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INVITED REVIEWS
1Department of Medical Microbiology, Immunology and Cell Biology; and 2Department of Neurology, Southern Illinois University School of Medicine, Springfield, Illinois
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ABSTRACT |
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bioenergetics; synaptic dysfunction; neurodegeneration; nicotinamide adenine dinucleotide; free radicals; mitochondrial membrane potential
5% of AD cases are caused by known genetic abnormalities. The pathogenic pathways leading to neurodegeneration in AD include accumulation of aberrant or misfolded proteins, ubiquitin-proteasome system dysfunction, excitotoxic reactions, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis, dysfunction of axonal and dendritic transport, and misoperation of chaperones (46, 130). The presence of extracellular amyloid-
(A) peptide-containing neuritic plaques and intracellular neurofibrillary tangles and the loss of synapses in defined regions of the brain are the hallmarks associated with both familial and sporadic AD postmortem pathology. A deposition in the plaques is composed of a 39- to 42-amino acid peptide (A), which is the proteolytic product of the amyloid precursor protein (APP) (182). Although the underlying cause for the selective neuronal loss remains unclear, experimental approaches indicate that fibrillar or oligomeric A accumulation in vivo may initiate and/or contribute to the process of neurodegeneration observed in the brain (66, 272). Neurodegeneration could result from A acting to inhibit mitochondrial function as part of a cascade of mitoenergetic failure (90, 155). The major obstacle in managing the disease and designing rational therapeutic targets is our incomplete understanding of the pathogenesis of the disease. Several hypotheses, mainly focusing on these hallmarks, have been proposed in an attempt to explain the pathogenesis of AD, including theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation, and inflammation. Unfortunately, despite strong evidence that these aspects are associated with AD and almost certainly play a role in the disease process, no single one of these theories is sufficient to explain the spectrum of abnormalities found in the disease. Therefore, it is worthwhile to look for a fundamental initiator of the pathophysiological cascade. Dysregulation of mitochondrial metabolism together with oxidative abnormalities may be such an initiator for the major known pathological events (276). The recent short-term improvement of AD patients treated with memantine implies a need for better control of responses to glutamate toxicity (148), including calcium dysregulation and oxidative stress. Oxidative stress and therapeutic interventions have been extensively reviewed (121, 204). Given the known differences in energy metabolism between the normal and AD brain (22, 207), we discuss the need for further investigation of the neural mechanisms through which brain cell functions influence energy balance during cellular stress. As such, targeting both oxidative stress and mitochondrial energy metabolism may be therapeutically efficacious for the treatment of AD. Therefore, in this review, we focus on the role of reduction in mitochondrial activity and energy availability for neuronal function, depletion of energy metabolizing substrates in AD, and potential therapeutic targets. We also comment on the role of dysregulation in calcium homeostasis and oxidative stress in mediating the effects of mitochondrial respiratory chain and DNA damage for AD pathogenesis.
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NORMAL BRAIN ENERGY METABOLISM |
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90% of the required energy for cellular functions (264) by two linked metabolic processes: the citric acid cycle (anaerobic) and the electron transport chain (ETC; aerobic). Under aerobic conditions, the majority of ATP used to maintain cellular homeostasis results from oxidation of the glycolytic product pyruvate. ATP-generating systems, including glucose uptake, glycolysis, NADH, and fatty acid oxidation (260), are induced with a rise in AMP-to-ATP ratio by activation of AMP-activated protein kinase (54, 110). However, to fulfill all cellular energetic needs, such arrangements are insufficient (83). Thus other homeostatic mechanisms contribute to efficient intracellular energetic communication in maintaining the ATP-generating and ATP-consuming processes. Such systems include intracellular enzymatic networks, catalyzed by creatine kinase, adenylate kinase, carbonic anhydrase, and glycolytic enzymes (82, 223, 265). The creatine kinase-creatine phosphate and adenylate kinase systems facilitate processes in the brain that would otherwise depend entirely on the diffusion of ATP and ADP (for review, see Ref. 3). Creatine kinase is a major phosphotransfer system in cells specifically located at places of energy metabolism (266) and acts in concert with other enzymatic systems to facilitate intracellular energetic communication (84, 127, 190) and enhancement of cytoplasmic high-energy phosphates (39). Because of its location at the adenine nucleotide transporter