosine triphosphate production may play a role. RECENT FINDINGS: Over the past 2 years a series of results argued that glucocorticoids influence energy balance, the efficiency of adenosine triphosphate production, and are thermogenic. The sites for this effect are discussed, probably both the liver and muscle. Evidence of the genes involved in this regulation is substantial for muscle but remains to be studied in the liver. On the other hand, leptin could be a thermogenic hormone, especially in situations of calorie restriction. Finally, recent data and opinions suggest that mitochondria and adenosine triphosphate production could be central in the pathogenesis of both insulin resistance and beta cell deficiency. SUMMARY: The adaptation of mitochondrial adenosine triphosphate production appears to play a role in both diabetes and weight loss (voluntary and involuntary). Hormonal and nutritional manipulation could be a therapeutic possibility for weight management.
PMID: 15930967
20: Delaying the mitochondrial decay of aging with acetylcarnitine
Ames BN, Liu J.
Ann N Y Acad Sci. 2004 Nov;1033:108-16.
Oxidative mitochondrial decay is a major contributor to aging. Some of this decay can be reversed in old rats by feeding them normal mitochondrial metabolites, acetylcarnitine (ALC) and lipoic acid (LA), at high levels. Feeding the substrate ALC with LA, a mitochondrial antioxidant, restores the velocity of the reaction (K(m)) for ALC transferase and mitochondrial function. The principle appears to be that, with age, increased oxidative damage to protein causes a deformation of structure of key enzymes with a consequent lessening of affinity (K(m)) for the enzyme substrate. The effect of age on the enzyme-binding affinity can be mimicked by reacting it with malondialdehyde (a lipid peroxidation product that increases with age). In old rats (vs. young rats), mitochondrial membrane potential, cardiolipin level, respiratory control ratio, and cellular O(2) uptake are lower; oxidants/O(2), neuron RNA oxidation, and mutagenic aldehydes from lipid peroxidation are higher. Ambulatory activity and cognition decline with age. Feeding old rats ALC with LA for a few weeks restores mitochondrial function; lowers oxidants, neuron RNA oxidation, and mutagenic aldehydes; and increases rat ambulatory activity and cognition (as assayed with the Skinner box and Morris water maze). A recent meta-analysis of 21 double-blind clinical trials of ALC in the treatment of mild cognitive impairment and mild Alzheimer's disease showed significant efficacy vs. placebo. A meta-analysis of 4 clinical trials of LA for treatment of neuropathic deficits in diabetes showed significant efficacy vs. placebo.
PMID: 15591008
21: Mitochondrial signaling pathways: a receiver/integrator organelle.
Goldenthal MJ, Marín-García J.
Mol Cell Biochem. 2004 Jul;262(1-2):1-16.
Research over the last decade has extended the prevailing view of cell mitochondrial function well beyond its critical bioenergetic role in supplying ATP. Recently, it has been recognized that the mitochondria play a critical role in cell regulatory and signaling events, in the responses of cells to a multiplicity of physiological and genetic stresses, inter-organelle communication, cell proliferation and cell death. Nevertheless, a broad-based review on mitochondrial signaling is not presently available. To bridge that gap, this review examines the perspective of mitochondria as the receiver integrator and transmitter of signals, dissecting the multiple and interrelated signaling pathways at both the molecular and biochemical levels with particular focus on nuclear and cytoplasmic factors, fundamentally involved in the shaping of the organelles' responses. We examine evidence that the mitochondria act as a dynamic receiver and integrator of numerous translocated signaling proteins (including protein kinases and transcription factors), regulatory Ca2+ fluxes and membrane phospholipids as well the transmission of mitochondrial-generated oxidative stress and energy-related signaling. Novel experimental approaches studying mitochondrial signaling including cell studies using metabolic inhibitors and genetic stresses (e.g. mtDNA depletion) are discussed. While there is abundant interest and information concerning its integral role to apoptosis, mitochondrial signaling also plays a fundamental role in proliferative pathways, nutrient sensing, inter-organellar cross-talk and in the responses of cells to metabolic transition and physiological stresses which remain relatively unexplored.
PMID: 15532704
22: Antioxidant and prooxidant properties of mitochondrial Coenzyme Q
James AM, Smith RA, Murphy MP.
Arch Biochem Biophys. 2004 Mar 1;423(1):47-56.
