Mitochondrial Functioning:
The Neuro-Ophthalmology of Mitochondrial Disease
"Mitochondrial diseases frequently manifest neuro-ophthalmologic symptoms
and signs. Because of the predilection of mitochondrial disorders to
involve the optic nerves, extraocular muscles, retina, and even the
retrochiasmal visual pathways, the ophthalmologist is often the first
physician to be consulted. Disorders caused by mitochondrial dysfunction
can result from abnormalities in either the mitochondrial DNA or in
nuclear genes which encode mitochondrial proteins."
Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals.
"A reduction in fatty acid (FA) oxidation has been associated with lipid accumulation and insulin resistance in skeletal muscle of obese individuals. Whole-muscle mitochondrial content and FA oxidation was reduced in the obese, but there was no decrease in the ability of isolated mitochondria to oxidize FA. The mitochondrial content of the transport protein, FA translocase (FAT/CD36), did not differ between lean and obese women but was correlated with mitochondrial FA oxidation. It was concluded that the reduced FA oxidation in obesity is attributable to decreased muscle mitochondrial content and not intrinsic defects in mitochondrial FA oxidation, and that mitochondrial FAT/CD36 is involved in regulating FA oxidation in human skeletal muscle. The reduced skeletal muscle mitochondrial content with obesity may result from impaired mitochondrial biogenesis."
"As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death."
Fibromyalgia is caused by mitochondrial dysfunction
People with Fibromyalgia experience a wide range of symptoms occurring in most of their body systems, including muscles, brain and nervous system, digestive system, urinary problems, joints and skin, and more. This range of symptoms indicates a systemic disease not isolated to one organ or type of tissue. Mitochondrial Dysfunction typically involves many different body systems as well, as nearly all cells (with the exception of red blood cells) have mitochondria in them to make their own energy. If the mitochondria are not able to make adequate energy for the cell than it's function will be diminished. When muscle cells don't have enough energy, they hurt. When the brain doesn't have enough energy you get brain fog, depression, memory and cognitive problems. Your digestive system won't break down and absorb nutrients from your food as well.
There are 3 basic approaches to improving mitochondrial function featured in this video. The first is to heal the gut because in many ways the gut's ability to absorb and produce the needed nutrients is the foundation for other approaches. This includes eating a variety of nutritious foods including taking probiotics, eating fresh fruits and vegetables in a variety of colors, low sugar intake, and high levels of healthy fats. Reduce inflammation which includes not eating gluten and dairy, taking anti-inflammatory supplements such as quercetin and fish oil, and a myriad of other supplements and changes in behavior. The third important thing is to heal the cell walls of the mitochondria so that they can better function and produce energy, which they do by creating a charge gradient between their two cell walls. This doctor advocates lipid therapy in which appropriate fats are administered intravenously in order to restore the fats of the mitochondrial walls which have been damaged by oxidative stress, something that occurs when mitochondria burn oxygen to make energy.
Fibromyalgia is caused by mitochondrial dysfunction
People with Fibromyalgia experience a wide range of symptoms occurring in most of their body systems, including muscles, brain and nervous system, digestive system, urinary problems, joints and skin, and more. This range of symptoms indicates a systemic disease not isolated to one organ or type of tissue. Mitochondrial Dysfunction typically involves many different body systems as well, as nearly all cells (with the exception of red blood cells) have mitochondria in them to make their own energy. If the mitochondria are not able to make adequate energy for the cell than it's function will be diminished. When muscle cells don't have enough energy, they hurt. When the brain doesn't have enough energy you get brain fog, depression, memory and cognitive problems. Your digestive system won't break down and absorb nutrients from your food as well.