on the mitochondrial membrane, intramitochondrial ATP is actually released from mitochondria by interconversion to phosphocreatine (228). The importance of phosphocreatine to the heart and its role in the protection from heart attacks (222) probably also apply to the brain and brain attacks (strokes). Both mitochondrial and cytosolic creatine kinase isozymes are active in brain cells with high and variable ATP metabolic rates (119). The importance of phosphocreatine to energetic homeostasis is indicated by promotion of hypoxic seizures (120) and glutamate and A toxicity (30) in its absence. The central focus underlying brain energy metabolism is predominantly, if not exclusively, placed on neuronal energy metabolism. However, other brain cells such as glial and vascular endothelial cells play an active role in the flux of energy substrates to neurons (156). Brain cells generate most of the energy in the form of ATP through the mitochondrial ETC coupled to oxidative phosphorylation from the oxidation of NADH, a substrate for complex I, and FADH2, a complex II substrate (Fig. 1) with atomic oxygen to generate water and ATP. NADH and FADH2 serve as electron carriers by transferring electrons derived from glycolysis and Krebs cycle into the ETC through NADH:ubiquinone oxidoreductase (complex I) and succinate:ubiquinone oxidoreductase (complex II), respectively. Ubiquinone:cytochrome c-oxidoreductase (complex III) couples the oxidation of ubiquinol to cytochrome c reduction (217), whereas cytochrome c:oxygen oxidoreductase (complex IV) catalyzes the oxidation of cytochrome c, which ultimately reduces molecular oxygen to water (52, 116). During redox cycling, released potential energy drives the extrusion of protons across the mitochondrial inner membrane at complexes I, III, and IV. This electrochemical gradient produced as a result of proton translocation powers ATP synthesis by the activity of ATPase (153). It is possible to measure in vivo O2 consumption and ATP synthesis rates, which lead to assessment of the mitochondrial ATP-to-O2 or P-to-O ratio (162). The P-to-O ratio represents the efficiency of coupling between mitochondrial phosphorylation and oxygen consumption.
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-hydroxybutyrate, derived from fat metabolism in the liver, are transported into the brain through the blood-brain barrier via monocarboxylic transporters (202, 134). The basal rate of glucose utilization in astrocytes is higher than in neurons (156). A metabolic compartmentation exists whereby glucose taken up by astrocytes is metabolized to lactate glycolytically, which is then released in the extracellular space to be utilized by neurons. Lactate, which is characteristically found in the brain, can sustain synaptic activity by serving as an energy source through pyruvate by lactate dehydrogenase (20). Pyruvate is another important energy substrate abundantly distributed in brain synapses (191). Because of limited permeability across the blood-brain barrier, both lactate and pyruvate cannot adequately substitute for plasma glucose to maintain normal brain function (200); however, they are useful metabolic substrates for neurons if formed inside brain parenchyma (123, 253). Mitochondrial electron transport is not always perfect. Even under ideal conditions, some electrons "leak" from the ETC and interact with oxygen to produce superoxide anion and other reactive oxygen nitrogen species. Leakage of electrons can increase significantly with mitochondrial dysfunction during aging. The close proximity of mitochondrial DNA (mtDNA) to the flux of reactive oxygen nitrogen species and the relative lack of mtDNA protection and repair mechanisms lead to free radical-mediated mutations and deletions (135).
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DECLINES IN SYNAPTIC ACTIVITY AND ENERGY DEMAND |
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(172). In several different animal and cell culture models of AD, overactivation of glutamate receptors, which are concentrated on postsynaptic spines of neuronal dendrites, plays an important role in the neuronal death process (17, 105). Studies on transgenic mice expressing AD-linked APP and/or PS1 mutations have provided considerable support for the importance of perturbation of calcium homeostasis in AD (137). Synaptic loss associated with downstream processes may elicit neurodegeneration through reduction in metabolic activity, regional cerebral blood flow (150), and activation of microglia (125). Neuronal-astrocytic interactions are also impaired during AD (115, 157). Does synaptic loss occur because of excess release of glutamate or increased susceptibility to glutamate levels released by young neurons? The clinical success of memantine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, could support either of these possibilities. Our study (29) of aging rat neurons support the increased susceptibility hypothesis as an age-related contributor to the problem. The basic question is where does synaptic pathology start? Distal dendrites are first to be affected before the appearance of neurofibrillary tangles (28). Synaptophysin as a presynaptic marker is lost early in the AD frontal cortex (166).
