Search tips
Search criteria

Results 1-25 (51)

Clipboard (0)

Select a Filter Below

Year of Publication
1.  Common defects of mitochondria and iron in neurodegeneration and diabetes (MIND): A paradigm worth exploring 
Biochemical pharmacology  2013;88(4):573-583.
A popular, if not centric, approach to the study of an event is to first consider that of the simplest cause. When dissecting the underlying mechanisms governing idiopathic diseases, this generally takes the form of an ab initio genetic approach. To date, this genetic ‘smoking gun’ has remained elusive in diabetes mellitus and for many affected by neurodegenerative diseases. With no single gene, or even subset of genes, conclusively causative in all cases, other approaches to the etiology and treatment of these diseases seem reasonable, including the correlation of a systems’ predisposed sensitivity to particular influence. In the cases of diabetes mellitus and neurodegenerative diseases, overlapping themes of mitochondrial influence or dysfunction and iron dyshomeostasis are apparent and relatively consistent. This mini-review discusses the influence of mitochondrial function and iron homeostasis on diabetes mellitus and neurodegenerative disease, namely Alzheimer’s disease. Also discussed is the incidence of diabetes accompanied by neuropathy and neurodegeneration along with neurodegenerative disorders prone to development of diabetes. Mouse models containing multiple facets of this overlap are also described alongside current molecular trends attributed to both diseases. As a way of approaching the idiopathic and complex nature of these diseases we are proposing the consideration of a MIND (mitochondria, iron, neurodegeneration, and diabetes) paradigm in which systemic metabolic influence, iron homeostasis, and respective genetic backgrounds play a central role in the development of disease.
PMCID: PMC3972369  PMID: 24361914
2.  Bioenergetic medicine 
British Journal of Pharmacology  2014;171(8):1854-1869.
Here we discuss a specific therapeutic strategy we call ‘bioenergetic medicine’. Bioenergetic medicine refers to the manipulation of bioenergetic fluxes to positively affect health. Bioenergetic medicine approaches rely heavily on the law of mass action, and impact systems that monitor and respond to the manipulated flux. Since classically defined energy metabolism pathways intersect and intertwine, targeting one flux also tends to change other fluxes, which complicates treatment design. Such indirect effects, fortunately, are to some extent predictable, and from a therapeutic perspective may also be desirable. Bioenergetic medicine-based interventions already exist for some diseases, and because bioenergetic medicine interventions are presently feasible, new approaches to treat certain conditions, including some neurodegenerative conditions and cancers, are beginning to transition from the laboratory to the clinic.
Linked Articles
This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit
PMCID: PMC3976609  PMID: 24004341
Alzheimer's disease; cancer; glycolysis; law of mass action; mitochondria; neurodegeneration
3.  Lactate Administration Reproduces Specific Brain and Liver Exercise-Related Changes 
Journal of neurochemistry  2013;127(1):91-100.
The effects of exercise are not limited to muscle, and its ability to mitigate some chronic diseases is under study. A more complete understanding of how exercise impacts non-muscle tissues might facilitate design of clinical trials and exercise mimetics. Here, we focused on lactate’s ability to mediate changes in liver and brain bioenergetic-associated parameters. In one group of experiments, C57BL/6 mice underwent seven weeks of treadmill exercise sessions at intensities intended to exceed the lactate threshold. Over time, the mice dramatically increased their lactate threshold. To ensure that plasma lactate accumulated during the final week, the mice were run to exhaustion. In the liver, mRNA levels of gluconeogenesis-promoting genes increased. And while PGC-1α expression increased, there was a decrease in PGC-1β expression, and overall gene expression changes favored respiratory chain down-regulation. In the brain, PGC-1α and PGC-1β were unchanged but PRC expression and mtDNA copy number increased. Brain TNFα expression fell, while VEGF-A expression rose. In another group of experiments, exogenously administered lactate was found to reproduce some but not all of these observed liver and brain changes. Our data suggest that lactate, an exercise byproduct, could mediate some of the effects exercise has on the liver and the brain, and that lactate itself can act as a partial exercise mimetic.
