Publications by authors named "Hani Atamna"

38 Publications

Profiling of tRNA Halves and YRNA Fragments in Serum and Tissue From Oral Squamous Cell Carcinoma Patients Identify Key Role of 5' tRNA-Val-CAC-2-1 Half.

Front Oncol 2019 26;9:959. Epub 2019 Sep 26.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States.

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancer and, as indicated by The Oral Cancer Foundation, kills at an alarming rate of roughly one person per hour. With this study, we aimed at better understanding disease mechanisms and identifying minimally invasive disease biomarkers by profiling novel small non-coding RNAs (specifically, tRNA halves and YRNA fragments) in both serum and tumor tissue from humans. Small RNA-Sequencing identified multiple 5' tRNA halves and 5' YRNA fragments that displayed significant differential expression levels in circulation and/or tumor tissue, as compared to control counterparts. In addition, by implementing a modification of weighted gene coexpression network analysis, we identified an upregulated genetic module comprised of 5' tRNA halves and miRNAs (miRNAs were described in previous study using the same samples) with significant association with the cancer trait. By consequently implementing miRNA-overtargeting network analysis, the biological function of the module (and by "guilt by association," the function of the 5' tRNA-Val-CAC-2-1 half) was found to involve the transcriptional targeting of specific genes involved in the negative regulation of the G1/S transition of the mitotic cell cycle. These findings suggest that 5' tRNA-Val-CAC-2-1 half (reduced in serum of OSCC patients and elevated in the tumor tissue) could potentially serve as an OSCC circulating biomarker and/or target for novel anticancer therapies. To our knowledge, this is the first time that the specific molecular function of a 5'-tRNA half is specifically pinpointed in OSCC.
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http://dx.doi.org/10.3389/fonc.2019.00959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775249PMC
September 2019

Curriculum mapping as a tool to facilitate curriculum development: a new School of Medicine experience.

BMC Med Educ 2018 Aug 6;18(1):185. Epub 2018 Aug 6.

Department of Medical Education, School of Medicine, California University of Science & Medicine, Colton, California, USA.

Background: Every curriculum needs to be reviewed, implemented and evaluated; it must also comply with the regulatory standards. This report demonstrates the value of curriculum mapping (CM), which shows the spatial relationships of a curriculum, in developing and managing an integrated medical curriculum.

Methods: A new medical school developed a clinical presentation driven integrated curriculum that incorporates the active-learning pedagogical practices of many educational institutions worldwide while adhering to the mandated requirements of the accreditation bodies. A centralized CM process was run in parallel as the curriculum was being developed. A searchable database, created after the CM data was uploaded into an electronic curriculum management system, was used to ensure placing, integrating, evaluating and revising the curricular content appropriately.

Results: CM facilitated in a) appraising the content integration, b) identifying gaps and redundancies, c) linking learning outcomes across all educational levels (i.e. session to course to program), c) organizing the teaching schedules, instruction methods, and assessment tools and d) documenting compliance with accreditation standards.

Conclusions: CM is an essential tool to develop, review, improve and refine any integrated curriculum however complex. Our experience, with appropriate modifications, should help other medical schools efficiently manage their curricula and fulfill the accreditation requirements at the same time.
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http://dx.doi.org/10.1186/s12909-018-1289-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090862PMC
August 2018

Data Mining of Small RNA-Seq Suggests an Association Between Prostate Cancer and Altered Abundance of 5' Transfer RNA Halves in Seminal Fluid and Prostatic Tissues.

Biomark Cancer 2018 20;10:1179299X18759545. Epub 2018 Feb 20.

Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.

Extracellular RNAs are gaining clinical interest as biofluid-based noninvasive markers for diseases, especially cancer. In particular, derivatives of transfer RNA (tRNA) are emerging as a new class of small-noncoding RNAs with high biomarker potential. We and others previously reported alterations in serum levels of specific tRNA halves in disease states including cancer. Here, we explored seminal fluid for tRNA halves as potential markers of prostate cancer. We found that 5' tRNA halves are abundant in seminal fluid and are elevated in prostate cancer relative to noncancer patients. Importantly, most of these tRNA halves are also detectable in prostatic tissues, and a subset were increased in malignant relative to adjacent normal tissue. These findings emphasize the potential of 5' tRNA halves as noninvasive markers for prostate cancer screening and diagnosis and provide leads for future work to elucidate a putative role of the 5' tRNA halves in carcinogenesis.
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http://dx.doi.org/10.1177/1179299X18759545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824904PMC
February 2018

Organ reserve, excess metabolic capacity, and aging.

Biogerontology 2018 04 15;19(2):171-184. Epub 2018 Jan 15.

School of Medicine, California University of Science and Medicine (CUSM), 217 E Club Center Dr. Suite A, San Bernardino, CA, 92408, USA.

"Organ reserve" refers to the ability of an organ to successfully return to its original physiological state following repeated episodes of stress. Clinical evidence shows that organ reserve correlates with the ability of older adults to cope with an added workload or stress, suggesting a role in the process of aging. Although organ reserve is well documented clinically, it is not clearly defined at the molecular level. Interestingly, several metabolic pathways exhibit excess metabolic capacities (e.g., bioenergetics pathway, antioxidants system, plasticity). These pathways comprise molecular components that have an excess of quantity and/or activity than that required for basic physiological demand in vivo (e.g., mitochondrial complex IV or glycolytic enzymes). We propose that the excess in mtDNA copy number and tandem DNA repeats of telomeres are additional examples of intrinsically embedded structural components that could comprise excess capacity. These excess capacities may grant intermediary metabolism the ability to instantly cope with, or manage, added workload or stress. Therefore, excess metabolic capacities could be viewed as an innate mechanism of adaptability that substantiates organ reserve and contributes to the cellular defense systems. If metabolic excess capacities or organ reserves are impaired or exhausted, the ability of the cell to cope with stress is reduced. Under these circumstances cell senescence, transformation, or death occurs. In this review, we discuss excess metabolic and structural capacities as integrated metabolic pathways in relation to organ reserve and cellular aging.
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http://dx.doi.org/10.1007/s10522-018-9746-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835208PMC
April 2018

Caloric restriction impacts plasma microRNAs in rhesus monkeys.

