线粒体缺陷与阿尔采末病

阿尔采末病（Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ,ＡＤ）存在线粒体氧化磷酸化异常与线粒体ＤＮＡ（ｍｔＤＮＡ）缺陷,主要表现为;线粒体呼吸链复合体Ⅳ（细胞以素ｃ氧化酶,ＣＯＸ）活性在ＡＤ患者血小板,培养的皮肤成纤维细胞及脑中显著下降。其可能则遗传性ｍｔＤＮＡ突变与自由基介导的体细胞ｍｔＤＮＡ突变的共同作用,也可能继发于其它改变。     

The involvement of lipid rafts in Alzheimer's disease

The amyloidogenesis occurring in Alzheimer's disease represents a fundamental membrane-related pathology involving a membrane-bound substrate metabolized by integral membrane proteases (secretases). Thus, the amyloid-beta peptide (Abeta), which accumulates extracellularly as plaques in the brains of Alzheimer's disease patients, is derived by sequential proteolytic cleavage of the integral transmembrane amyloid precursor protein (APP). Beta-Secretase or BACE-1 (beta-site APP cleaving enzyme) is a transmembrane aspartic protease responsible for the first of these cleavage events, generating the soluble APP ectodomain sAPPbeta, and a C-terminal fragment CTFbeta. CTFbeta is subsequently cleaved by the ?gamma-secretase complex, of which presenilin is the catalytic core, to produce Ass. A variety of studies indicate that cholesterol is an important factor in the regulation of Ass production, with high cholesterol levels being linked to increased Ass generation and deposition. However, the mechanism(s) underlying this effect are unclear at present. Recent evidence suggests that amyloidogenic APP processing may preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts, and that changes in cholesterol levels could exert their effects by altering the distribution of APP-cleaving enzymes within the membrane. Rafts may be involved in the aggregation of Ass and also in its clearance by amyloid-degrading enzymes such as plasmin or possibly neprilysin (NEP).     

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.     

Mitochondrial DNA haplogroups in early-onset Alzheimer's disease and frontotemporal lobar degeneration

Background

Alleles of apolipoprotein E (APOE) are the major genetic risk factor for late onset Alzheimer's Disease (LOAD). Recently, an APOE splice variant that retains intron 3 (APOE-I3) was identified. To gain insight into the possible role of this isoform in LOAD, we quantified its expression in a cohort of 56 human brain specimens by using quantitative RT-PCR.

Results

We found that APOE-I3 generally represents a low percentage (< 0.5%) of overall APOE expression. However, in one specimen, the proportion of APOE-I3 was increased about ~13 fold. This specimen was unique in the cohort for possessing the minor allele of an intron 3 single nucleotide polymorphism (SNP), rs12982192. Additionally, an allelic expression imbalance study indicated that the rs12982192 minor allele was associated with increased APOE-I3 expression.

Conclusions

Overall, we interpret our results as suggesting that APOE-I3 represents a minor portion of APOE expression and that rs12982192 is associated with APOE intron 3 retention. Since the minor allele of this SNP is on the same haplotype as the minor allele of rs429358, which defines the APOE4 allele, we speculate that rs12982192 may reflect a modest loss of mRNA encoding functional APOE4.     

Genetic evidence for the involvement of lipid metabolism in Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia in the elderly and presents a great burden to sufferers and to society. The genetics of rare Mendelian forms of AD have been central to our understanding of AD pathogenesis for the past twenty years and now the genetics of the common form of the disease in the elderly is beginning to be unravelled by genome-wide association studies. Four new genes for common AD have been revealed in the past year, CLU, CR1, PICALM and BIN1. Their possible involvement in lipid metabolism and how that relates to AD is discussed here.     

Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer's disease

Deficits in mitochondrial function are a characteristic finding in Alzheimer's disease (AD), though the mechanism remains to be clarified. Recent studies revealed that amyloid beta peptide (Abeta) gains access into mitochondrial matrix, which was much more pronounced in both AD brain and transgenic mutant APP mice than in normal controls. Abeta progressively accumulates in mitochondria and mediates mitochondrial toxicity. Interaction of mitochondrial Abeta with mitochondrial enzymes such as amyloid beta binding alcohol dehydrogenase (ABAD) exaggerates mitochondrial stress by inhibiting the enzyme activity, releasing reactive oxygen species (ROS), and affecting glycolytic, Krebs cycle and/or the respiratory chain pathways through the accumulation of deleterious intermediate metabolites. The pathways proposed may play a key role in the pathogenesis of this devastating neurodegenerative disorder, Alzheimer's disease.     