PMCID: PMC4276250  PMID: 23927032
exercise; lactate; brain; liver
4.  Glycolysis-Respiration Relationships in a Neuroblastoma Cell Line 
Biochimica et biophysica acta  2013;1830(4):2891-2898.
Although some reciprocal glycolysis-respiration relationships are well recognized, the relationship between reduced glycolysis flux and mitochondrial respiration has not been critically characterized.
We concomitantly measured the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of SH-SY5Y neuroblastoma cells under free and restricted glycolysis flux conditions.
Under conditions of fixed energy demand ECAR and OCR values showed a reciprocal relationship. In addition to observing an expected Crabtree effect in which increasing glucose availability raised the ECAR and reduced the OCR, a novel reciprocal relationship was documented in which reducing the ECAR via glucose deprivation or glycolysis inhibition increased the OCR. Substituting galactose for glucose, which reduces net glycolysis ATP yield without blocking glycolysis flux, similarly reduced the ECAR and increased the OCR. We further determined how reduced ECAR conditions affect proteins that associate with energy sensing and energy response pathways. ERK phosphorylation, SIRT1, and HIF1a decreased while AKT, p38, and AMPK phosphorylation increased.
These data document a novel intracellular glycolysis-respiration effect in which restricting glycolysis flux increases mitochondrial respiration.
General Significance
Since this effect can be used to manipulate cell bioenergetic infrastructures, this particular glycolysis-respiration effect can practically inform the development of new mitochondrial medicine approaches.
PMCID: PMC3594384  PMID: 23313167
Crabtree effect; glycolysis; mitochondria; oxidative phosphorylation; Pasteur effect; respiration
5.  Role of Mitochondrial Homeostasis and Dynamics in Alzheimer’s Disease 
Neurobiology of disease  2012;51:3-12.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects a staggering percentage of the aging population and causes memory loss and cognitive decline. Mitochondrial abnormalities can be observed systemically and in brains of patients suffering from AD, and may account for part of the disease phenotype. In this review, we summarize some of the key findings that indicate mitochondrial dysfunction is present in AD-affected subjects, including cytochrome oxidase deficiency, endophenotype data, and altered mitochondrial morphology. Special attention is given to recently described perturbations in mitochondrial autophagy, fission-fusion dynamics, and biogenesis. We also briefly discuss how mitochondrial dysfunction may influence amyloidosis in Alzheimer’s disease, why mitochondria are a valid therapeutic target, and strategies for addressing AD-specific mitochondrial dysfunction.
PMCID: PMC3337963  PMID: 22266017
Alzheimer’s disease; autophagy; bioenergetics; biogenesis; fission; mitochondria; mitochondrial DNA; mitochondrial dysfunction; mitochondrial medicine
6.  Bioenergetic Dysfunction and Inflammation in Alzheimer’s Disease: A Possible Connection 
Inflammation is observed in Alzheimer’s disease (AD) subject brains. Inflammation-relevant genes are increasingly implicated in AD genetic studies, and inflammatory cytokines to some extent even function as peripheral biomarkers. What underlies AD inflammation is unclear, but no “foreign” agent has been implicated. This suggests that internally produced damage-associated molecular pattern (DAMPs) molecules may drive inflammation in AD. A more complete characterization and understanding of AD-relevant DAMPs could advance our understanding of AD and suggest novel therapeutic strategies. In this review, we consider the possibility that mitochondria, intracellular organelles that resemble bacteria in many ways, trigger and maintain chronic inflammation in AD subjects. Data supporting the possible nexus between AD-associated bioenergetic dysfunction are discussed.
PMCID: PMC4226164  PMID: 25426068
inflammation; bioenergetics; DAMP; mitochondria; Alzheimer’s disease
7.  Alzheimer’s Disease Pathologic Cascades: Who Comes First, What Drives What 
Neurotoxicity research  2011;22(3):182-194.
