References of "Jha, Pooja"
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See detailQuantifying and Localizing the Mitochondrial Proteome Across Five Tissues in A Mouse Population.
Williams, Evan UL; Wu, Yibo; Wolski, Witold et al

in Molecular and Cellular Proteomics (2018), 17(9), 1766-1777

We have used SWATH mass spectrometry to quantify 3648 proteins across 76 proteomes collected from genetically diverse BXD mouse strains in two fractions (mitochondria and total cell) from five tissues ... [more ▼]

We have used SWATH mass spectrometry to quantify 3648 proteins across 76 proteomes collected from genetically diverse BXD mouse strains in two fractions (mitochondria and total cell) from five tissues: liver, quadriceps, heart, brain, and brown adipose (BAT). Across tissues, expression covariation between genes' proteins and transcripts-measured in the same individuals-broadly aligned. Covariation was however far stronger in certain subsets than others: only 8% of transcripts in the lowest expression and variance quintile covaried with their protein, in contrast to 65% of transcripts in the highest quintiles. Key functional differences among the 3648 genes were also observed across tissues, with electron transport chain (ETC) genes particularly investigated. ETC complex proteins covary and form strong gene networks according to tissue, but their equivalent transcripts do not. Certain physiological consequences, such as the depletion of ATP synthase in BAT, are thus obscured in transcript data. Lastly, we compared the quantitative proteomic measurements between the total cell and mitochondrial fractions for the five tissues. The resulting enrichment score highlighted several hundred proteins which were strongly enriched in mitochondria, which included several dozen proteins were not reported in literature to be mitochondrially localized. Four of these candidates were selected for biochemical validation, where we found MTAP, SOAT2, and IMPDH2 to be localized inside the mitochondria, whereas ABCC6 was in the mitochondria-associated membrane. These findings demonstrate the synergies of a multi-omics approach to study complex metabolic processes, and this provides a resource for further discovery and analysis of proteoforms, modified proteins, and protein localization. [less ▲]

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See detailGenetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes.
Jha, Pooja; McDevitt, Molly T.; Halilbasic, Emina et al

in Cell systems (2018), 6(6), 709-7216

The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either ... [more ▼]

The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for approximately 94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits. [less ▲]

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See detailSystems Analyses Reveal Physiological Roles and Genetic Regulators of Liver Lipid Species.
Jha, Pooja; McDevitt, Molly T.; Gupta, Rahul et al

in Cell systems (2018), 6(6), 722-7336

The genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 ... [more ▼]

The genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 strains of the BXD mouse population fed chow or high-fat diet and integrated these data with complementary multi-omics datasets. We identified several lipid species and lipid clusters with specific phenotypic and molecular signatures and, in particular, cardiolipin species with signatures of healthy and fatty liver. Genetic analyses revealed quantitative trait loci for 68% of the lipids (lQTL). By multi-layered omics analyses, we show the reliability of lQTLs to uncover candidate genes that can regulate the levels of lipid species. Additionally, we identified lQTLs that mapped to genes associated with abnormal lipid metabolism in human GWASs. This work provides a foundation and resource for understanding the genetic regulation and physiological significance of lipid species. [less ▲]

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See detailSystems proteomics of liver mitochondria function.
Williams, Evan UL; Wu, Yibo; Jha, Pooja et al

in Science (New York, N.Y.) (2016), 352(6291), 0189

Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across ... [more ▼]

Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein's activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics--a combination moving us forward in complex trait analysis. [less ▲]

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See detailUrolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.
Ryu, Dongryeol; Mouchiroud, Laurent; Andreux, Penelope A. et al

in Nature medicine (2016), 22(8), 879-88

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the ... [more ▼]

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function. [less ▲]

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