Mitochondrial involvement in non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is an increasing recognized condition that may progress to end-stage liver disease. There are consistent evidences that mitochondrial dysfunction plays a central role in NASH whatever its origin. Mitochondria are the key controller of fatty acids removal and this is part of an intensive gene program that modifies hepatocytes to counteract the excessive fat storage. Mitochondrial dysfunction participates at different levels in NASH pathogenesis since it impairs fatty liver homeostasis and induces overproduction of ROS that in turn trigger lipid peroxidation, cytokines release and cell death. In this review we briefly recall the role of mitochondria in fat metabolism and energy homeostasis and focus on the role of mitochondrial impairment and uncoupling proteins in the pathophysiology of NASH progression. We suggest that mitochondrial respiratory chain, UCP2 and redox balance cooperate in a common pathway that permits to set down the mitochondrial redox pressure, limits the risk of oxidative damage, and allows the maximal rate of fat removal. When the environmental conditions change and high energy supply occurs, hepatocytes are unable to replace their ATP store and steatosis progress to NASH and cirrhosis. The beneficial effects of some drugs on mitochondrial function are also discussed.     

Mitochondrial involvement in Parkinson's disease, Huntington's disease, hereditary spastic paraplegia and Friedreich's ataxia

Respiratory chain dysfunction has been identified in several neurodegenerative disorders. In Friedreich's ataxia (FA) and Huntington's disease (HD), where the respective mutations are in nuclear genes encoding non-respiratory chain mitochondrial proteins, the defects in oxidative phosphorylation are clearly secondary. In Parkinson's disease (PD) the situation is less clear, with some evidence for a primary role of mitochondrial DNA in at least a proportion of patients. The pattern of the respiratory chain defect may provide some clue to its cause; in PD there appears to be a selective complex I deficiency; in HD and FA the deficiencies are most severe in complex II/III with a less severe defect in complex IV. Aconitase activity in HD and FA is severely decreased in brain and muscle, respectively, but appears to be normal in PD brain. Free radical generation is thought to be of importance in both HD and FA, via excitotoxicity in HD and abnormal iron handling in FA. The oxidative damage observed in PD may be secondary to the mitochondrial defect. Whatever the cause(s) and sequence of events, respiratory chain deficiencies appear to play an important role in the pathogenesis of neurodegeneration. The mitochondrial abnormalities induced may converge on the function of the mitochondrion in apoptosis. This mode of cell death is thought to play an important role in neurodegenerative diseases and it is tempting to speculate that the observed mitochondrial defects in PD, HD and FA result directly in apoptotic cell death, or in the lowering of a cell's threshold to undergo apoptosis. Clarifying the role of mitochondria in pathogenesis may provide opportunities for the development of treatments designed to reverse or prevent neurodegeneration.     

Mitochondrial permeability transition pore in Alzheimer's disease: Cyclophilin D and amyloid beta

Amyloid beta (Aβ) plays a critical role in the pathophysiology of Alzheimer's disease. Increasing evidence indicates mitochondria as an important target of Aβ toxicity; however, the effects of Aβ toxicity on mitochondria have not yet been fully elucidated. Recent biochemical studies in vivo and in vitro implicate mitochondrial permeability transition pore (mPTP) formation involvement in Aβ-mediated mitochondrial dysfunction. mPTP formation results in severe mitochondrial dysfunction such as reactive oxygen species (ROS) generation, mitochondrial membrane potential dissipation, intracellular calcium perturbation, decrease in mitochondrial respiration, release of pro-apoptotic factors and eventually cell death. Cyclophilin D (CypD) is one of the more well-known mPTP components and recent findings reveal that Aβ has significant impact on CypD-mediated mPTP formation. In this review, the role of Aβ in the formation of mPTP and the potential of mPTP inhibition as a therapeutic strategy in AD treatment are examined.     

Mitochondrial involvement in amyotrophic lateral sclerosis

Despite numerous reports demonstrating mitochondrial abnormalities associated with amyotrophic lateral sclerosis (ALS), the role of mitochondrial dysfunction in the disease onset and progression remains unknown. The intrinsic mitochondrial apoptotic program is activated in the central nervous system of mouse models of ALS harboring mutant superoxide dismutase 1 protein. This is associated with the release of cytochrome-c from the mitochondrial intermembrane space and mitochondrial swelling. However, it is unclear if the observed mitochondrial changes are caused by the decreasing cellular viability or if these changes precede and actually trigger apoptosis. This article discusses the current evidence for mitochondrial involvement in familial and sporadic ALS and concludes that mitochondria is likely to be both a trigger and a target in ALS and that their demise is a critical step in the motor neuron death.     

Mitochondrial DNA involvement in human longevity

The main message of this review can be summarized as follows: aging and longevity, as complex traits having a significant genetic component, likely depend on a number of nuclear gene variants interacting with mtDNA variability both inherited and somatic. We reviewed the data available in the literature with particular attention to human longevity, and argued that what we hypothesize for aging and longevity could have a more general relevance and be extended to other age-related complex traits such as Alzheimer's and Parkinson's diseases. The genetics which emerges for complex traits, including aging and longevity, is thus even more complicated than previously thought, as epistatic interactions between nuclear gene polymorphisms and mtDNA variability (both somatic and inherited) as well as between mtDNA somatic mutations (tissue specific) and mtDNA inherited variants (haplogroups and sub-haplogroups) must be considered as additional players capable of explaining a part of the aging and longevity phenotype. To test this hypothesis is one of the main challenge in the genetics of aging and longevity in the next future.     