This review discusses known and speculated relationships between Alzheimer’s disease (AD) biochemical, molecular, and histologic phenomena. In the AD brain, various pathologies including neuritic plaques, neurofibrillary tangles, synaptic loss, oxidative stress, cell cycle re-entry, and mitochondrial changes have all been described. In an attempt to explain what exactly goes wrong in the AD brain various investigators have proposed different heuristic and hierarchical schemes. It is important to accurately define the AD pathology hierarchy because treatments targeting the true apex of its pathologic cascade arguably have the best chance of preventing, mitigating, or even curing this disease.
PMCID: PMC3635146  PMID: 21913048
aging; Alzheimer’s disease; amyloid; brain; oxidative stress; mitochondria
8.  Mitochondria and Cell Bioenergetics: Increasingly Recognized Components and a Possible Etiologic Cause of Alzheimer's Disease 
Antioxidants & Redox Signaling  2012;16(12):1434-1455.
Significance: Mitochondria and brain bioenergetics are increasingly thought to play an important role in Alzheimer's disease (AD). Recent Advances: Data that support this view are discussed from the perspective of the amyloid cascade hypothesis, which assumes beta-amyloid perturbs mitochondrial function, and from an opposite perspective that assumes mitochondrial dysfunction promotes brain amyloidosis. A detailed review of cytoplasmic hybrid (cybrid) studies, which argue mitochondrial DNA (mtDNA) contributes to sporadic AD, is provided. Recent AD endophenotype data that further suggest an mtDNA contribution are also summarized. Critical Issues and Future Directions: Biochemical, molecular, cybrid, biomarker, and clinical data pertinent to the mitochondria–bioenergetics–AD nexus are synthesized and the mitochondrial cascade hypothesis, which represents a mitochondria-centric attempt to conceptualize sporadic AD, is discussed. Antioxid. Redox Signal. 16, 1434–1455.
PMCID: PMC3329949  PMID: 21902597
9.  The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives 
Biochimica et biophysica acta  2013;1842(8):1219-1231.
Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.
PMCID: PMC3962811  PMID: 24071439
aging; amyloid; brain; dementia; Alzheimer's disease; mitochondria
10.  Mitochondrial abnormalities in Alzheimer’s disease: Possible targets for therapeutic intervention 
Mitochondria from persons with Alzheimer’s disease (AD) differ from those of age-matched, control subjects. Differences in mitochondrial morphology and function are well-documented, and are not brain-limited. Some of these differences are present during all stages of AD, and are even seen in individuals who are without AD symptoms and signs but who have an increased risk of developing AD. This chapter considers the status of mitochondria in AD subjects, the potential basis for AD subject mitochondrial perturbations, and the implications of these perturbations. Data from multiple lines of investigation, including epidemiologic, biochemical, molecular, and cytoplasmic hybrid studies are reviewed. The possibility that mitochondria could potentially constitute a reasonable AD therapeutic target is discussed, as are several potential mitochondrial medicine treatment strategies.
PMCID: PMC3625400  PMID: 22840745
aging; Alzheimer’s disease; bioenergetics; cybrids; mitochondria; therapeutics
11.  Mitochondria in Neurodegeneration 
Many neurodegenerative diseases demonstrate abnormal mitochondrial morphology and biochemical dysfunction. Alterations are often systemic rather than brain-limited. Mitochondrial dysfunction may arise as a consequence of abnormal mitochondrial DNA, mutated nuclear proteins that interact directly or indirectly with mitochondria, or through unknown causes. In most cases it is unclear where mitochondria sit in relation to the overall disease cascades that ultimately causes neuronal dysfunction and death, and there is still controversy regarding the question of whether mitochondrial dysfunction is a necessary step in neurodegeneration. In this chapter we highlight and catalogue mitochondrial perturbations in some of the major neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). We consider data that suggest mitochondria may be critically involved in neurodegenerative disease neurodegeneration cascades.
PMCID: PMC3618469  PMID: 22399427
cybrid; mitochondria; mitochondrial DNA; neurodegenerative disease
12.  Effect of Cholinergic Signaling on Neuronal Cell Bioenergetics 
Journal of Alzheimer's disease : JAD  2013;33(4):1135-1146.