Aging Cell 2017 10 5;16(5):1200-1203. Epub 2017 Jul 5.

Department of Medicine, University of Wisconsin, Madison, WI, 53705, USA.

Caloric restriction (CR) is one of the most robust interventions shown to delay aging in diverse species, including rhesus monkeys (Macaca mulatta). Identification of factors involved in CR brings a promise of translatability to human health and aging. Here, we show that CR induced a profound change in abundance of circulating microRNAs (miRNAs) linked to growth and insulin signaling pathway, suggesting that miRNAs are involved in CR's mechanisms of action in primates. Deep sequencing of plasma RNA extracts enriched for short species revealed a total of 243 unique species of miRNAs including 47 novel species. Approximately 70% of the plasma miRNAs detected were conserved between rhesus monkeys and humans. CR induced or repressed 24 known and 10 novel miRNA species. Regression analysis revealed correlations between bodyweight, adiposity, and insulin sensitivity for 10 of the CR-regulated known miRNAs. Sequence alignment and target identification for these 10 miRNAs identify a role in signaling downstream of the insulin receptor. The highly abundant miR-125a-5p correlated positively with adiposity and negatively with insulin sensitivity and was negatively regulated by CR. Putative target pathways of CR-associated miRNAs were highly enriched for growth and insulin signaling that have previously been implicated in delayed aging. Clustering analysis further pointed to CR-induced miRNA regulation of ribosomal, mitochondrial, and spliceosomal pathways. These data are consistent with a model where CR recruits miRNA-based homeostatic mechanisms to coordinate a program of delayed aging.
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http://dx.doi.org/10.1111/acel.12636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595684PMC
October 2017

MicroRNAs Circulate in the Hemolymph of Drosophila and Accumulate Relative to Tissue microRNAs in an Age-Dependent Manner.

Genomics Insights 2016 28;9:29-39. Epub 2016 Mar 28.

Department of Biochemistry, University of California at Riverside, Riverside, CA, USA.

In mammals, extracellular miRNAs circulate in biofluids as stable entities that are secreted by normal and diseased tissues, and can enter cells and regulate gene expression. Drosophila melanogaster is a proven system for the study of human diseases. They have an open circulatory system in which hemolymph (HL) circulates in direct contact with all internal organs, in a manner analogous to vertebrate blood plasma. Here, we show using deep sequencing that Drosophila HL contains RNase-resistant circulating miRNAs (HL-miRNAs). Limited subsets of body tissue miRNAs (BT-miRNAs) accumulated in HL, suggesting that they may be specifically released from cells or particularly stable in HL. Alternatively, they might arise from specific cells, such as hemocytes, that are in intimate contact with HL. Young and old flies accumulated unique populations of HL-miRNAs, suggesting that their accumulation is responsive to the physiological status of the fly. These HL-miRNAs in flies may function similar to the miRNAs circulating in mammalian biofluids. The discovery of these HL-miRNAs will provide a new venue for health and disease-related research in Drosophila.
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http://dx.doi.org/10.4137/GEI.S38147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811268PMC
April 2016

Combined activation of the energy and cellular-defense pathways may explain the potent anti-senescence activity of methylene blue.

Redox Biol 2015 Dec 10;6:426-435. Epub 2015 Sep 10.

Department of Biochemistry, University of California at Riverside, 92521, USA.

Methylene blue (MB) delays cellular senescence, induces complex-IV, and activates Keap1/Nrf2; however, the molecular link of these effects to MB is unclear. Since MB is redox-active, we investigated its effect on the NAD/NADH ratio in IMR90 cells. The transient increase in NAD/NADH observed in MB-treated cells triggered an investigation of the energy regulator AMPK. MB induced AMPK phosphorylation in a transient pattern, which was followed by the induction of PGC1α and SURF1: both are inducers of mitochondrial and complex-IV biogenesis. Subsequently MB-treated cells exhibited >100% increase in complex-IV activity and a 28% decline in cellular oxidants. The telomeres erosion rate was also significantly lower in MB-treated cells. A previous research suggested that the pattern of AMPK activation (i.e., chronic or transient) determines the AMPK effect on cell senescence. We identified that the anti-senescence activity of MB (transient activator) was 8-times higher than that of AICAR (chronic activator). Since MB lacked an effect on cell cycle, an MB-dependent change to cell cycle is unlikely to contribute to the anti-senescence activity. The current findings in conjunction with the activation of Keap1/Nrf2 suggest a synchronized activation of the energy and cellular defense pathways as a possible key factor in MB's potent anti-senescence activity.
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http://dx.doi.org/10.1016/j.redox.2015.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588422PMC
December 2015

Circulating microRNA signature of genotype-by-age interactions in the long-lived Ames dwarf mouse.

Aging Cell 2015 Dec 14;14(6):1055-66. Epub 2015 Jul 14.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL, 32827, USA.