Synaptic plasticity is likely dependent on the capacity of neurons to meet energy demands to maintain ionic homeostasis (261). Emerging evidence indicates that events associated with energy balance can impact synaptic and cognitive function (149). Brain-derived neurotrophic factor (BDNF) has been found to facilitate synaptic plasticity (183) through modulation of molecules such as synapsin I and cAMP-response element-binding protein, which have been implicated in synaptic function underlying learning and memory (270). Given the involvement of BDNF in energy balance and synaptic plasticity, a central question is whether alterations in energy balance can impact aspects of synaptic plasticity modulated by BDNF. A role of uncoupling protein 2 (UCP2), a member of the super family of UCPs located in the mitochondrial inner membrane and abundantly expressed in the hippocampus (215), may support the synapse (7). UCP2 may function to control reactive oxygen species (ROS) production during increased energy consumption. There is a critical need to identify genetic and imaging tracers to predict synaptic dysfunction before the appearance of substantial clinical symptoms of AD to initiate effective synaptic-preserving therapy. Pharmaceutical and neutraceutical interventions could then be tested on a shorter time scale than the 6–12 mo now required for clinical trials in AD.
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METABOLIC DECLINE: EVIDENCE FROM IMAGING STUDIES |
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4 for apolipoprotein E with no signs of cognitive impairment, known as a risk factor in late-onset AD (213). Although significant changes in energy metabolism are seen in AD, a major mechanistic issue remains regarding whether vascular aging or pathology causes the deficit or whether the reductions in metabolic rates measured in vivo arise from decreased neuronal function following neuronal loss or synaptic degeneration. |
PYRIDINE NUCLEOTIDES AS PRIMARY ENERGY SUBSTRATES |
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NAD+ is required for Sir2 deacetylase activity (103), a NAD-dependent histone deacetylase (9). Its activation is central to promoting increased life span in yeast and Caenorhabditis elegans (128). In humans and rodents, seven molecules that share the Sir2-conserved domain [sirtuin (SIRT) 1 to 7] have been identified (40). SIRT1 is located in the nucleus and is involved in chromatin remodeling and the regulation of transcription factors such as p53 (154), whereas other SIRT proteins are located within the cytoplasm and mitochondria (196, 194). Both SirT1 and the Sir2 family of protein deacetylases and poly(ADP-ribose) polymerase (PARP) are involved in major NAD-dependent nuclear enzymatic activities. Increased nuclear NAD+ biosynthesis and consequent activation of the protein deacetylase SIRT1 have been found to protect against axonal degeneration (9). A decrease in NAD+ levels could stimulate neurodegeneration.
NAD+ is closely tied to cellular metabolism and genomic DNA repair (142). PARP (EC 2.4.2.30 [EC] ), a nuclear enzyme that is activated by double- or single-stranded breaks in DNA (229) and thought to assist in DNA repair by the ADP ribosylation of histones and other nuclear proteins (263), is another major consumer of the NAD+ pool. PARP-1 activity is detected in both neuronal and nonneuronal cells in the central nervous system (CNS), and excessive PARP-1 activity is known to be detrimental to tissue because of the cellular energy loss (107). PARP and poly(ADP-ribose) can be detected in the frontal and temporal cortex of AD patients, suggesting significant consumption of NAD+ stores (153). Both NAD+ and NADP are substrates for PARP (179). Depletion of intracellular NAD+ by PARP has been observed in conditions associated with excess free radical burden and DNA damage (229). The activated enzyme catalyzes the transfer of ADP-ribose units from NAD+ to a protein acceptor to produce ADP-ribose polymers. As a result, cellular NAD+ concentrations rapidly decline, thus posing a heavy demand on cellular ATP stores for resynthesis of NAD+ (206). When cells cannot overcome this energy crisis, cell death occurs via necrotic-type pathways (106). Other intracellular events that affect NAD+ levels or NAD+-to-NADH ratios, such as energy transfer through respiration, may also affect physiological and pathological processes in the nervous system through SIRT1-dependent pathways (146). It is possible that alteration of NAD+ levels by manipulation of the NAD+ biosynthetic pathway, Sir2 protein activity, or other downstream effectors will provide new therapeutic opportunities for the treatment of diseases involving axonopathy and neurodegeneration (9).