Alzheimer's disease (AD) patients have reduced brain acetylcholine and reversing this deficit yields clinical benefits. In this study we explored how increased cholinergic tone impacts cell bioenergetics, which are also perturbed in AD. We treated SHSY5Y neuroblastoma cells with carbachol, a cholinergic agonist, and tested for bioenergetic flux and bioenergetic infrastructure changes. Carbachol rapidly increased both oxidative phosphorylation and glycolysis fluxes. ATP levels rose slightly, as did cell energy demand, and AMPK phosphorylation occurred. At least some of these effects depended on muscarinic receptor activation, ER calcium release, and ER calcium re-uptake. Our data show that increasing cholinergic signaling enhances cell bioenergetics, and reveal mechanisms that mediate this effect. Phenomena we observed could potentially explain why cholinesterase inhibitor therapy increases AD brain glucose utilization and N-acetyl aspartate levels. The question of whether cholinesterase inhibitors have a disease modifying effect in AD has long been debated; our data suggest a theoretical mechanism through which such an effect could potentially arise.
PMCID: PMC3553319  PMID: 23099815
Acetylcholine; Alzheimer's disease; bioenergetics; carbachol; glycolysis; mitochondria
13.  High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging 
Neurobiology of aging  2014;35(7):1686-1694.
Altered brain metabolism is likely to be an important contributor to normal cognitive decline and brain pathology in elderly individuals. To characterize the metabolic changes associated with normal brain aging, we used high-field proton magnetic resonance spectroscopy in vivo to quantify 20 neurochemicals in the hippocampus and sensorimotor cortex of young adult and aged rats. We found significant differences in the neurochemical profile of the aged brain when compared with younger adults, including lower aspartate, ascorbate, glutamate, and macromolecules, and higher glucose, myo-inositol, N-acetylaspartylglutamate, total choline, and glutamine. These neurochemical biomarkers point to specific cellular mechanisms that are altered in brain aging, such as bioenergetics, oxidative stress, inflammation, cell membrane turnover, and endogenous neuroprotection. Proton magnetic resonance spectroscopy may be a valuable translational approach for studying mechanisms of brain aging and pathology, and for investigating treatments to preserve or enhance cognitive function in aging.
PMCID: PMC4174428  PMID: 24559659
Aging; Biomarker; Proton magnetic resonance spectroscopy; Magnetic resonance imaging; In vivo; Neurochemical profile; Inflammation; Bioenergetics; Membrane turnover; Oxidative stress
14.  Mitochondria and Parkinson's Disease 
Parkinson's Disease  2012;2011:261791.
PMCID: PMC3437634  PMID: 22973533
15.  Role and Treatment of Mitochondrial DNA-Related Mitochondrial Dysfunction in Sporadic Neurodegenerative Diseases 
Current Pharmaceutical Design  2011;17(31):3356-3373.
Several sporadic neurodegenerative diseases display phenomena that directly or indirectly relate to mitochondrial function. Data suggesting altered mitochondrial function in these diseases could arise from mitochondrial DNA (mtDNA) are reviewed. Approaches for manipulating mitochondrial function and minimizing the downstream consequences of mitochondrial dysfunction are discussed.
PMCID: PMC3351798  PMID: 21902672
cybrids; endophenotype; mitochondria; mitochondrial DNA; mitochondrial medicine; neurodegenerative disease
16.  Mitochondrial Manipulation and the Quest for Alzheimer's Treatments 
EBioMedicine  2015;2(4):276-277.