Coenzyme Q is both an essential electron carrier and an important antioxidant in the mitochondrial inner membrane. The reduced form, ubiquinol, decreases lipid peroxidation directly by acting as a chain breaking antioxidant and indirectly by recycling Vitamin E. The ubiquinone formed in preventing oxidative damage is reduced back to ubiquinol by the respiratory chain. As well as preventing lipid peroxidation, Coenzyme Q reacts with other reactive oxygen species, contributing to its effectiveness as an antioxidant. There is growing interest in using Coenzyme Q and related compounds therapeutically because mitochondrial oxidative damage contributes to degenerative diseases. Paradoxically, Coenzyme Q is also involved in superoxide production by the respiratory chain. To help understand how Coenzyme Q contributes to both mitochondrial oxidative damage and antioxidant defences, we have reviewed its antioxidant and prooxidant properties.
PMID: 14989264
23: Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes
Green K, Brand MD, Murphy MP.
Diabetes. 2004 Feb;53 Suppl 1:S110-8.
Hyperglycemia causes many of the pathological consequences of both type 1 and type 2 diabetes. Much of this damage is suggested to be a consequence of elevated production of reactive oxygen species by the mitochondrial respiratory chain during hyperglycemia. Mitochondrial radical production associated with hyperglycemia will also disrupt glucose-stimulated insulin secretion by pancreatic beta-cells, because pancreatic beta-cells are particularly susceptible to oxidative damage. Therefore, mitochondrial radical production in response to hyperglycemia contributes to both the progression and pathological complications of diabetes. Consequently, strategies to decrease mitochondrial radical production and oxidative damage may have therapeutic potential. This could be achieved by the use of antioxidants or by decreasing the mitochondrial membrane potential. Here, we outline the background to these strategies and discuss how antioxidants targeted to mitochondria, or selective mitochondrial uncoupling, may be potential therapies for diabetes.
PMID: 14749275
24: Gastrointestinal manifestations of mitochondrial disease
Gillis LA, Sokol RJ.
Gastroenterol Clin North Am. 2003 Sep;32(3):789-817, v.
Although non-specific gastrointestinal and hepatic symptoms are commonly found in most mitochondrial disorders, they are among the cardinal manifestations of several primary mitochondrial diseases, such as: mitochondrial neurogastrointestinal encephalomyopathy; mitochondrial DNA depletion syndrome; Alpers syndrome; and Pearson syndrome. Management of these heterogeneous disorders includes the empiric supplementation with various "mitochondrial cocktails," supportive therapies, and avoidance of drugs and conditions known to have a detrimental effect on the respiratory chain. There is a great need for improved methods of treatment and controlled clinical trials of existing therapies. Liver transplantation is successful in acquired cases; however neuromuscular involvement in primary mitochondrial disorders should be a contraindication for liver transplantation.
PMID: 14562575
25: Role of vitamin A in mitochondrial gene expression
Berdanier CD, Everts HB, Hermoyian C, Mathews CE.
Diabetes Res Clin Pract. 2001 Dec;54 Suppl 2:S11-27.
Diabetes-prone BHE/Cdb and Sprague-Dawley (SD) rats were studied with respect to mitochondrial (mt) function and mt gene expression. The BHE/Cdb rats carry mutations in the mt ATPase 6 gene that phenotype as decreased OXPHOS efficiency with subsequent development of impaired glucose tolerance. The base substitutions result in amino acid substitutions in the proton channel and this, in turn, affects the efficiency of energy capture in the ATP molecule. Feeding studies showed that BHE/Cdb rats required 10 times more vitamin E and three times more vitamin A in their diets than do normal SD rats. Vitamin A supplementation 'normalized' mt OXPHOS as well as increased the amount of ATPase subunit a protein in the mt compartment. Western blot analysis of retinoic acid receptors in the mitochondrial and nuclear compartments showed that these proteins were present in the mt compartment. The effect of the vitamin A supplementation plus the observation of retinoic acid receptors suggest that vitamin A functions to enhance the transcription of the ATPase 6 gene. Work with primary cultures of hepatocytes showed that not only does retinoic acid increase mitochondrial ATPase 6 gene expression but so too does the steroid hormone intermediate, dehydroepiandrosterone (DHEA). Triiodothyronine also plays a role in this process but not as an independent factor. Rather, this hormone potentiates the effects of retinoic acid and DHEA on ATPase gene expression. These results suggest that mt gene expression requires more than just the mt transcription factor A. More than likely the process requires a number of factors in much the same way as does nuclear gene expression.
PMID: 11733105
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