There are 3 basic approaches to improving mitochondrial function featured in this video. The first is to heal the gut because in many ways the gut's ability to absorb and produce the needed nutrients is the foundation for other approaches. This includes eating a variety of nutritious foods including taking probiotics, eating fresh fruits and vegetables in a variety of colors, low sugar intake, and high levels of healthy fats. Reduce inflammation which includes not eating gluten and dairy, taking anti-inflammatory supplements such as quercetin and fish oil, and a myriad of other supplements and changes in behavior. The third important thing is to heal the cell walls of the mitochondria so that they can better function and produce energy, which they do by creating a charge gradient between their two cell walls. This doctor advocates lipid therapy in which appropriate fats are administered intravenously in order to restore the fats of the mitochondrial walls which have been damaged by oxidative stress, something that occurs when mitochondria burn oxygen to make energy.
In Alzheimer's Disease (and Diabetes)
"Extensive literature exists supporting a role for mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer's disease. Mitochondria are a major source of intracellular reactive oxygen species and are particularly vulnerable to oxidative stress. This review discusses evidence supporting the notion that mitochondrial dysfunction is intimately associated with Alzheimer's disease pathogenesis. Furthermore, the potential connection between mitochondrial dysfunction/oxidative stress and autophagy in Alzheimer's disease is also discussed. As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy, neurons progressively accumulate lipofuscin (biological garbage) that could exacerbate neuronal dysfunction. The knowledge that mitochondrial dysfunction has a preponderant role in several pathological conditions instigated the development of mitochondrial antioxidant therapies. Mitochondria-targeted antioxidant treatments are briefly discussed in this review."
Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology.
"Mitochondria are uniquely poised to play a pivotal role in neuronal cell survival or death because they are regulators of both energy metabolism and cell death pathways. Extensive literature exists supporting a role for mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer's disease. This review discusses evidence indicating that mitochondrial dysfunction has an early and preponderant role in Alzheimer's disease. Furthermore, the link between mitochondrial dysfunction and autophagy in Alzheimer's disease is also discussed. As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy, neurons progressively accumulate lipofuscin that could exacerbate neuronal dysfunction. Since autophagy is the major pathway involved in the degradation of protein aggregates and defective organelles, an intense interest in developing autophagy-related therapies is growing among the scientific community. The final part of this review is devoted to discuss autophagy as a potential target of therapeutic interventions in Alzheimer's disease pathophysiology."
"This review is mainly focused in the discussion of evidence suggesting a clear association between amyloid-beta toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage/death in Alzheimer's disease pathophysiology. The knowledge that mitochondrial dysfunction has a preponderant role in Alzheimer's disease opened a window for new therapeutic strategies aimed to preserve/ameliorate mitochondrial function. Based on recent developments in mitochondrial research, increased pharmacological and pharmaceutical efforts have lead to the emergence of 'Mitochondrial Medicine' as a whole new field of biomedical research being this topic discussed in the last section of this review."
Alzheimer's disease and diabetes: an integrative view of the role of mitochondria, oxidative stress, and insulin.
"An increasing number of studies have demonstrated a connection between Alzheimer's disease (AD) and diabetes, particularly type 2 diabetes (T2D). The risk for developing T2D and AD increases exponentially with age and having T2D increases the risk of developing AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. This review critically discusses the involvement of mitochondrial abnormalities and oxidative stress in AD and diabetes highlighting the similarities between both pathologies. The impact of insulin resistance/insulin signaling impairment in AD pathogenesis will be also debated. A better understanding of the key mechanisms underlying the interaction between AD and diabetes is needed for the design of effective preventive and therapeutic strategies."
An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer's disease.
"The processes underlying the pathogenesis of Alzheimer's disease involve several factors including impaired glucose/energy metabolism, mitochondrial dysfunction, oxidative stress and altered insulin-signaling pathways. This review is mainly devoted to discuss evidence supporting the notion that mitochondrial dysfunction and oxidative stress are interconnected and intimately associated with the development and progression of Alzheimer's disease."