Recent evidence demonstrates that serum levels of specific miRNAs significantly change with age. The ability of circulating sncRNAs to act as signaling molecules and regulate a broad spectrum of cellular functions implicates them as key players in the aging process. To discover circulating sncRNAs that impact aging in the long-lived Ames dwarf mice, we conducted deep sequencing of small RNAs extracted from serum of young and old mice. Our analysis showed genotype-specific changes in the circulating levels of 21 miRNAs during aging [genotype-by-age interaction (GbA)]. Genotype-by-age miRNAs showed four distinct expression patterns and significant overtargeting of transcripts involved in age-related processes. Functional enrichment analysis of putative and validated miRNA targets highlighted cellular processes such as tumor suppression, anti-inflammatory response, and modulation of Wnt, insulin, mTOR, and MAPK signaling pathways, among others. The comparative analysis of circulating GbA miRNAs in Ames mice with circulating miRNAs modulated by calorie restriction (CR) in another long-lived mouse suggests CR-like and CR-independent mechanisms contributing to longevity in the Ames mouse. In conclusion, we showed for the first time a signature of circulating miRNAs modulated by age in the long-lived Ames mouse.
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http://dx.doi.org/10.1111/acel.12373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4693471PMC
December 2015

Circulating small non-coding RNA signature in head and neck squamous cell carcinoma.

Oncotarget 2015 Aug;6(22):19246-63

University of Central Florida, Burnett School of Biomedical Sciences, College of Medicine Orlando, FL, USA.

The Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common human cancer, causing 350,000 individuals die worldwide each year. The overall prognosis in HNSCC patients has not significantly changed for the last decade. Complete understanding of the molecular mechanisms in HNSCC carcinogenesis could allow an earlier diagnosis and the use of more specific and effective therapies. In the present study we used deep sequencing to characterize small non-coding RNAs (sncRNAs) in serum from HNSCC patients and healthy donors. We identified, for the first time, a multi-marker signature of 3 major classes of circulating sncRNAs in HNSCC, revealing the presence of circulating novel and known miRNAs, and tRNA- and YRNA-derived small RNAs that were significantly deregulated in the sera of HNSCC patients compared to healthy controls. By implementing a triple-filtering approach we identified a subset of highly biologically relevant miRNA-mRNA interactions and we demonstrated that the same genes/pathways affected by somatic mutations in cancer are affected by changes in the abundance of miRNAs. Therefore, one important conclusion from our work is that during cancer development, there seems to be a convergence of oncogenic processes driven by somatic mutations and/or miRNA regulation affecting key cellular pathways.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662488PMC
http://dx.doi.org/10.18632/oncotarget.4266DOI Listing
August 2015

ApoHRP-based assay to measure intracellular regulatory heme.

Metallomics 2015 Feb;7(2):309-21

Department of Basic Sciences, TCMC, Scranton, PA, USA.

The majority of the heme-binding proteins possess a "heme-pocket" that stably binds to heme. Usually known as housekeeping heme-proteins, they participate in a variety of metabolic reactions (e.g., catalase). Heme also binds with lower affinity to the "Heme-Regulatory Motifs" (HRM) in specific regulatory proteins. This type of heme binding is known as exchangeable or regulatory heme (RH). Heme binding to HRM proteins regulates their function (e.g., Bach1). Although there are well-established methods for assaying total cellular heme (e.g., heme-proteins plus RH), currently there is no method available for measuring RH independent of the total heme (TH). The current study describes and validates a new method to measure intracellular RH. This method is based on the reconstitution of apo-horseradish peroxidase (apoHRP) with heme to form holoHRP. The resulting holoHRP activity is then measured with a colorimetric substrate. The results show that apoHRP specifically binds RH but not with heme from housekeeping heme-proteins. The RH assay detects intracellular RH. Furthermore, using conditions that create positive (hemin) or negative (N-methyl protoporphyrin IX) controls for heme in normal human fibroblasts (IMR90), the RH assay shows that RH is dynamic and independent of TH. We also demonstrated that short-term exposure to subcytotoxic concentrations of lead (Pb), mercury (Hg), or amyloid-β (Aβ) significantly alters intracellular RH with little effect on TH. In conclusion the RH assay is an effective assay to investigate intracellular RH concentration and demonstrates that RH represents ∼6% of total heme in IMR90 cells.
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http://dx.doi.org/10.1039/c4mt00246fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326600PMC
February 2015

Deep Sequencing of Serum Small RNAs Identifies Patterns of 5' tRNA Half and YRNA Fragment Expression Associated with Breast Cancer.

Biomark Cancer 2014 8;6:37-47. Epub 2014 Dec 8.

Center for Genetics, Children's Hospital Oakland Research Institute, Oakland, CA, USA.

Small noncoding RNAs circulating in the blood may serve as signaling molecules because of their ability to carry out a variety of cellular functions. We have previously described tRNA- and YRNA-derived small RNAs circulating as components of larger complexes in the blood of humans and mice; the characteristics of these small RNAs imply specific processing, secretion, and physiological regulation. In this study, we have asked if changes in the serum abundance of these tRNA and YRNA fragments are associated with a diagnosis of cancer. We used deep sequencing and informatics analysis to catalog small RNAs in the sera of breast cancer cases and normal controls. 5' tRNA halves and YRNA fragments are abundant in both groups, but we found that a breast cancer diagnosis is associated with changes in levels of specific subtypes. This prompted us to look at existing sequence datasets of serum small RNAs from 42 breast cancer cases, taken at the time of diagnosis. We find significant changes in the levels of specific 5' tRNA halves and YRNA fragments associated with clinicopathologic characteristics of the cancer. Although these findings do not establish causality, they suggest that circulating 5' tRNA halves and YRNA fragments with known cellular functions may participate in breast cancer syndromes and have potential as circulating biomarkers. Larger studies with multiple types of cancer are needed to adequately evaluate their potential use for the development of noninvasive cancer screening.
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http://dx.doi.org/10.4137/BIC.S20764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260766PMC
December 2014

Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males.

Aging Cell 2014 Apr 19;13(2):273-82. Epub 2013 Nov 19.