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CONSEQUENCES OF NAD DECLINE: ENERGY CRISIS |
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The oxidation of NADH by complex I of the ETC is coupled to the phosphorylation of ADP by ATP synthase. The relationship between the rate of ATP production and the ratio of reduced NADH to oxidized NAD+, known as the redox ratio, has been used to measure metabolic states in single cells by fluorescence techniques (80). In neurons cultured from 24-mo-old rats, we found an age-related reduction in NAD(P)H at rest that suggests an imbalance in production and demand (Fig. 2). Glutamate treatment that stimulates an influx of Ca2+ caused a robust decline in NAD(P)H in old neurons compared with that shown in middle-age and embryonic neurons, as complex I tries to keep up with the need for electrons to power the proton gradient and ATP production (Parihar and Brewer, unpublished observations). These findings could explain the vulnerability of old neurons to metabolic stressors (29). Considering the number of enzymes and transcription factors sensitive to the redox potential (232) or oxidized with age (42), the observed decreases in NAD(P)H, glutathione, and NAD(P)H redox ratio may be of pathophysiological relevance for aging and neurodegenerative diseases.
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CHANGES IN EXPRESSION OF MITOCHONDRIAL GENES |
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mtDNA MUTATIONS AFFECTING ENERGY TRANSFER |
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DECLINES IN MITOCHONDRIAL ENZYMES |
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-ketoglutarate dehydrogenase complex (KGDHC), which catalyzes a key step in the TCA cycle and is also an enzyme of glutamate metabolism; and 3) COX, the component of the ETC that uses molecular oxygen as one of its substrates.
Reductions in the key TCA cycle enzyme complexes, KGDHC (21) and PDHC (233, 247), are associated with chronic neurodegenerative disorders, including AD. The reduction in KGDHC activity may be responsible for the decreases in brain metabolism; its activity correlates better with the degree of cognitive impairment than does the amount of amyloid plaques or neurofibrillary tangles (97). Others agree that abnormally low levels of PDHC deficiency occur not only in regions of brain that are neuropathologically damaged in AD but also in regions that are histopathologically normal (45). COX is kinetically abnormal, and its activity is decreased in brain and peripheral tissue in late-onset AD (73). COX deficiency is found in the regions of brain that show histopathological damage in AD (225, 238). Mitochondria isolated from rat brain and other tissues showed a direct effect of micromolar A on mitochondrial respiration (51), ATP synthesis (186), and activities of various enzymes involved in energy transfer (55, 113, 235). A direct interaction of A with mitochondrial membranes could be the cause of perturbation of mitochondrial properties (187) and inhibition of COX activity in AD (51). These findings were strengthened by studies of Aleardi et al. (2), who observed a concentration-dependent decrease in ATP/O (number of moles of ATP produced per g-atom of oxygen consumed by the respiratory chain), respiratory chain complex inhibition, a potentiation of ROS production, and cytochrome c release. These abnormalities in brain mitochondrial metabolism precede the onset of neurological dysfunction as well as gross neuropathology of AD. As early events, they should be investigated as potential therapeutic targets.
Levels of mRNA for COX subunits I and III encoded by mtDNA that are sensitive to neuronal metabolic demands are decreased in AD brain regions that demonstrate neuropathology, such as midtemporal association neocortex, but are not changed in the relatively unaffected primary sensory and motor cortices (61, 189). The distribution of decreased COX activity and mRNA in the postmortem AD brain corresponds to premortem-decreased glucose metabolism (211). Therefore, COX III mRNA levels and COX activity appear to be useful as indicators of impaired neuronal function in AD. Because the COX activity reduction under these conditions has been linked to a decrease in neuronal firing, a decrease in Na+-K+-ATPase activity, and presumably a decrease in utilization and demand for ATP (269), reductions in COX activity and mitochondrial mRNA transcripts in AD reflect a primary defect in mitochondrial energy metabolism (12). The question of whether downregulation of various respiratory chain complexes with age and also in AD has a genetic or epigenetic basis for the shutting down of ATP production in glycolysis, the TCA cycle, and the ETC and/or consequence of an increased oxidant activity remains open for further investigation.