"Many epidemiological studies have shown that diabetes, particularly type 2 diabetes, significantly increases the risk to develop Alzheimer's disease. Both diseases share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and deposition of amyloidogenic proteins. It has been suggested that these two diseases disrupt common cellular and molecular pathways and each disease potentiates the progression of the other. This review discusses clinical and biochemical features shared by Alzheimer's disease and diabetes, giving special attention to the involvement of insulin signaling, glucose metabolism and mitochondria."
"The results demonstrate that AD is associated with early and striking increases in the molecular indices of oxidative stress, including up-regulation of NOS and NOX genes, which could impair the function of Complexes IV and V within the electron transport chain. The simultaneous reductions in cyto-protective mechanisms (UCP and PPAR), could allow oxidative injury to go unchecked and persist or increase over time. Adopting strategies to reduce the effects of NOS and NOX activities, and improve the actions of UCPs and PPARs may help in the treatment of AD."
"In this review, we examine current evidence supporting the involvement of mitochondria and mitochondrially generated stress signaling in AD and discuss potential implications for the mechanism of pathogenesis of this disease. Mitochondria are pivotal in controlling cell life and death not only by producing ATP, and sequestering calcium, but by also generating free radicals and serving as repositories for proteins which regulate the intrinsic apoptotic pathway. Perturbations in the physiological function of mitochondria inevitably disturb cell function, sensitize cells to neurotoxic insults and may initiate cell death, all significant phenomena in the pathogenesis of a number of neurodegenerative disorders including AD."
Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders.
Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders.
"Synaptic degeneration and death of neurons in limbic and cortical brain regions are the fundamental processes responsible for the manifestation of cognitive dysfunction and behavioural abnormalities in Alzheimer's disease (AD). Despite the various genetic and environmental factors, and the aging process itself that may lead to the manifestation of AD, multiple evidence from studies in experimental models and in AD brain tissue demonstrate that the underlying neurodegeneration is associated with morphological and biochemical features of apoptosis. At the cellular level, neuronal apoptosis in AD may be initiated by oxidative stress and related DNA damage, disruption of cellular calcium homeostasis, or endoplasmic reticulum (ER) stress. The molecular mechanisms of the biochemical cascades of apoptosis are beginning to be understood and involve upstream effectors such as Par-4, p53, and pro-apoptotic Bcl-2 family members, which mediate mitochondrial dysfunction and subsequent release of pro-apoptotic proteins, such as cytochrome c or apoptosis inducing factor (AIF), and subsequent caspase-dependent and -independent pathways which finally result in degradation of proteins and nuclear DNA."
"It has been argued that in late-onset Alzheimer's disease a disturbance in the control of neuronal glucose metabolism consequent to impaired insulin signalling strongly resembles the pathophysiology of type 2 diabetes in non-neural tissue. The fact that mitochondria are the major generators and direct targets of reactive oxygen species led several investigators to foster the idea that oxidative stress and damage in mitochondria are contributory factors to several disorders including Alzheimer's disease and diabetes. Since brain possesses high energetic requirements, any decline in brain mitochondria electron chain could have a severe impact on brain function and particularly on the etiology of neurodegenerative diseases. This review is primarily focused in the discussion of brain mitochondrial dysfunction as a link between diabetes and Alzheimer's disease."
" While the etiology of AD remains largely unclear, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in AD. Mitochondria are exceptionally poised to play a crucial role in neuronal cell survival or death because they are regulators of both energy metabolism and apoptotic pathways. This review is mainly focused in the discussion of evidence suggesting a clear association between mitochondrial dysfunction, autophagy impairment and amyloid-beta accumulation in Alzheimer's disease pathophysiology. The knowledge that autophagic insufficiency may compromise the cellular degradation mechanisms that may culminate in the progressive accumulation of dysfunctional mitochondria, aberrant protein aggregates buildup and lysossomal burden shield new insights to the way we address Alzheimer's disease."