The Jackson Laboratory, Bar Harbor, ME, 04609, USA.

Four agents--acarbose (ACA), 17-α-estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB)--were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. NDGA increased male median lifespan by 8-10% at three different doses, with P-values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late-life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.
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http://dx.doi.org/10.1111/acel.12170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954939PMC
April 2014

5'-YRNA fragments derived by processing of transcripts from specific YRNA genes and pseudogenes are abundant in human serum and plasma.

Physiol Genomics 2013 Nov 10;45(21):990-8. Epub 2013 Sep 10.

Department of Biochemistry, University of California at Riverside, Riverside, California;

Small noncoding RNAs carry out a variety of functions in eukaryotic cells, and in multiple species they can travel between cells, thus serving as signaling molecules. In mammals multiple small RNAs have been found to circulate in the blood, although in most cases the targets of these RNAs, and even their functions, are not well understood. YRNAs are small (84-112 nt) RNAs with poorly characterized functions, best known because they make up part of the Ro ribonucleoprotein autoantigens in connective tissue diseases. In surveying small RNAs present in the serum of healthy adult humans, we have found YRNA fragments of lengths 27 nt and 30-33 nt, derived from the 5'-ends of specific YRNAs and generated by cleavage within a predicted internal loop. Many of the YRNAs from which these fragments are derived were previously annotated only as pseudogenes, or predicted informatically. These 5'-YRNA fragments make up a large proportion of all small RNAs (including miRNAs) present in human serum. They are also present in plasma, are not present in exosomes or microvesicles, and circulate as part of a complex with a mass between 100 and 300 kDa. Mouse serum contains far fewer 5'-YRNA fragments, possibly reflecting the much greater copy number of YRNA genes and pseudogenes in humans. The function of the 5'-YRNA fragments is at present unknown, but the processing and secretion of specific YRNAs to produce 5'-end fragments that circulate in stable complexes are consistent with a signaling function.
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http://dx.doi.org/10.1152/physiolgenomics.00129.2013DOI Listing
November 2013

5' tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction.

BMC Genomics 2013 May 2;14:298. Epub 2013 May 2.

Department of Biochemistry, University of California at Riverside, Riverside, CA 92521, USA.

Background: Small RNAs complex with proteins to mediate a variety of functions in animals and plants. Some small RNAs, particularly miRNAs, circulate in mammalian blood and may carry out a signaling function by entering target cells and modulating gene expression. The subject of this study is a set of circulating 30-33 nt RNAs that are processed derivatives of the 5' ends of a small subset of tRNA genes, and closely resemble cellular tRNA derivatives (tRFs, tiRNAs, half-tRNAs, 5' tRNA halves) previously shown to inhibit translation initiation in response to stress in cultured cells.

Results: In sequencing small RNAs extracted from mouse serum, we identified abundant 5' tRNA halves derived from a small subset of tRNAs, implying that they are produced by tRNA type-specific biogenesis and/or release. The 5' tRNA halves are not in exosomes or microvesicles, but circulate as particles of 100-300 kDa. The size of these particles suggest that the 5' tRNA halves are a component of a macromolecular complex; this is supported by the loss of 5' tRNA halves from serum or plasma treated with EDTA, a chelating agent, but their retention in plasma anticoagulated with heparin or citrate. A survey of somatic tissues reveals that 5' tRNA halves are concentrated within blood cells and hematopoietic tissues, but scant in other tissues, suggesting that they may be produced by blood cells. Serum levels of specific subtypes of 5' tRNA halves change markedly with age, either up or down, and these changes can be prevented by calorie restriction.

Conclusions: We demonstrate that 5' tRNA halves circulate in the blood in a stable form, most likely as part of a nucleoprotein complex, and their serum levels are subject to regulation by age and calorie restriction. They may be produced by blood cells, but their cellular targets are not yet known. The characteristics of these circulating molecules, and their known function in suppression of translation initiation, suggest that they are a novel form of signaling molecule.
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http://dx.doi.org/10.1186/1471-2164-14-298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654920PMC
May 2013

Deep sequencing identifies circulating mouse miRNAs that are functionally implicated in manifestations of aging and responsive to calorie restriction.

Aging (Albany NY) 2013 Feb;5(2):130-41

Department of Biochemistry, University of California at Riverside, Riverside, CA 92521, USA.

MicroRNAs (miRNAs) function to modulate gene expression, and through this property they regulate a broad spectrum of cellular processes. They can circulate in blood and thereby mediate cell-to-cell communication. Aging involves changes in many cellular processes that are potentially regulated by miRNAs, and some evidence has implicated circulating miRNAs in the aging process. In order to initiate a comprehensive assessment of the role of circulating miRNAs in aging, we have used deep sequencing to characterize circulating miRNAs in the serum of young mice, old mice, and old mice maintained on calorie restriction (CR). Deep sequencing identifies a set of novel miRNAs, and also accurately measures all known miRNAs present in serum. This analysis demonstrates that the levels of many miRNAs circulating in the mouse are increased with age, and that the increases can be antagonized by CR. The genes targeted by this set of age-modulated miRNAs are predicted to regulate biological processes directly relevant to the manifestations of aging including metabolic changes, and the miRNAs themselves have been linked to diseases associated with old age. This finding implicates circulating miRNAs in the aging process, raising questions about their tissues of origin, their cellular targets, and their functional role in metabolic changes that occur with aging.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616200PMC
http://dx.doi.org/10.18632/aging.100540DOI Listing
February 2013

Mitochondrial pharmacology: electron transport chain bypass as strategies to treat mitochondrial dysfunction.

Biofactors 2012 Mar-Apr;38(2):158-66. Epub 2012 Mar 15.