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PROTON LEAKS AND UNCOUPLING |
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REGULATION AND DYSREGULATION OF CALCIUM DYNAMICS |
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m) in general (68) and the plasma membrane potential in particular. Ca2+ activates neurotransmitter vesicle release after action potential through voltage-gated calcium channels (133). Elevated intracellular calcium affects enzymes involved in normal cellular and physiological processes, including several protein kinases and phospholipases (257), cytoskeletal integrity (227), and synaptic transmission between neurons (36, 220, 221). The major fast metabolic effect of elevated mitochondrial calcium is activation of dehydrogenases of the TCA cycle (177, 219). However, increases in calcium also play a critical role in pathophysiological events, such as excitotoxicity in several neurodegenerative diseases. The mechanism of events occurring downstream of neuronal calcium overloading and neurodegeneration is being actively investigated.
Dysregulation of intracellular calcium signaling has been implicated in the pathophysiology of AD (175), which occurs during the initial phase of the disease, before the development of symptoms (254). Abnormal calcium regulation and an increased production of neurotoxic A and both APP and presenilin-1 (PS1) mutations in AD patients support a role for perturbed calcium homeostasis in AD. Increased accumulation of intracellular calcium elicits the accumulation of A and the hyperphosphorylation of tau and neuronal death (137). Because disruption of calcium homeostasis is an important mechanism underlying such loss of neurons, this function of PS1 may lead to apoptotic neuronal cell death in AD (59). PS1 is intimately linked to cellular calcium homeostasis, and AD-related mutations of PS1 can alter inositol trisphosphate-coupled intracellular calcium stores and calcium influx pathways (273). Dysregulation of calcium homeostasis has also been demonstrated in fibroblasts from patients with AD and in fibroblasts and neurons from transgenic mice bearing a PS1 mutation (122). The deregulation of calcium homeostasis in aging is evident from our report of an age-related increase in resting intracellular calcium in hippocampal neurons that becomes profoundly dysregulated after glutamate exposure (33). Interestingly, we found that the dysregulation, glutamate toxicity, and A toxicity could all be reversed by pretreatment with estrogen. Therefore, rapid inactivation of calcium currents is the critical step terminating calcium influx and preventing calcium overloading of the cell (234).
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ROS PRODUCTION AND OXIDATIVE STRESS |
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(60). Low levels of ROS are important for many life-sustaining processes of cells and tissues (95, 261), but they induce cell damage and death at higher levels. In normal aging, ROS production increases, whereas the antioxidant capacity fails to increase sufficiently (163, 208). Observations that support the concept of oxidative stress in aging have been well supported by evidence of oxidative damage in isolated mitochondria (246). A number of related questions concern the nature of the ROS present in mitochondria and what are the steady-state concentrations of the O2– vs. H2O2 in AD patients (91). The primary ROS generated in the organelle is O2–, which is rapidly converted to H2O2 by mitochondrial manganese superoxide dismutase or cytosolic copper/zinc superoxide dismutase enzymes. The resulting H2O2 is reduced to water by glutathione peroxidase or catalase. Ubisemiquinone, localized at the CoQ binding sites of complexes I, II, and III, appears to be the primary electron donor (136, 256). However, H2O2, in the presence of reduced transition metals, is converted to the highly reactive hydroxyl radical (OH). The redox state of the mitochondrial respiratory chain is the primary factor governing mitochondrial ROS generation, and this property is inherently governed by the trans-membrane proton gradient (pH) and the 
m. Inhibitors such as rotenone (complex I) or antimycin (complex III) increase mitochondrial ROS production by raising the concentration of electron donors. The pathophysiological inhibition of any of these sites results in an upregulation of ROS formation (34). The Fe-S centers of these complexes are major targets for acute ROS toxicity. Hence, mitochondria are particularly sensitive to oxidative stress (11, 99).