Mitochondrial involvement in drug-induced hepatic injury

Hepatic injury remains not only the commonest reason for the termination of drugs in their pre-clinical development but is also the most frequent reason for the withdrawal of approved drugs from the market. Mitochondria are the central point where the different signals responsible for initiating hepatocyte cell death converge, irrespective of whether the cells ultimately die by apoptosis, necrosis (oncosis) or autophagic cell death. These signals can be in the form of direct damage to the mitochondria leading to permeability transition or can act indirectly through activation of death receptors and downstream pro-apoptotic Bcl-2 family proteins. This paper reviews our current knowledge about how hepatotoxic drugs, whether direct acting or through induction of steatosis or cholestasis, target mitochondria and cause hepatic injury.     

Mitochondrial involvement in amyotrophic lateral sclerosis

The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are so far unknown. The involvement of mitochondria in the disease was initially suggested by ultrastructural studies. More recently these observations have been supported by studies of mitochondrial function in ALS. Alterations in the activity of complexes which make up the mitochondrial electron transport chain have been recorded as well as mutations in the mitochondrial genome. The calcium buffering function of the mitochondria may also be affected in the disease. This review will discuss how mitochondrial dysfunction could be of relevance in ALS and the evidence that an alteration of mitochondrial function is a feature of the disease. The way in which the involvement of mitochondria fits with other aetiological hypotheses for ALS will also be discussed.     

Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease

Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.     

Mitochondrial involvement in bladder function and dysfunction

Benign bladder pathology resulting from prostatic hypertrophy or other causes is a significant problem associated with ageing in humans. This condition is characterized by increased bladder mass, decreased urinary flow rate, decreased compliance, and these and other changes in bladder function often subject patients to increased risk of urinary tract infection. While the physiologic attributes of benign bladder pathology have been extensively described in humans and in various animal model systems, the biochemical and molecular genetic bases for that pathology have only recently been investigated in detail. Studies demonstrate that mitochondrial energy production and utilization are severely impaired in bladder smooth muscle during benign bladder disease, and to a large extent this realization has provided a rational basis for understanding the characteristic alterations in urinary flow and compliance in bladder tissue. Recent investigations targeting the detailed molecular basis for impaired mitochondrial function in the disease have shown that performance of the organellar genetic system, and to a large extent that of relevant portions of the nuclear genetic system as well, is severely aberrant in bladder tissue. In this article, we discuss the physiologic aspects of benign bladder disease, summarize biochemical evidence for the altered mitochondrial energy metabolism that appears to underlie bladder pathology, review the structure and function of the mitochondrial genetic system, and discuss molecular genetic studies of that system which have begun to provide a mechanistic explanation for the biochemical and physiological abnormalities that characterize the disease. We also discuss areas for further research which will be critically important in increasing our understanding of the detailed causes of benign bladder pathology.     

Mitochondrial involvement in cell death of non-mammalian eukaryotes

Although mitochondria are essential organelles for long-term survival of eukaryotic cells, recent discoveries in biochemistry and genetics have advanced our understanding of the requirements for mitochondria in cell death. Much of what we understand about cell death is based on the identification of conserved cell death genes in Drosophila melanogaster and Caenorhabditis elegans. However, the role of mitochondria in cell death in these models has been much less clear. Considering the active role that mitochondria play in apoptosis in mammalian cells, the mitochondrial contribution to cell death in non-mammalian systems has been an area of active investigation. In this article, we review the current research on this topic in three non-mammalian models, C. elegans, Drosophila, and Saccharomyces cerevisiae. In addition, we discuss how non-mammalian models have provided important insight into the mechanisms of human disease as they relate to the mitochondrial pathway of cell death. The unique perspective derived from each of these model systems provides a more complete understanding of mitochondria in programmed cell death. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.     

Mitochondrial involvement in tracheary element programmed cell death

The mitochondria pathway is regarded as a central component of some types of programmed cell death (PCD) in animal cells where specific signals cause the release of cytochrome c from mitochondria to trigger a proteolytic cascade involving caspases. However, plant cells lack canonical caspases, therefore a role for the mitochondria in programmed cell death in plant cells is not obvious. Using plant cells which terminally differentiate, we provide evidence supporting the involvement of mitochondria in PCD, however the release of cytochrome c is insufficient to trigger the PCD. Prior to execution of cellular autolysis initiated by the rupture of the large central vacuole to release sequestered hydrolases, mitochondria adopt a definable morphology, the inner membrane depolarizes prior to death, and cytochrome c is released from mitochondria. However, PCD can be blocked despite translocation of cytochrome c. These results suggest a role for the mitochondria in this PCD but do not support the current animal model for a causative role of cytochrome c in triggering PCD.