Department of Basic Sciences, Neuroscience, The Commonwealth Medical College, Scranton, PA 18509, USA.

Mitochondrial dysfunction (primary or secondary) is detrimental to intermediary metabolism. Therapeutic strategies to treat/prevent mitochondrial dysfunction could be valuable for managing metabolic and age-related disorders. Here, we review strategies proposed to treat mitochondrial impairment. We then concentrate on redox-active agents, with mild-redox potential, who shuttle electrons among specific cytosolic or mitochondrial redox-centers. We propose that specific redox agents with mild redox potential (-0.1 V; 0.1 V) improve mitochondrial function because they can readily donate or accept electrons in biological systems, thus they enhance metabolic activity and prevent reactive oxygen species (ROS) production. These agents are likely to lack toxic effects because they lack the risk of inhibiting electron transfer in redox centers. This is different from redox agents with strong negative (-0.4 V; -0.2 V) or positive (0.2 V; 0.4 V) redox potentials who alter the redox status of redox-centers (i.e., become permanently reduced or oxidized). This view has been demonstrated by testing the effect of several redox active agents on cellular senescence. Methylene blue (MB, redox potential ≅10 mV) appears to readily cycle between the oxidized and reduced forms using specific mitochondrial and cytosolic redox centers. MB is most effective in delaying cell senescence and enhancing mitochondrial function in vivo and in vitro. Mild-redox agents can alter the biochemical activity of specific mitochondrial components, which then in response alters the expression of nuclear and mitochondrial genes. We present the concept of mitochondrial electron-carrier bypass as a potential result of mild-redox agents, a method to prevent ROS production, improve mitochondrial function, and delay cellular aging. Thus, mild-redox agents may prevent/delay mitochondria-driven disorders.
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http://dx.doi.org/10.1002/biof.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299858PMC
August 2012

mRNA-Seq reveals complex patterns of gene regulation and expression in the mouse skeletal muscle transcriptome associated with calorie restriction.

Physiol Genomics 2012 Mar 24;44(6):331-44. Epub 2012 Jan 24.

Department of Biochemistry, University of California at Riverside, 92521, USA.

Sarcopenia is an age-associated loss of skeletal muscle mass and strength that increases the risk of disability. Calorie restriction (CR), the consumption of fewer calories while maintaining adequate nutrition, mitigates sarcopenia and many other age-related diseases. To identify potential mechanisms by which CR preserves skeletal muscle integrity during aging, we used mRNA-Seq for deep characterization of gene regulation and mRNA abundance in skeletal muscle of old mice compared with old mice subjected to CR. mRNA-Seq revealed complex CR-associated changes in expression of mRNA isoforms, many of which occur without a change in total message abundance and thus would not be detected by methods other than mRNA-Seq. Functional annotation of differentially expressed genes reveals CR-associated upregulation of pathways involved in energy metabolism and lipid biosynthesis, and downregulation of pathways mediating protein breakdown and oxidative stress, consistent with earlier microarray-based studies. CR-associated changes not noted in previous studies involved downregulation of genes controlling actin cytoskeletal structures and muscle development. These CR-associated changes reflect generally healthier muscle, consistent with CR's mitigation of sarcopenia. mRNA-Seq generates a rich picture of the changes in gene expression associated with CR, and may facilitate identification of genes that are primary mediators of CR's effects.
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http://dx.doi.org/10.1152/physiolgenomics.00129.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327143PMC
March 2012

Deep sequencing reveals novel microRNAs and regulation of microRNA expression during cell senescence.

PLoS One 2011 26;6(5):e20509. Epub 2011 May 26.

Center for Genetics, Children's Hospital Oakland Research Institute, Oakland, California, United States of America.

In cell senescence, cultured cells cease proliferating and acquire aberrant gene expression patterns. MicroRNAs (miRNAs) modulate gene expression through translational repression or mRNA degradation and have been implicated in senescence. We used deep sequencing to carry out a comprehensive survey of miRNA expression and involvement in cell senescence. Informatic analysis of small RNA sequence datasets from young and senescent IMR90 human fibroblasts identifies many miRNAs that are regulated (either up or down) with cell senescence. Comparison with mRNA expression profiles reveals potential mRNA targets of these senescence-regulated miRNAs. The target mRNAs are enriched for genes involved in biological processes associated with cell senescence. This result greatly extends existing information on the role of miRNAs in cell senescence and is consistent with miRNAs having a causal role in the process.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020509PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102725PMC
September 2011

Therapeutic approaches to delay the onset of Alzheimer's disease.

J Aging Res 2011 Mar 3;2011:820903. Epub 2011 Mar 3.

Department of Basic Sciences, Neuroscience, The Commonwealth Medical College, Tobin Hall, 501 Madison Avenue, Scranton, PA 18510, USA.

The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of small aggregates of amyloid-β (Aβ) peptides. Thus, targeting these two abnormalities of the AD brain may hold promising therapeutic value for delaying the onset of AD. In his paper, we discuss two potential approaches to delay the onset of AD. The first is the use of low dose of diaminophenothiazins (redox active agents) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. Diaminophenothiazines enhance mitochondrial metabolic activity and heme synthesis, both key factors in intermediary metabolism of the AD brain.The second is to use the naturally occurring osmolytes to prevent the formation of toxic forms of Aβ and prevent oxidative stress. Scientific evidence suggests that both approaches may change course of the basic mechanism of neurodegeneration in AD. Osmolytes are brain metabolites which accumulate in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation without perturbing other cellular processes. Osmolytes may inhibit the formation of Aβ oligomers in vivo, thus preventing the formation of soluble oligomers. The potential significance of combining diaminophenothiazins and osmolytes to treat AD is discussed.
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http://dx.doi.org/10.4061/2011/820903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056246PMC
March 2011

Protective role of methylene blue in Alzheimer's disease via mitochondria and cytochrome c oxidase.