Because age is the major risk factor for AD, it is reasonable that the aging process itself plays an important role in promoting oxidative stress in the aging brain. The major question in these studies is whether oxidative damage increases in mitochondria with age, which terminal-oxidizing species are most likely to cause it, and which targets (proteins, lipids, DNA) are most susceptible to damage. The brain is particularly susceptible to the damaging affects of ROS because of its high metabolic rate, its high unsaturated lipid-to-volume ratio, and its reduced capacity for cellular regeneration compared with other organs (6). Thus neurons are particularly susceptible to life-long accumulation of oxidative damage. Oxidative stress and free radical damage have been consistently associated with AD pathogenesis (44, 164, 198, 203). Proteins that are involved in protofibril formation might themselves produce oxidative stress. This assumption is based on the findings of the occurrence of A within brain mitochondria of human AD patients (71, 155) and transgenic mice (5). The accumulation of A in mitochondrial membranes inhibits enzymatic activity of respiratory chain complexes (III and IV) (56, 71, 161) in the presence of Cu2+ in a dose-dependent manner (71), causes reduction in the rate of oxygen consumption (56), and enhances ROS production (161). An increase in A deposition resulted in the induction of oxidative stress in transgenic mice overexpressing mutant APP and PS1 (168) and has been demonstrated to produce H2O2 in cultured cells (14). Age-related alterations in proteolytic processing of APP have been suggested to play a major role in the increased levels of oxidative stress in neurons in AD (171). This abnormality leads to neuronal death, which manifests as cognitive impairment and the development of brain pathology, as in AD. Thus both protein aggregation and oxidative stress clearly have an important impact on one another; however, it is difficult to determine whether oxidative stress or protein aggregation is the initiating event in neurodegeneration. It is still unclear whether oxidative stress is the primary initiating event or is the result of a secondary response associated with neurodegeneration in AD. Results emerging from cell and animal model studies will continue to have an enormous impact on the development of future human clinical antioxidant trials for these disorders.
Much evidence for increased levels of cellular oxidative stress in vulnerable regions of AD comes from analyses of tissue homogenates from postmortem brain tissue, which were compared with the same brain regions from age-matched controls and to less vulnerable brain regions from the same patients (241). For example, markers for lipid peroxidation, including 4-OH-nonenal and malondialdehyde, and protein nitration as a marker of protein oxidation have been identified in the cortex and hippocampus of patients with AD (8, 43, 243). Protein carbonyls in brain samples of AD patients are greater than those in age-matched controls and correlate well with tangles (244). Cellular injury during AD marked by the presence of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative damage in intact DNA, was examined in the cerebrospinal fluid of AD patients, suggesting that these patients suffer from impaired DNA repair. mtDNA damage could also have greater implications than damage to nuclear DNA, since the whole mitochondrial genome codes for genes that are expressed, whereas nuclear DNA contains a large number of sequences that are not transcribed in the brain (258). The accumulation of free radicals and mtDNA mutations during the life span can lead to progressive mitochondrial dysfunction and decreased ATP levels, which in turn might influence the neuropathology of late-onset neurodegenerative diseases such as AD. The resultant oxidative damage to mitochondria may increase oxidized proteins with age (18, 25), and these may also cause mitochondrial decline in energy transfer perhaps due, in part, to altered conformation of critical enzymes (98). The significant loss of mitochondrial cardiolipin, coupled with oxidation of critical thiol groups in key proteins, may adversely affect cytochrome c-oxidase activity necessary for mitochondrial function (199). Levels of malondialdehyde in the neocortex of the brain of individuals with AD (197) and 4-OH-nonenal in the plasma of patients with AD (180) are elevated. Chronic oxidative stress can also reduce expression of metabolic enzymes as part of the stress response mediated by signaling pathways through redox-sensitive transcription factors, kinases, and phosphatases (214, 254). These changes could directly impact the ability of mitochondria to maintain their membrane potential and energy transfer.