PMCID: PMC4486190  PMID: 26137567
Alzheimer's disease; Beta amyloid; Mitochondria; Neurodegeneration
17.  Polymorphic Variation in Cytochrome Oxidase Subunit Genes 
Cytochrome oxidase (COX) activity varies between individuals and low activities associate with Alzheimer’s disease. Whether genetic heterogeneity influences function of this multimeric enzyme is unknown. To explore this we sequenced 3 mitochondrial DNA (mtDNA) and 10 nuclear COX subunit genes from at least 50 individuals. 20% had non-synonymous mtDNA COX gene polymorphisms, 12% had a COX4I1 non-synonymous G to A transition, and other genes rarely contained non-synonymous polymorphisms. Frequent untranslated region (UTR) polymorphisms were seen in COX6A1, COX6B1, COX6C, and COX7A1; heterogeneity in a COX7A1 5′ UTR Sp1 site was extensive. Synonymous polymorphisms were common and less frequent in the more conserved COX1 than the less conserved COX3, suggesting at least in mtDNA synonymous polymorphisms experience selection pressure and are not functionally silent. Compound gene variations occurred within individuals. To test whether variations could have functional consequences we studied the COX4I1 G to A transition and an AGCCCC deletion in the COX7A1 5′ UTR Sp1 site. Cells expressing the COX4I1 polymorphism had reduced COX Vmax activity. In reporter construct-transduced cells where green fluorescent protein expression depended on the COX7A1 Sp1 site, AGCCCC deletion reduced fluorescence. Our findings indicate COX subunit gene heterogeneity is pervasive and may mediate COX functional variation.
PMCID: PMC2910218  PMID: 20413852
Alzheimer’s disease; cytochrome oxidase; mitochondria; mitochondrial DNA; polymorphisms
18.  The Alzheimer's Disease Mitochondrial Cascade Hypothesis 
Journal of Alzheimer's disease : JAD  2010;20(Suppl 2):265-279.
We first proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD) in 2004. Our core assumptions were a person's genes determine baseline mitochondrial function and durability, this durability determines how mitochondria change with advancing age, and critical changes in mitochondrial function initiate other pathologies characteristic of AD. Since then several lines of investigation report data consistent with or supportive of our hypothesis. In particular, AD endophenotype studies suggest a strong maternal genetic contribution, and links between mitochondrial function, tau phosphorylation, and beta amyloid (Aβ) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce Aβ thus far have had at best very limited clinical benefits; our hypothesis identifies alternative therapeutic targets. While placing mitochondria at the apex of an AD cascade certainly remains controversial, it is increasingly accepted by the AD research community that mitochondria play an important role in the late-onset forms of the disease. Even if the mitochondrial cascade hypothesis proves incorrect, considering its assumptions could potentially advance our understanding of sporadic, late-onset AD.
PMCID: PMC2883665  PMID: 20442494
Alzheimer's disease; beta amyloid; cytochrome oxidase; endophenotype; mitochondria; mitochondrial DNA
19.  Effects of Memantine on Mitochondrial Function 
Biochemical pharmacology  2007;75(4):956-964.
Because NMDA complex and mitochondrial function are related, we hypothesized memantine would influence mitochondrial function. We addressed this in vitro by studying the effects of chronic and acute memantine exposures on mitochondrial function. For acute exposure experiments, mitochondria were isolated from NT2 cells and assayed for electron transport chain (ETC) enzyme function and peroxide production in buffers containing up to 60 uM memantine. For chronic exposure experiments, NT2 cells were maintained for at least two weeks in medium containing up to 60 uM memantine, following which we assayed cells or their mitochondria for ETC enzyme activities, cytochrome oxidase protein levels, oxidative stress, calcium levels, and mitochondrial DNA levels. The ability of the NMDA receptor antagonist aminophosphonovaleric acid (APV) to modify memantine's mitochondrial effects was evaluated. Acute and chronic memantine similarly affected complex I (increased at high concentrations) and IV (decreased at high concentrations) Vmax activities. APV did not alter the effects of chronic memantine exposure on citrate synthase and complex IV. We detected a lower mitochondrial peroxide production rate with acute exposure, and an increased mitochondrial peroxide production rate with chronic exposure. Micromolar memantine concentrations affect mitochondria, some of these effects are directly mediated, and acute and chronic effects may differ.
PMCID: PMC2270256  PMID: 18053965
20.  Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations 
Parkinsonism & related disorders  2013;19(10):869-877.
Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies including leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene.
We studied neuropathologically verified HDLS patients with CSF1R mutations to assess Parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with Parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11).
We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of Parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.
PMCID: PMC3977389  PMID: 23787135
HDLS; CSF1R mutation; Parkinsonism; Autosomal dominant; White matter disorders
21.  Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines 
Human Molecular Genetics  2013;22(19):3931-3946.
Bioenergetic dysfunction occurs in Alzheimer's disease (AD) and mild cognitive impairment (MCI), a clinical syndrome that frequently precedes symptomatic AD. In this study, we modeled AD and MCI bioenergetic dysfunction by transferring mitochondria from MCI, AD and control subject platelets to mtDNA-depleted SH-SY5Y cells. Bioenergetic fluxes and bioenergetics-related infrastructures were characterized in the resulting cytoplasmic hybrid (cybrid) cell lines. Relative to control cybrids, AD and MCI cybrids showed changes in oxygen consumption, respiratory coupling and glucose utilization. AD and MCI cybrids had higher ADP/ATP and lower NAD+/NADH ratios. AD and MCI cybrids exhibited differences in proteins that monitor, respond to or regulate cell bioenergetic fluxes including HIF1α, PGC1α, SIRT1, AMPK, p38 MAPK and mTOR. Several endpoints suggested mitochondrial mass increased in the AD cybrid group and probably to a lesser extent in the MCI cybrid group, and that the mitochondrial fission–fusion balance shifted towards increased fission in the AD and MCI cybrids. As many of the changes we observed in AD and MCI cybrid models are also seen in AD subject brains, we conclude reduced bioenergetic function is present during very early AD, is not brain-limited and induces protean retrograde responses that likely have both adaptive and mal-adaptive consequences.
PMCID: PMC3888119  PMID: 23740939
22.  Pathogenesis of Alzheimer’s disease 
Clinical Interventions in Aging  2007;2(3):347-359.
Alzheimer’s disease (AD) is incredibly common. Increasing longevity ensures its prevalence will rise even further. Ongoing efforts to understand AD pathogenesis reveal numerous tantalizing leads. Formulating a comprehensive AD pathogenesis theory capable of incorporating these disparate leads, though, has proven difficult. This review discusses current attempts to formulate a comprehensive AD pathogenesis theory. In doing so, it focuses on clinical and molecular relationships between AD and aging. A better understanding of these relationships could inform and impact future development of AD-directed treatment strategies.
PMCID: PMC2685260  PMID: 18044185
Alzheimer’s disease; aging; amyloid; cascade; mitochondria
23.  Ubiquitin Proteasome System in Parkinson Disease: a keeper or a witness? 
Experimental neurology  2012;238(2):89-99.
The aim of this work was to evaluate the role of Ubiquitin-Proteasome System (UPS) on mitochondrial-driven alpha-synuclein (aSN) clearance in in vitro, ex vivo and in vivo Parkinson disease (PD) cellular models.
We used SH-SY5Y ndufa2 knock-down (KD) cells, PD cybrids and peripheral blood mononuclear cells (PBMC) from patients meeting the diagnostic criteria for PD. We quantified aSN aggregation, proteasome activity and protein ubiquitination levels. In PBMC of PD patients population we evaluated aSN levels in plasma and the influence of several demographic characteristics in the above mentioned determinations.
We found that ubiquitin-independent proteasome activity was up-regulated in SH-SY5Y ndufa2 KD cells while a down regulation was observed in PD cybrids and PBMC. Moreover, we observed an increase in protein ubiquitination that correlates with a decrease in ubiquitin-dependent proteasome activity. Accordingly, proteasome inhibition prevented ubiquitin-dependent aSN clearance. Ubiquitin-independent proteasome activity was positively correlated with ubiquitination in PBMC.