J Alzheimers Dis 2010 ;20 Suppl 2:S439-52

Department of Basic Sciences, Neuroscience, The Commonwealth Medical College, Scranton, PA, USA.

The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of toxic species of amyloid-beta (Abeta) peptides. This review discusses two potential approaches to delay the onset of AD. The first approach is use of diaminophenothiazines (e.g., methylene blue; MB) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. We have shown that MB increases heme synthesis, cytochrome c oxidase (complex IV), and mitochondrial respiration, which are impaired in AD brains. Consistently, MB is one of the most effective agents to delay senescence in normal human cells. A key action of MB appears to be enhancing mitochondrial function, which is achieved at nM concentrations. We propose that the cycling of MB between the reduced leucomethylene blue (MBH2) and the oxidized (MB) forms may explain, in part, the mitochondria-protecting activities of MB. The second approach is use of naturally occurring osmolytes to prevent the formation of toxic forms of Abeta. Osmolytes (e.g., taurine, carnosine) are brain metabolites typically accumulated in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation, without perturbing other cellular processes. Experimental evidence suggests that the level of carnosine is significantly lower in AD patients. Osmolytes may inhibit the formation of Abeta species in vivo, thus preventing the formation of soluble oligomers. Osmolytes are efficient antioxidants that may also increase neural resistance to Abeta. The potential significance of combining MB and osmolytes to treat AD are discussed.
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http://dx.doi.org/10.3233/JAD-2010-100414DOI Listing
September 2010

Amino acids variations in amyloid-beta peptides, mitochondrial dysfunction, and new therapies for Alzheimer's disease.

Authors:
Hani Atamna

J Bioenerg Biomembr 2009 Oct;41(5):457-64

Department of Basic Sciences, Neuroscience, The Commonwealth Medical College, 501 Madison Avenue, Scranton, PA 18510, USA.

Soluble oligomers and/or aggregates of Amyloid-beta (Abeta) are viewed by many as the principal cause for neurodegeneration in Alzheimer's disease (AD). However, the mechanism by which Abeta and its aggregates cause neurodegeneration is not clear. The toxicity of Abeta has been attributed to its hydrophobicity. However, many specific mitochondrial cytopathologies e.g., loss of complex IV, loss of iron homeostasis, or oxidative damage cannot be explained by Abeta's hydrophobicity. In order to understand the role of Abeta in these cytopathologies we hypothesized that Abeta impairs specific metabolic pathways. We focused on heme metabolism because it links iron, mitochondria, and Abeta. We generated experimental evidence showing that Abeta alters heme metabolism in neuronal cells. Furthermore, we demonstrated that Abeta binds to and depletes intracellular regulatory heme (forming an Abeta-heme complex), which provides a strong molecular connection between Abeta and heme metabolism. We showed that heme depletion leads to key cytopathologies identical to those seen in AD including loss of iron homeostasis and loss of mitochondrial complex IV. Abeta-heme exhibits a peroxidase-like catalytic activity, which catalytically accelerates oxidative damage. Interestingly, the amino acids sequence of rodent Abeta (roAbeta) and human Abeta (huAbeta) is identical except for three amino acids within the hydrophilic region, which is also the heme-binding motif that we identified. We found that huAbeta, unlike roAbeta, binds heme tightly and forms a peroxidase. Although, roAbeta and huAbeta equally form fibrils and aggregates, rodents do not develop AD-like neuropathology. These findings led us to propose a new mechanism for mitochondrial dysfunction and huAbeta's neurotoxicity. This mechanism prompted the development of methylene blue (MB), which increased heme synthesis, complex IV, and mitochondrial function. Thus, MB may delay the onset and progression of AD and serve as a lead to develop novel drugs to treat AD.
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http://dx.doi.org/10.1007/s10863-009-9246-2DOI Listing
October 2009

Human and rodent amyloid-beta peptides differentially bind heme: relevance to the human susceptibility to Alzheimer's disease.

Arch Biochem Biophys 2009 Jul 18;487(1):59-65. Epub 2009 May 18.

Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.

Amyloid-beta (Abeta) peptides are implicated in the neurodegeneration of Alzheimer's disease (AD). We previously investigated the mechanism of neurotoxicity of Abeta and found that human Abeta (huAbeta) binds and depletes heme, forming an Abeta-heme complex with peroxidase activity. Rodent Abeta (roAbeta) is identical to huAbeta, except for three amino acids within the proposed heme-binding motif (Site-H). We studied and compared heme-binding between roAbeta and huAbeta. Unlike roAbeta, huAbeta binds heme tightly (K(d)=140+/-60 nM) and forms a peroxidase. The plot of bound (huAbeta-heme) vs. unbound heme fits best to a two site binding hyperbola, suggesting huAbeta possesses two heme-binding sites. Consistently, a second high affinity heme-binding site was identified in the lipophilic region (site-L) of huAbeta (K(d)=210+/-80 nM). The plot of (roAbeta-heme) vs. unbound heme, on the other hand, was different as it fits best to a sigmoidal binding curve, indicating different binding and lower affinity of roAbeta for heme (K(d)=1 microM). The effect of heme-binding to site-H on heme-binding to site-L in roAbeta and huAbeta is discussed. While both roAbeta and huAbeta form aggregates equally, rodents lack AD-like neuropathology. High huAbeta/heme ratio increases the peroxidase activity. These findings suggest that depletion of regulatory heme and formation of Abeta-heme peroxidase contribute to huAbeta's neurotoxicity in the early stages of AD. Phylogenic variations in the amino acid sequence of Abeta explain tight heme-binding to huAbeta and likely contribute to the increased human susceptibility to AD.
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http://dx.doi.org/10.1016/j.abb.2009.05.003DOI Listing
July 2009

Gender and age-dependent differences in the mitochondrial apoptogenic pathway in Alzheimer's disease.