In addition to ROS, reactive nitrogen species such as nitric oxide (NO) and peroxynitrite (ONOO–) are also synthesized in mitochondria. NO is synthesized from L-arginine by a constitutive isoform of nitric oxide synthase (NOS) called mitochondrial NOS (mtNOS) (251, 275). mtNOS has been identified as the neuronal NOS isoform (89), and it is likely coded by the same neuronal NOS gene (129). The level of basal NO appears to be a key factor in this regulatory process (74). The activation of NOS in mitochondria brings about a decrease in oxygen consumption and regulation of cellular energetic metabolism (193). In addition, NO causes reversible inhibition of COX activity (37), a regulation that can explain the existence of mtNOS (184). The mitochondrial respiratory chain is sensitive to both NO- and ONOO–-mediated damage (210). NO is suggested to play an important role in A-induced mitochondrial dysfunction and cell death (131). However, the role of NO in regulation of mitochondrial functions, including energy homeostasis, has not been fully explored. The threshold level of O2–, which favors reaction with NO to generate ONOO– and plays a significant role in mitochondrial decay, warrants study in greater depth.
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DEPLETION OF ENERGY AND GLUTAMATE EXCITOTOXICITY |
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, 2) increases in NMDA receptor activation in response to A, 3) downregulation of glutamate transporters in AD, 4) inhibition of glutamate reuptake by A, 5) increased hyperphosphorylation of tau by NMDA receptor activation, 6) protection conferred by the NMDA receptor antagonist memantine from intrahippocampal injection of A (148), and 7) clinical efficacy of memantine (148).
During acute and chronic neurodegenerative disorders, disruption of energy metabolism impairs the clearance of glutamate (58, 78, 157). Excitotoxicity propagates in a chainlike manner as dying neurons release more glutamate to neighboring neuronal cells, particularly during ischemia and stroke. Does improving energy metabolism also prevent glutamate toxicity in neurodegenerative disorders? One study from our group (30) showed protection from glutamate and A toxicity by preloading neurons with creatine. We hypothesize that long-term energy deficiencies lead to failure to reduce intracellular calcium and overactivation of NMDA receptors to cause excitotoxicity, since short-term energy failure is not toxic to neurons with healthy energetics (148).
Electron paramagnetic resonance spectroscopy provided direct evidence that NMDA receptor activation leads to the generation of superoxide radicals (138). Schulz et al. (230) provided the first in vivo evidence that excitotoxic neuronal injury is linked to free radical generation and showed the depletion of antioxidant glutathione in neurodegeneration. Glutamate toxicity may involve defects in electron transport complexes or other perturbations of mitochondria, which can be responsible for excess production of ROS (81, 109). Expression of AD-linked PS1 mutations in cultured neural cells and transgenic mice results in aberrant processing of APP (111) and increased vulnerability of neurons to apoptosis and excitotoxicity (13). Glutamate and A insults cause impairment of calcium homeostasis in neurons expressing mutant PS1 (104). This perturbed calcium homeostasis appears to contribute to increased levels of cellular oxidative stress and mitochondrial dysfunction in neurons subjected to apoptotic insults. A strong indication of the mitochondrial ROS generation in glutamate neurotoxicity derives from evidence that enhanced cellular O2– production and cytotoxicity are abolished in the presence of rotenone and oligomycin, inhibitors of mitochondrial complexes I and IV (57). In addition, NOS, which is induced by activation of the NMDA receptor, generates NO, as well as O2– and H2O2. The immediate consequence of glutamate excitotoxicity and reduced respiration may be the depolarization of m.
Several studies have identified depolarized m in brain mitochondria after NMDA receptor activation and elevated intracellular calcium (226). The relationship of ROS production and membrane depolarization could be clarified from the time course of the ROS production in relation to m in response to glutamate exposure. We used laser scanning confocal microscopy to simultaneously observe both ROS production and changes in m in individual mitochondria as a function of age in the rat neurons (Parihar and Brewer, unpublished observations). Fluorescent labeling with tetramethylrhodamine ethyl ester monitors m, and simultaneously monitors ROS with 2',7'-dichlorofluorescin diacetate. In response to 5-, 10-, and 15-min exposure to glutamate, individual mitochondria increased the ROS levels simultaneous with depolarization of m for all ages (Fig. 3). However, age-related deficits were observed before glutamate (time 0), which give old neurons a head start in m depolarization and ROS production. This mitochondrial head start may prove to be the catastrophic age-related deficit that makes old neurons more susceptible to glutamate and A (29). In a comparison of p53-overexpressing senescent cells with preapoptotic PC12 cells, Sugrue et al. (250) also found decreased m in aged cells. Fluctuations in m reflect an intermediate, unstable state of mitochondria that may lead to or reflect mitochondrial permeability transition or calcium cycling (216). In addition to causing mitochondrial membrane depolarization, increased mitochondrial oxidative stress, and dysregulation in calcium homeostasis, A can cause damage to mtDNA (27), although it is not known whether DNA damage precedes or follows mitochondrial dysfunction. Overall, our results showed a high rate of ROS production and depolarization of membrane potential in old neurons, which may be one of the most relevant causes of cell impairment during excitotoxicity. In particular, these events could impair mitochondrial energy transfer, enhancing depletion of cellular energy stores and leading to metabolic catastrophe.