Diabetes
"A growing body of evidence suggests that mitochondrial abnormalities are involved in diabetes and associated complications. This chapter gives an overview about the effects of diabetes in mitochondrial function of several tissues including the pancreas, skeletal and cardiac muscle, liver, and brain. The realization that mitochondria are at the intersection of cells' life and death has made them a promising target for drug discovery and therapeutic interventions. Here, we also discuss literature that examined the potential protective effect of insulin, insulin-sensitizing drugs, and mitochondrial-targeted antioxidants."
Mitochondria as a therapeutic target in Alzheimer's disease and diabetes.
"Due to the increasing number of data demonstrating a connection between diabetes and Alzheimer's disease (AD), efforts have been developed to elucidate the exact mechanism(s) underlying this connection. Although both disorders possess several overlapping features, mitochondrial dysfunction is one of the most relevant rendering mitochondria an important target of scientific research. This review discusses clinical and biochemical features shared by AD and diabetes, giving special attention to the involvement of mitochondria. The realization that mitochondria are at the intersection of cells' life and death has made them a promising target for drug discovery and therapeutic interventions. Here we also discuss in vitro, in vivo and clinical studies that examined the effect of mitochondria-directed therapeutics particularly mitochondrial target antioxidants and Szeto-Schiller peptides."
"An increasing number of studies have demonstrated a connection between Alzheimer's disease (AD) and diabetes, particularly type 2 diabetes (T2D). The risk for developing T2D and AD increases exponentially with age and having T2D increases the risk of developing AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. This review critically discusses the involvement of mitochondrial abnormalities and oxidative stress in AD and diabetes highlighting the similarities between both pathologies. The impact of insulin resistance/insulin signaling impairment in AD pathogenesis will be also debated. A better understanding of the key mechanisms underlying the interaction between AD and diabetes is needed for the design of effective preventive and therapeutic strategies."
"Evidence is mounting of the involvement of mitochondrial dysfunction in insulin resistance, diabetes and associated complications. This review aims to provide an overview of the effects of insulin resistance on mitochondrial function in several tissues. We consider the pathogenesis of insulin resistance from a mitochondrial perspective and contemplate potential beneficial effects of strategies aimed at modulating mitochondrial function in insulin resistance, including insulin and insulin-sensitizing drugs, antioxidants, and selectively targeting antioxidants to mitochondria."
Fibromyalgia is caused by mitochondrial dysfunction
People with Fibromyalgia experience a wide range of symptoms occurring in most of their body systems, including muscles, brain and nervous system, digestive system, urinary problems, joints and skin, and more. This range of symptoms indicates a systemic disease not isolated to one organ or type of tissue. Mitochondrial Dysfunction typically involves many different body systems as well, as nearly all cells (with the exception of red blood cells) have mitochondria in them to make their own energy. If the mitochondria are not able to make adequate energy for the cell than it's function will be diminished. When muscle cells don't have enough energy, they hurt. When the brain doesn't have enough energy you get brain fog, depression, memory and cognitive problems. Your digestive system won't break down and absorb nutrients from your food as well.
There are 3 basic approaches to improving mitochondrial function featured in this video. The first is to heal the gut because in many ways the gut's ability to absorb and produce the needed nutrients is the foundation for other approaches. This includes eating a variety of nutritious foods including taking probiotics, eating fresh fruits and vegetables in a variety of colors, low sugar intake, and high levels of healthy fats. Reduce inflammation which includes not eating gluten and dairy, taking anti-inflammatory supplements such as quercetin and fish oil, and a myriad of other supplements and changes in behavior. The third important thing is to heal the cell walls of the mitochondria so that they can better function and produce energy, which they do by creating a charge gradient between their two cell walls. This doctor advocates lipid therapy in which appropriate fats are administered intravenously in order to restore the fats of the mitochondrial walls which have been damaged by oxidative stress, something that occurs when mitochondria burn oxygen to make energy.
Mitochondrial diseases of the brain.