Free Radic Biol Med 2008 Jun 20;44(12):2019-25. Epub 2008 Mar 20.

Departamento de Fisiología, Facultad de Medicina, Avda. Blasco Ibáñez 15, 46010 Valencia, Spain.

Age-related mitochondrial oxidative stress is highly gender dependent. The aim of this study was to determine the role of gender in the mitochondrial contribution to neuronal apoptosis in Alzheimer's disease (AD). We used mitochondria isolated from brains of Wistar rats to study the toxicity of ss-amyloid peptide (Ass), and found that it increases mitochondrial peroxide production, nitration and oxidation of proteins, and release of cytochrome c. The toxic effects occurred in young males and in old females but not in young females, indicating their resistance to Ass. This resistance was abolished with age. These toxic effects of Ass were prevented by heme. Our findings provide a molecular mechanism for the contribution of Abeta to the mitochondrial dysfunction and oxidative stress seen in AD, as well as for the mitochondria-dependent pathway of apoptosis in AD. Gender and age-related differences seen in the development of AD can also be partially explained.
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http://dx.doi.org/10.1016/j.freeradbiomed.2008.02.017DOI Listing
June 2008

Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways.

FASEB J 2008 Mar 10;22(3):703-12. Epub 2007 Oct 10.

Nutrition & Metabolism Center, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673, USA.

Methylene blue (MB) has been used clinically for about a century to treat numerous ailments. We show that MB and other diaminophenothiazines extend the life span of human IMR90 fibroblasts in tissue culture by >20 population doubling (PDLs). MB delays senescence at nM levels in IMR90 by enhancing mitochondrial function. MB increases mitochondrial complex IV by 30%, enhances cellular oxygen consumption by 37-70%, increases heme synthesis, and reverses premature senescence caused by H2O2 or cadmium. MB also induces phase-2 antioxidant enzymes in hepG2 cells. Flavin-dependent enzymes are known to use NAD(P)H to reduce MB to leucomethylene blue (MBH2), whereas cytochrome c reoxidizes MBH2 to MB. Experiments on lysates from rat liver mitochondria suggest the ratio MB/cytochrome c is important for the protective actions of MB. We propose that the cellular senescence delay caused by MB is due to cycling between MB and MBH2 in mitochondria, which may partly explain the increase in specific mitochondrial activities. Cycling of MB between oxidized and reduced forms may block oxidant production by mitochondria. Mitochondrial dysfunction and oxidative stress are thought to be key aberrations that lead to cellular senescence and aging. MB may be useful to delay mitochondrial dysfunction with aging and the decrease in complex IV in Alzheimer disease.
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http://dx.doi.org/10.1096/fj.07-9610comDOI Listing
March 2008

N-tert-butyl hydroxylamine, a mitochondrial antioxidant, protects human retinal pigment epithelial cells from iron overload: relevance to macular degeneration.

FASEB J 2007 Dec 26;21(14):4077-86. Epub 2007 Jul 26.

Children's Hospital Oakland Research Institute, Nutrition and Metabolism Center, 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673, USA.

Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in the elderly in developed countries. AMD patients have elevated levels of iron within the retinal pigment epithelia (RPE), which may lead to oxidative damage to mitochondria, disruption of retinal metabolism, and vision impairment or loss. As a possible model for iron-induced AMD, we investigated the effects of excess iron in cultured human fetal RPE cells on oxidant levels and mitochondrial cytochrome c oxidase (complex IV) function and tested for protection by N-tert-butyl hydroxylamine (NtBHA), a known mitochondrial antioxidant. RPE exposure to ferric ammonium citrate resulted in a time- and dose-dependent increase in intracellular iron, which increased oxidant production and decreased glutathione (GSH) levels and mitochondrial complex IV activity. NtBHA addition to iron-overloaded RPE cells led to a reduction of intracellular iron content, oxidative stress, and partial restoration of complex IV activity and GSH content. NtBHA might be useful in AMD due to its potential to reduce oxidative stress, mitochondrial damage, and age-related iron accumulation, which may damage normal RPE function and lead to loss of vision.
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http://dx.doi.org/10.1096/fj.07-8396comDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597693PMC
December 2007

Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer's disease.

Mitochondrion 2007 Sep 13;7(5):297-310. Epub 2007 Jun 13.

Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673, USA.

Several studies have demonstrated aberrations in the Electron Transport Complexes (ETC) and Krebs (TCA) cycle in Alzheimer's disease (AD) brain. Optimal activity of these key metabolic pathways depends on several redox active centers and metabolites including heme, coenzyme Q, iron-sulfur, vitamins, minerals, and micronutrients. Disturbed heme metabolism leads to increased aberrations in the ETC (loss of complex IV), dimerization of APP, free radical production, markers of oxidative damage, and ultimately cell death all of which represent key cytopathologies in AD. The mechanism of mitochondrial dysfunction in AD is controversial. The observations that Abeta is found both in the cells and in the mitochondria and that Abeta binds with heme may provide clues to this mechanism. Mitochondrial Abeta may interfere with key metabolites or metabolic pathways in a manner that overwhelms the mitochondrial mechanisms of repair. Identifying the molecular mechanism for how Abeta interferes with mitochondria and that explains the established key cytopathologies in AD may also suggest molecular targets for therapeutic interventions. Below we review recent studies describing the possible role of Abeta in altered energy production through heme metabolism. We further discuss how protecting mitochondria could confer resistance to oxidative and environmental insults. Therapies targeted at protecting mitochondria may improve the clinical outcome of AD patients.
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http://dx.doi.org/10.1016/j.mito.2007.06.001DOI Listing
September 2007

Biotin deficiency inhibits heme synthesis and impairs mitochondria in human lung fibroblasts.