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WHAT FACTORS DETERMINE HOW A NEURON WILL DIE? |
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m and AIF release from mitochondria (139). Our study (32) of age-related elevation in caspase-3 in old neurons at rest supports a head start on the path to apoptosis.
The mitochondrial permeability transition can be stimulated to open by uptake of excessive calcium, increased oxidative stress, and decreased m, ADP, and ATP (100). Thus inhibition of oxidative phosphorylation in disease states increases the susceptibility of cells to undergo apoptosis (38, 165). The energetic state of the cell determines whether a given stress can be tolerated or whether this leads to energetic failure based on certain thresholds (192). Dropping ATP levels too low results in necrotic cell death; however, without severe ATP depletion, apoptosis develops instead. If ATP is depleted during the progression of apoptosis, necrotic cell death will intervene to produce the secondary necrosis that is so often associated with apoptosis (41).
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ANTIOXIDANT DEFENSES |
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THERAPEUTIC TARGETS |
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m (–150 to –170 mV), drugs effective in controlling ROS production and detoxification can be delivered by covalent attachment to a lipophilic cation (188). Mitochondrial-targeted derivatives of vitamin E and coenzyme Q show efficacy in protecting mitochondria from oxidative damage (101). Heat shock proteins (70-kDa heat shock protein and 78-kDa glucose-regulated protein) that can be increased by dietary restriction are expressed in cortical, striatal, and hippocampal neurons in AD (209) and confer cytoprotection in neurodegenerative disease and aging (49). Recently, several in vivo (169) and in vitro (76) studies have suggested the neuroprotective potentiality of some energy substrates against neuronal damage induced by excitotoxicity, oxidative stress, and metabolic inhibition. Therapeutic strategies for reducing neurodegeneration could address restoration of m and reduction of elevated A secretion. Creatine is neuroprotective against A-induced neurotoxicity in hippocampal cultured neurons (30) and shows promise for treatment of Huntington disease (114). Pyruvate is neuroprotective against glutamate-mediated neuronal damage (167). N-acetyl-L-carnitine and lipoic acid given to old rats improve memory loss and lower nucleic acid oxidation (4). In an APP + PS1 mouse model of AD, supplementation with blueberry extract prevented the behavioral decline in these animals (126). Does this represent the slowing of a mitochondrial function or the delaying of the pathological process of mitochondrial damage? Understanding the dynamic stages and subsequent loss of mitochondrial membrane permeability and the eventual induction of apoptotic and inflammatory activation may ultimately serve to elucidate therapeutic strategies linked to brain cellular metabolism. |
CONCLUSION |
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GRANTS |
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FOOTNOTES |
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REFERENCES |
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  J. Nilsen, R. W. Irwin, T. K. Gallaher, and R. D. Brinton Estradiol In Vivo Regulation of Brain Mitochondrial Proteome J. Neurosci., December 19, 2007; 27(51): 14069 - 14077. [Abstract] [Full Text] [PDF]
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ABSTRACT
NORMAL BRAIN ENERGY METABOLISM
), middle-age (
), and old-age (
) neurons in culture. After resting fluorescence results were collected, glutamate (200 µM) was applied to the cell, causing an immediate stimulation of NAD(P)H, but with NAD(P)H declining after 33 min of exposure to glutamate. Note that old neurons start with the lowest levels of NAD(P)H (from Parihar and Brewer, unpublished observations).