Fibromyalgia is caused by mitochondrial dysfunction
People with Fibromyalgia experience a wide range of symptoms occurring in most of their body systems, including muscles, brain and nervous system, digestive system, urinary problems, joints and skin, and more. This range of symptoms indicates a systemic disease not isolated to one organ or type of tissue. Mitochondrial Dysfunction typically involves many different body systems as well, as nearly all cells (with the exception of red blood cells) have mitochondria in them to make their own energy. If the mitochondria are not able to make adequate energy for the cell than it's function will be diminished. When muscle cells don't have enough energy, they hurt. When the brain doesn't have enough energy you get brain fog, depression, memory and cognitive problems. Your digestive system won't break down and absorb nutrients from your food as well.
There are 3 basic approaches to improving mitochondrial function featured in this video. The first is to heal the gut because in many ways the gut's ability to absorb and produce the needed nutrients is the foundation for other approaches. This includes eating a variety of nutritious foods including taking probiotics, eating fresh fruits and vegetables in a variety of colors, low sugar intake, and high levels of healthy fats. Reduce inflammation which includes not eating gluten and dairy, taking anti-inflammatory supplements such as quercetin and fish oil, and a myriad of other supplements and changes in behavior. The third important thing is to heal the cell walls of the mitochondria so that they can better function and produce energy, which they do by creating a charge gradient between their two cell walls. This doctor advocates lipid therapy in which appropriate fats are administered intravenously in order to restore the fats of the mitochondrial walls which have been damaged by oxidative stress, something that occurs when mitochondria burn oxygen to make energy.
Neurodegenerative Disease
"Neurodegenerative disorders are debilitating diseases of the brain, characterized by behavioral, motor and cognitive impairments. Ample evidence underpins mitochondrial dysfunction as a central causal factor in the pathogenesis of neurodegenerative disorders including Parkinson's disease, Huntington's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Friedreich's ataxia and Charcot-Marie-Tooth disease. In this review, we discuss the role of mitochondrial dysfunction such as bioenergetics defects, mitochondrial DNA mutations, gene mutations, altered mitochondrial dynamics (mitochondrial fusion/fission, morphology, size, transport/trafficking, and movement), impaired transcription and the association of mutated proteins with mitochondria in these diseases. We highlight the therapeutic role of mitochondrial bioenergetic agents in toxin and in cellular and genetic animal models of neurodegenerative disorders. We also discuss clinical trials of bioenergetics agents in neurodegenerative disorders. Lastly, we shed light on PGC-1α, TORC-1, AMP kinase, Nrf2-ARE, and Sirtuins as novel therapeutic targets for neurodegenerative disorders."
Mitochondria and neurodegeneration.
"Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question "is mitochondrial dysfunction a necessary step in neurodegeneration?" is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration."
Oxidative stress and neurotoxicity.
"There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field."
"The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinson's disease may be due to an environmental toxin with action(s) similar to those of MPTP."
"Mitochondrial dysfunction has long been associated with neurodegenerative disease. Therefore, mitochondrial protective agents represent a unique direction for the development of drug candidates that can modify the pathogenesis of neurodegeneration. This review discusses evidence showing that mitochondrial dysfunction has a central role in the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis. We also debate the potential therapeutic efficacy of metabolic antioxidants, mitochondria-directed antioxidants and Szeto-Schiller (SS) peptides. Since these compounds preferentially target mitochondria, a major source of oxidative damage, they are promising therapeutic candidates for neurodegenerative diseases. Furthermore, we will briefly discuss the novel action of the antihistamine drug Dimebon on mitochondria."
Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia.
"There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration."
"The mitochondria have several important functions in the cell. A mitochondrial dysfunction causes an abatement in ATP production, oxidative damage and the induction of apoptosis, all of which are involved in the pathogenesis of numerous disorders. This review focuses on mitochondrial dysfunctions and discusses their consequences and potential roles in the pathomechanism of neurodegenerative disorders. There are a number of neurodegenerative disorders whose pathogenesis has been demonstrated to involve multiple imbalances of the kynurenine pathway metabolism. These changes may disturb normal brain function and can add to the pathomechanisms of the diseases. In certain disorders, there is a quinolinic acid overproduction, while in others the alterations in brain kynurenic acid levels are more pronounced. A more precise knowledge of these alterations yields a basis for getting better therapeutic possibilities. The last part of the review discusses metabolic disturbances and changes in the kynurenine metabolic pathway in Parkinson's, Alzheimer's and Huntington's diseases."