J Nutr 2007 Jan;137(1):25-30

Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.

Four of the 5 biotin-dependent carboxylases (BDC) are in the mitochondria. BDC replace intermediates in the Krebs [tricarboxylic acid (TCA)] cycle that are regularly removed for the synthesis of key metabolites such as heme or amino acids. Heme, unlike amino acids, is not recycled to regenerate these intermediates, is not utilized from the diet, and must be synthesized in situ. We studied whether biotin deficiency (BD) lowers heme synthesis and whether mitochondria would be disrupted. Biotin-deficient medium was prepared by using bovine serum stripped of biotin with charcoal/dextran or avidin. Biotin-deficient primary human lung fibroblasts (IMR90) lost their BDC and senesced before biotin-sufficient cells. BD caused heme deficiency; there was a decrease in heme content and heme synthesis, and biotin-deficient cells selectively lost mitochondrial complex IV, which contains heme-a. Loss of complex IV, which is part of the electron transport chain, triggered oxidant release and oxidative damage, hallmarks of heme deficiency. Restoring biotin to the biotin-deficient medium prevented the above changes. Old cells were more susceptible to biotin shortage than young cells. These findings highlight the biochemical connection among biotin, heme, and iron metabolism, and the mitochondria, due to the role of biotin in maintaining the biochemical integrity of the TCA cycle. The findings are discussed in relation to aging and birth defects in humans.
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http://dx.doi.org/10.1093/jn/137.1.25DOI Listing
January 2007

Heme binding to Amyloid-beta peptide: mechanistic role in Alzheimer's disease.

Authors:
Hani Atamna

J Alzheimers Dis 2006 Nov;10(2-3):255-66

Nutrition & Metabolism Center, Children's Hospital Oakland Research Institute (CHORI), Oakland, CA 94609, USA.

Genetic, biochemical, and immunological evidences support a mechanistic role for amyloid-beta (Abeta) peptide in the pathophysiology of Alzheimer's disease (AD). Abeta appears to trigger most of the disparate cytopathologies of AD (e.g. loss of iron homeostasis and mitochondrial complex IV), which may initiate synaptic dysfunction, hypometabolism, and memory loss. However, the molecular mechanism that links Abeta to the neurodegeneration of AD is not clear. We have provided evidence for heme's key role in the important cytopathologies of AD, hypothesizing a functional deficiency for heme in the brains of AD patients. The molecular link between beta and heme required to support this hypothesis was demonstrated by our discovery that heme binds with Abeta, forming a complex (Abeta-heme). Heme prevented the aggregation of Abeta by forming Abeta-heme, suggesting Abeta-heme may prevent Abeta aggregation in vivo. The downside, however, is that Abeta-heme is a peroxidase, which if not regulated might indiscriminately oxidize diverse biomolecules. Additionally, excessive production of Abeta in AD brain may bind to and restrict the bioavailability of regulatory heme, creating a condition of heme-deficiency. Regulatory heme regulates heme synthesis, iron homeostasis, specific signaling pathways, and intermediary metabolism. A novel model of Abeta-induced heme-deficiency leading to mitochondrial dysfunction, Abeta-heme peroxidase, and altered metabolic activity is presented. Genetic, nutritional, and toxicological factors that influence heme metabolism will be discussed in relevance to AD.
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http://dx.doi.org/10.3233/jad-2006-102-310DOI Listing
November 2006

Amyloid-beta peptide binds with heme to form a peroxidase: relationship to the cytopathologies of Alzheimer's disease.

Proc Natl Acad Sci U S A 2006 Feb 21;103(9):3381-6. Epub 2006 Feb 21.

Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, CA 94609, USA.

Amyloid-beta peptide (Abeta) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive Abeta binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H(2)O(2)) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that Abeta binding to regulatory heme in vivo is the mechanism by which Abeta causes HD. Heme binds to Abeta, thus preventing Abeta aggregation by forming an Abeta-heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The Abeta-heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H(2)O(2). Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of Abeta to heme supports a unifying mechanism by which excessive Abeta induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive Abeta for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.
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http://dx.doi.org/10.1073/pnas.0600134103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413946PMC
February 2006

Mineral and vitamin deficiencies can accelerate the mitochondrial decay of aging.

Mol Aspects Med 2005 Aug-Oct;26(4-5):363-78

Nutrition, Metabolisms and Genomics Center, Children's Hospital Oakland Research Institute, Oakland, CA 94609, U States.

Mitochondrial oxidative decay, which is a major contributor to aging, is accelerated by many common micronutrient deficiencies. One major mechanism is inhibition of the pathway of heme biosynthesis in mitochondria, which causes a deficit of heme-a. Heme-a, only found in Complex IV, is selectively diminished, resulting in oxidant leakage and accelerated mitochondrial decay, which leads to DNA damage, neural decay, and aging. We emphasize those deficiencies, which appear to cause damage through this mechanism, particularly minerals such as iron (25% of menstruating women ingest <50% of the RDA) or zinc (10% of the population ingest <50% of the RDA). Several vitamin deficiencies, such as biotin or pantothenic acid, also increase mitochondrial oxidants through this mechanism. Additionally, other minerals such as magnesium and manganese that play a role in mitochondrial metabolism, but do not affect heme directly, are discussed. An optimum intake of micronutrients could tune up metabolism and give a marked increase in health, particularly for the poor, elderly, and obese, at little cost.
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http://dx.doi.org/10.1016/j.mam.2005.07.007DOI Listing
November 2005