Multilayered Genetic and Omics Dissection of Mitochondrial Activity in a Mouse Reference Population

Wu, Yibo; Williams, Evan G.; Dubuis, Sébastien; Mottis, Adrienne; Jovaisaite, Virginija; Houten, Sander M.; Argmann, Carmen; Faridi, Pouya; Wolski, Witold; Kutalik, Zoltán; Zamboni, Nicola; Auwerx, Johan; Aebersold, Ruedi

doi:10.1016/j.cell.2014.07.039

Cited by 222 publications

(252 citation statements)

References 66 publications

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“…Furthermore, the experimental demonstration that 2-aminoadipic acid is influenced by both diet and genetic background highlights the potential role for nutrigenomic interventions. 177 It is anticipated that as sufficiently large human data sets are acquired, investigators will begin to be able to parse the relative contributions of diet and genes in this pathway and others in disease development.…”

Section: Metabolomicsmentioning

confidence: 99%

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment

Ferguson¹,

Allayee²,

Gerszten³

et al. 2016

Circ Cardiovasc Genet

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Abstract-Cardiometabolic diseases are the leading cause of death worldwide and are strongly linked to both genetic and nutritional factors. The field of nutrigenomics encompasses multiple approaches aimed at understanding the effects of diet on health or disease development, including nutrigenetic studies investigating the relationship between genetic variants and diet in modulating cardiometabolic risk, as well as the effects of dietary components on multiple "omic" measures, including transcriptomics, metabolomics, proteomics, lipidomics, epigenetic modifications, and the microbiome. Here, we describe the current state of the field of nutrigenomics with respect to cardiometabolic disease research and outline a direction for the integration of multiple omics techniques in future nutrigenomic studies aimed at understanding mechanisms and developing new therapeutic options for cardiometabolic disease treatment and prevention. The interpretation and scope of nutrigenomics may vary, but it can be thought to encompass the spectrum of nutritional genomics research, including classic nutrigenetics studies of gene-diet interactions and molecular nutrition, in vitro and in vivo models, human nutrition studies, and the application of largescale, unbiased studies using high-throughput "omics" techniques to study the effects of nutrients on the body. 6 As the Figure shows, diet and the genome may influence cardiometabolic health through a variety of interconnected intermediates, perturbations in which can be measured through omics technologies, including RNA expression (transcriptome), epigenetic modifications (epigenome), metabolites (metabolome), lipids (lipidome), proteins (proteome), and resident microbial communities (microbiome). Although it is clear that both nutrients and genes play a distinct role in determining health, the complex interactions among genes, diet, and downstream networks are not well understood. The application of nutrigenomics approaches to questions of human health and disease is an important component in understanding the complexities of the interplay between basic metabolic processes and externalThe American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on January 22, 2016, and the American Heart Association Executive Committee on February 23, 2016. A copy of the document is available at http://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com.The...

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Section: Metabolomicsmentioning

confidence: 99%

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment

Ferguson¹,

Allayee²,

Gerszten³

et al. 2016

Circ Cardiovasc Genet

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“…Indeed, knockdown of DHTKD1 expression in a variety of cell lines suggests that this protein plays a role in mitochondrial function and energy production (Xu et al 2013); and a proteomic/metabolomic study in mice implicated DHTKD1 in glucose homeostasis through its connection to 2-aminoadipic acid (Wu et al 2014). These studies suggest the possibility that further phenotypes, perhaps with a later onset, may be associated with genetic abrogation of DHTKD1.…”

Section: Discussionmentioning

confidence: 93%

New Cases of DHTKD1 Mutations in Patients with 2-Ketoadipic Aciduria

et al. 2015

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2-Ketoadipic aciduria (OMIM 204750), a defect in the catabolic pathway of tryptophan, lysine, and hydroxylysine, is characterized by elevations in 2-ketoadipic, 2-aminoadipic, and 2-hydroxyadipic acids. Patients with the aforementioned biochemical profile have been described with a wide range of clinical presentations, from early-onset developmental delay, epilepsy, ataxia, and microcephaly to completely normal. This broad range of phenotypes has led some to question whether 2-ketoadipic aciduria represents a true disease state or if the biochemical abnormalities found in these patients merely reflect an ascertainment bias. We present four additional individuals from two families, with 2-ketoadipic aciduria with compound heterozygous or homozygous mutations in DHTKD1, three of which remain asymptomatic.

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“…The bZip transcriptional factor ATFS-1 required for UPRmt signaling is destined to the mitochondrial matrix where Lon degrades it; however, under stress conditions, ATFS-1 is stabilized and trafficked to the nucleus where it initiates the transcriptional response (76,135). Although UPRmt is conserved among worms, mice, and humans (191), it remains to be determined if stresssensing and signaling mechanisms in mammals are identical to the ones described for nematodes.…”

Section: Matrix Subproteomementioning

confidence: 99%

Mitochondrial Protein Quality Control: The Mechanisms Guarding Mitochondrial Health

Bohovych

Chan

Khalimonchuk

2015

Antioxidants & Redox Signaling

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Significance: Mitochondria are complex dynamic organelles pivotal for cellular physiology and human health. Failure to maintain mitochondrial health leads to numerous maladies that include late-onset neurodegenerative diseases and cardiovascular disorders. Furthermore, a decline in mitochondrial health is prevalent with aging. A set of evolutionary conserved mechanisms known as mitochondrial quality control (MQC) is involved in recognition and correction of the mitochondrial proteome. Recent Advances: Here, we review current knowledge and latest developments in MQC. We particularly focus on the proteolytic aspect of MQC and its impact on health and aging. Critical Issues: While our knowledge about MQC is steadily growing, critical gaps remain in the mechanistic understanding of how MQC modules sense damage and preserve mitochondrial welfare, particularly in higher organisms. Future Directions: Delineating how coordinated action of the MQC modules orchestrates physiological responses on both organellar and cellular levels will further elucidate the current picture of MQC's role and function in health, cellular stress, and degenerative diseases. Antioxid. Redox Signal. 22, 977-994.

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Multilayered Genetic and Omics Dissection of Mitochondrial Activity in a Mouse Reference Population

Cited by 222 publications

References 66 publications

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment

New Cases of DHTKD1 Mutations in Patients with 2-Ketoadipic Aciduria

Mitochondrial Protein Quality Control: The Mechanisms Guarding Mitochondrial Health

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