"Synaptic degeneration and death of nerve cells are defining features of Alzheimer's disease (AD) and Parkinson's disease (PD), the two most prevalent age-related neurodegenerative disorders. In AD, neurons in the hippocampus and basal forebrain (brain regions that subserve learning and memory functions) are selectively vulnerable. In PD dopamine-producing neurons in the substantia nigra-striatum (brain regions that control body movements) selectively degenerate. Studies of postmortem brain tissue from AD and PD patients have provided evidence for increased levels of oxidative stress, mitochondrial dysfunction and impaired glucose uptake in vulnerable neuronal populations. Studies of animal and cell culture models of AD and PD suggest that increased levels of oxidative stress (membrane lipid peroxidation, in particular) may disrupt neuronal energy metabolism and ion homeostasis, by impairing the function of membrane ion-motive ATPases and glucose and glutamate transporters. Such oxidative and metabolic compromise may there-by render neurons vulnerable to excitotoxicity and apoptosis. Studies of the pathogenic mechanisms of AD-linked mutations in amyloid precursor protein (APP) and presenilins strongly support central roles for perturbed cellular calcium homeostasis and aberrant proteolytic processing of APP as pivotal events that lead to metabolic compromise in neurons. Interestingly, while studies continue to elucidate cellular and molecular events occurring in the brain in AD and PD, recent data suggest that both AD and PD can manifest systemic alterations in energy metabolism (e.g., increased insulin resistance and dysregulation of glucose metabolism). Emerging evidence that dietary restriction can forestall the development of AD and PD is consistent with a major "metabolic" component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable."
"There is substantial evidence that mitochondrial dysfunction and oxidative damage may play a key role in the pathogenesis of neurodegenerative disease. Evidence supporting this in both Alzheimer's and Parkinson's diseases is continuing to accumulate. This review discusses the increasing evidence for a role of both mitochondrial dysfunction and oxidative damage in contributing to beta-amyloid deposition in Alzheimer's disease. I also discuss the increasing evidence that Parkinson's disease is associated with abnormalities in the electron transport gene as well as oxidative damage. Lastly, I reviewed the potential efficacy of coenzyme Q as well as a number of other antioxidants in the treatment of both Parkinson's and Alzheimer's diseases."
Mitochondrial abnormalities and oxidative imbalance in neurodegenerative disease.
"An increasing body of evidence now suggests the involvement of mitochondrial abnormalities in the etiology of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer disease. In this Perspective, we describe a recent study that shows that treatment of human patients with the antioxidant coenzyme Q(10'), which functions in concert with certain mitochondrial enzymes, reduced the worsening of symptoms associated with PD. These findings are consistent with the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of PD and that treatments that target mitochondrial biochemistry might ameliorate the functional decline observed in patients suffering from PD."
"The neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), are age-related disorders characterized by the deposition of abnormal forms of specific proteins in the brain. AD is characterized by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles in the brain. Biochemical analysis of amyloid plaques revealed that the main constituent is fibrillar aggregates of a 39-42 residue peptide referred to as the amyloid-β protein (Aβ). PD is associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD is the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the presynaptic soluble protein called α-synuclein. There are various factors influencing the pathological depositions, and in general, the cause of neuronal death in neurological disorders appears to be multifactorial. However, it is clear, that the underlying factor in the neurological disorders is increased oxidative stress substantiated by the findings that the protein side-chains are modified either directly by reactive oxygen species (ROS) or reactive nitrogen species (RNS), or indirectly, by the products of lipid peroxidation."
Mitochondria, oxidative damage, and inflammation in Parkinson's disease.