We also report a negative correlation of chymotrypsin-like activity with age in control and late-onset PD groups. Total ubiquitin content is positively correlated with aSN oligomers levels, which leads to an age-dependent increase of aSN ubiquitination in LOPD. Moreover, aSN levels are increased in the plasma of PD patients.
aSN oligomers are ubiquitinated and we identified an ubiquitin-dependent clearance insufficiency with accumulation of both aSN and ubiquitin. However, SH-SY5Y ndufa2 KD cells showed a significant up-regulation of ubiquitin-independent proteasomal enzymatic activity that could mean a cell rescue attempt. Moreover, we identified that UPS function is age-dependent in PBMC.
PMCID: PMC4077023  PMID: 22921536
Parkinson’s disease; Ubiquitin-proteasome system; Mitochondria; Alpha-synuclein; Ubiquitin
24.  Cytoplasmic hybrid (cybrid) cell lines as a practical model for mitochondriopathies 
Redox Biology  2014;2:619-631.
Cytoplasmic hybrid (cybrid) cell lines can incorporate human subject mitochondria and perpetuate its mitochondrial DNA (mtDNA)-encoded components. Since the nuclear background of different cybrid lines can be kept constant, this technique allows investigators to study the influence of mtDNA on cell function. Prior use of cybrids has elucidated the contribution of mtDNA to a variety of biochemical parameters, including electron transport chain activities, bioenergetic fluxes, and free radical production. While the interpretation of data generated from cybrid cell lines has technical limitations, cybrids have contributed valuable insight into the relationship between mtDNA and phenotype alterations. This review discusses the creation of the cybrid technique and subsequent data obtained from cybrid applications.
•The cytoplasmic hybrid (cybrid) model can be used to determine mitochondrial DNA (mtDNA) contributions to phenotypic alterations.•Cybrids are used to study mitochondriopathies such as Parkinson’s disease and Alzheimer’s disease.•mtDNA heteroplasmy threshold and nuclear DNA-mtDNA compatibility can be determined using cybrid models.
Graphical Abstract
PMCID: PMC4297942  PMID: 25460729
Cybrid; Mitochondria; Mitochondrial DNA; Rho zero
25.  Effect of exercise on mouse liver and brain bioenergetic infrastructures 
Experimental physiology  2012;98(1):207-219.
To assess the effects of exercise on liver and brain bioenergetic infrastructures, we exposed C57BL/6 mice to 6 weeks of moderate-intensity treadmill exercise. During the training period, fasting blood glucose was lower in exercised mice than in sedentary mice, but serum insulin levels were not reduced. At week 6, trained mice showed a paradoxical decrease in plasma lactate during exercise, which was accompanied by an increase in the liver monocarboxylate transporter 2 protein level (~30%, P < 0.05). Exercise increased liver peroxisomal proliferator-activated receptor-γ coactivator 1α expression (approximately twofold, P < 0.001), NAD-dependent deacetylase sirtuin-1 protein (~30%, P < 0.05), p38 protein (~15%, P < 0.05), cytochrome c oxidase subunit 4 isoform 1 protein (~50%, P < 0.05) and AMP-activated protein kinase phosphorylation (~40%, P < 0.05). Despite this, liver mitochondrial DNA copy number (~30%, P = 0.05), mitochondrial transcription factor A expression (~15%, P < 0.05), cytochrome c oxidase subunit 2 expression (~10%, P < 0.05), cAMP-response element binding protein phosphorylation (~60%, P < 0.05) and brain-derived neurotrophic factor expression (~40%, P < 0.05) were all reduced, while cytochrome oxidase and citrate synthase activities were unchanged. The only altered brain parameter observed was a reduction in tumour necrosis factor α expression (~35%, P < 0.05); tumour necrosis factor α expression was unchanged in liver. Our data suggest that lactate produced by exercising muscle modifies the liver bioenergetic infrastructure, and enhanced liver uptake may in turn limit the ability of exercise-generated lactate to modify brain bioenergetics. Also, it appears that, at least in the liver, a dissociated mitochondrial biogenesis, in which some components are strategically enhanced while others are minimized, can occur.
PMCID: PMC3540163  PMID: 22613742

Results 1-25 (51)