Vamsi K. Mootha

Bio: Vamsi K. Mootha is an academic researcher from Broad Institute. The author has contributed to research in topics: Mitochondrion & Mitochondrial DNA. The author has an hindex of 85, co-authored 227 publications receiving 73860 citations. Previous affiliations of Vamsi K. Mootha include Harvard University & Beth Israel Deaconess Medical Center.

Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men

Abstract: OBJECTIVE — The goal of this study was to examine the relationship between serum testosterone levels and insulin sensitivity and mitochondrial function in men. RESEARCH DESIGN AND METHODS —A total of 60 men (mean age 60.5 ± 1.2 years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring maximal aerobic capacity ( V o 2max ) and expression of oxidative phosphorylation genes in skeletal muscle. RESULTS —A total of 45% of subjects had normal glucose tolerance, 20% had impaired glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated with insulin sensitivity ( r = 0.4, P n = 10) had a BMI >25 kg/m 2 and a threefold higher prevalence of the metabolic syndrome than their eugonadal counterparts ( n = 50); this relationship held true after adjusting for age and sex hormone–binding globulin but not BMI. Testosterone levels also correlated with V o 2max ( r = 0.43, P r = 0.57, P CONCLUSIONS —These data indicate that low serum testosterone levels are associated with an adverse metabolic profile and suggest a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men.

MICU2, a Paralog of MICU1, Resides within the Mitochondrial Uniporter Complex to Regulate Calcium Handling

Abstract: Mitochondrial calcium uptake is present in nearly all vertebrate tissues and is believed to be critical in shaping calcium signaling, regulating ATP synthesis and controlling cell death. Calcium uptake occurs through a channel called the uniporter that resides in the inner mitochondrial membrane. Recently, we used comparative genomics to identify MICU1 and MCU as the key regulatory and putative pore-forming subunits of this channel, respectively. Using bioinformatics, we now report that the human genome encodes two additional paralogs of MICU1, which we call MICU2 and MICU3, each of which likely arose by gene duplication and exhibits distinct patterns of organ expression. We demonstrate that MICU1 and MICU2 are expressed in HeLa and HEK293T cells, and provide multiple lines of biochemical evidence that MCU, MICU1 and MICU2 reside within a complex and cross-stabilize each other's protein expression in a cell-type dependent manner. Using in vivo RNAi technology to silence MICU1, MICU2 or both proteins in mouse liver, we observe an additive impairment in calcium handling without adversely impacting mitochondrial respiration or membrane potential. The results identify MICU2 as a new component of the uniporter complex that may contribute to the tissue-specific regulation of this channel.

MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion

Abstract: The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral1 (OMIM 251880). Known mutant genes, including TK2 (ref. 2), SUCLA2 (ref. 3), DGUOK (ref. 4) and POLG5,6, account for only a fraction of MDDS cases7. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17 (ref. 8). We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product9, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17−/− mice.

Ca2+ activation of heart mitochondrial oxidative phosphorylation: role of the F0/F1-ATPase

Abstract: Ca(2+) has been postulated as a cytosolic second messenger in the regulation of cardiac oxidative phosphorylation. This hypothesis draws support from the well-known effects of Ca(2+) on muscle activity, which is stimulated in parallel with the Ca(2+)-sensitive dehydrogenases (CaDH). The effects of Ca(2+) on oxidative phosphorylation were further investigated in isolated porcine heart mitochondria at the level of metabolic driving force (NADH or Deltapsi) and ATP production rates (flow). The resulting force-flow (F-F) relationships permitted the analysis of Ca(2+) effects on several putative control points within oxidative phosphorylation, simultaneously. The F-F relationships resulting from additions of carbon substrates alone provided a model of pure CaDH activation. Comparing this curve with variable Ca(2+) concentration ([Ca(2+)]) effects revealed an approximate twofold higher ATP production rate than could be explained by a simple increase in NADH or Deltapsi via CaDH activation. The half-maximal effect of Ca(2+ )at state 3 was 157 nM and was completely inhibited by ruthenium red (1 microM), indicating matrix dependence of the Ca(2+) effect. Arsenate was used as a probe to differentiate between F(0)/F(1)-ATPase and adenylate translocase activity by a futile recycling of ADP-arsenate within the matrix, catalyzed by the F(0)/F(1)-ATPase. Ca(2+) increased the ADP arsenylation rate more than twofold, suggesting a direct effect on the F(0)/F(1)-ATPase. These results suggest that Ca(2+) activates cardiac aerobic respiration at the level of both the CaDH and F(0)/F(1)-ATPase. This type of parallel control of both intermediary metabolism and ATP synthesis may provide a mechanism of altering ATP production rates with minimal changes in the high-energy intermediates as observed in vivo.

Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity

Abstract: Bioinformatics and Integrative Genomics Award from National Human Genome Research Institute; National Institutes of Health (R01-HL-086875, R01-HL-083197); Heart Failure Society of America and the Harvard/MIT Clinical Investigator Training Program; National Institutes of Health (U01HL083141); Donald W Reynolds Foundation and Fondation Leducq; Burroughs Wellcome Career Award in the Biomedical Sciences; Howard Hughes Medical Institute Early Career Physician Scientist Award; Broad Institute Scientific Planning and Allocation of Resources Committee; National Institutes of Health (General Clinical Research Center grant); General Clinical Research Center (MO1-RR01066); National Institutes of Health/National Heart Lung and Blood Institute (N01-HC-25195).

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Abstract: Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.

Abstract: DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.

limma powers differential expression analyses for RNA-sequencing and microarray studies

Abstract: limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。