"The pathogenesis of Parkinson's disease (PD) remains obscure, but there is increasing evidence that impairment of mitochondrial function, oxidative damage, and inflammation are contributing factors. The present paper reviews the experimental and clinical evidence implicating these processes in PD. There is substantial evidence that there is a deficiency of complex I activity of the mitochondrial electron transport chain in PD. There is also evidence for increased numbers of activated microglia in both PD postmortem tissue as well as in animal models of PD. Impaired mitochondrial function and activated microglia may both contribute to oxidative damage in PD. A number of therapies targeting inflammation and mitochondrial dysfunction are efficacious in the MPTP model of PD. Of these, coenzyme Q(10) appears to be particularly promising based on the results of a recent phase 2 clinical trial in which it significantly slowed the progression of PD."
"A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease.
A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons."
A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons."
"In Parkinson's disease mitochondrial dysfunction can lead to a deficient ATP supply to microtubule protein motors leading to mitochondrial axonal transport disruption. Compromised axonal transport will then lead to a disorganized distribution of mitochondria and other organelles in the cell, as well as, the accumulation of aggregated proteins like alpha-synuclein. Moreover, axonal transport disruption can trigger synaptic accumulation of autophagosomes packed with damaged mitochondria and protein aggregates promoting synaptic failure. We previously observed that neuronal-like cells with an inherent mitochondrial impairment derived from PD patients contain a disorganized microtubule network, as well as, alpha-synuclein oligomer accumulation. In this work we provide new evidence that an agent that promotes microtubule network assembly, NAP (davunetide), improves microtubule-dependent traffic, restores the autophagic flux and potentiates autophagosome-lysosome fusion leading to autophagic vacuole clearance in Parkinson's disease cells. Moreover, NAP is capable of efficiently reducing alpha-synuclein oligomer content and its sequestration by the mitochondria. Most interestingly, NAP decreases mitochondrial ubiquitination levels, as well as, increases mitochondrial membrane potential indicating a rescue in mitochondrial function. Overall, we demonstrate that by improving microtubule-mediated traffic, we can avoid mitochondrial-induced damage and thus recover cell homeostasis. These results prove that NAP may be a promising therapeutic lead candidate for neurodegenerative diseases that involve axonal transport failure and mitochondrial impairment as hallmarks, like Parkinson's disease and related disorders."
Cardiac and Vascular Disease
"Energetic abnormalities in cardiac and skeletal muscle occur in heart failure and correlate with clinical symptoms and mortality. It is likely that the cellular mechanism leading to energetic failure involves mitochondrial dysfunction. Therefore, it is crucial to elucidate the causes of mitochondrial myopathy, in order to improve cardiac and skeletal muscle function, and hence quality of life, in heart failure patients."
"Energetic abnormalities in cardiac and skeletal muscle occur in heart failure and correlate with clinical symptoms and mortality. It is likely that the cellular mechanism leading to energetic failure involves mitochondrial dysfunction. Therefore, it is crucial to elucidate the causes of mitochondrial myopathy, in order to improve cardiac and skeletal muscle function, and hence quality of life, in heart failure patients."
"Endothelium-derived nitric oxide (NO) is a paracrine factor that
controls vascular tone, inhibits platelet function, prevents adhesion of
leukocytes, and reduces proliferation of the intima. An enhanced
inactivation and/or reduced synthesis of NO is seen in conjunction with
risk factors for cardiovascular disease. This condition, referred to as
endothelial dysfunction, can promote vasospasm, thrombosis, vascular
inflammation, and proliferation of vascular smooth muscle cells.
Vascular oxidative stress with an increased production of reactive
oxygen species (ROS) contributes to mechanisms of vascular dysfunction.
Oxidative stress is mainly caused by an imbalance between the activity
of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine
oxidase, or the mitochondrial respiratory chain) and anti-oxidative
enzymes (such as superoxide dismutase, glutathione peroxidase, heme
oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase, and
paraoxonase) in favor of the former."
