High-throughput screens using photo-highlighting discover BMP signaling in mitochondrial lipid oxidation

Yu, Yong Ming; Mutlu, Ayse Sena; Liu, Harrison; Wang, Meng C.

doi:10.1038/s41467-017-00944-3

Cited by 48 publications

(54 citation statements)

References 47 publications

(43 reference statements)

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“…TGF-β Sma/Mab signaling, a C. elegans growth factor pathway homologous to the mammalian BMP pathway (Savage-Dunn and Padgett, 2017), plays an integral role in promoting energy-expensive functions such as lipid storage (Clark et al, 2018; Yu et al, 2017), body growth (Savage-Dunn et al, 2003), and progeny production (Luo et al, 2010). All of these functions are regulated by the actions of the TGF-β Sma/Mab pathway in the hypodermis (Clark et al, 2018; Luo et al, 2010; Wang et al, 2002), but they can be dissociated from each other (Luo et al, 2010; Yu et al, 2017). Our results point to one downstream mechanism by which hypodermal TGF-β Sma/Mab signaling separately controls these biological processes: while growth is discretely regulated by CREB and the TGF-β Sma/Mab pathway, hypodermal TGF-β Sma/Mab signaling requires the presence of CREB to alter the rate of reproductive decline, indicating that CREB enables hypodermal TGF-β Sma/Mab signaling to cell non-autonomously control reproductive aging.…”

Section: Discussionmentioning

confidence: 99%

CREB non-autonomously regulates Reproductive Aging through Hedgehog/Patched Signalling

Templeman

Cota

Keyes

et al. 2020

Preprint

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Summary Evolutionarily conserved signaling pathways are crucial for adjusting growth, reproduction, and cell maintenance in response to altered environmental conditions or energy balance. However, we have an incomplete understanding of the signaling networks and mechanistic changes that coordinate physiological changes across tissues. We found that loss of the cAMP response element-binding protein (CREB) transcription factor significantly slows Caenorhabditis elegans’ reproductive decline, an early hallmark of aging in many animals. Our results indicate that CREB acts downstream of the transforming growth factor beta (TGF-β) Sma/Mab pathway in the hypodermis to control reproductive aging, and that it does so by regulating a Hedgehog-related signaling factor, WRT-10. Overexpression of hypodermal wrt-10 is sufficient to delay reproductive decline and oocyte quality deterioration, potentially acting via Patched-related receptors in the germline. This TGF-β/CREB/WRT-10 signaling axis allows a key metabolic tissue to communicate with the reproductive system to regulate oocyte quality and the rate of reproductive decline. Highlights The transcription factor CREB regulates oocyte quality and reproductive decline Hypodermal CREB downstream of TGF-β Sma/Mab signaling controls reproductive aging CREB targets in the hypodermis include a Hedgehog-related signaling factor, wrt-10 WRT-10 regulates reproductive aging, potentially via germline Patched receptors eTOC Blurb Templeman et al. describe how CREB, a highly conserved transcription factor, is a central regulator of age-dependent reproductive decline. CREB acts downstream of the TGF-β Sma/Mab pathway in the hypodermis, a key Caenorhabditis elegans metabolic tissue, to control oocyte quality maintenance and the rate of reproductive decline. Hypodermal CREB affects the expression of wrt-10, which encodes a Hedgehog-related signaling factor. The authors show that wrt-10 regulates reproductive aging, potentially via Patched-related receptors in the germline.

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Section: Discussionmentioning

confidence: 99%

CREB non-autonomously regulates Reproductive Aging through Hedgehog/Patched Signalling

Templeman

Cota

Keyes

et al. 2020

Preprint

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“…Gene ontology assays were performed by using DAVID (Huang da et al, 2009). Changes in the expression of metabolic genes were displayed as previously shown with modifications (Steinbaugh et al, 2015;Yu et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

C. elegans Mediator 15 permits low temperature-induced longevity via regulation of lipid and protein homeostasis

Lee

Jung

et al. 2018

Preprint

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Low temperatures slow aging and extend lifespan in many organisms, including Caenorhabditis elegans. However, the metabolic and homeostatic aspects of low temperature-induced longevity remain poorly understood. Here, we show that changes in lipid composition regulated by MDT-15/Mediator 15, transcriptional co-regulator, is essential for low temperature-induced longevity and proteostasis in C. elegans. We find that inhibition of mdt-15 prevents animals from living long at low temperatures. We show that MDT-15 up-regulates fat-7, a fatty acid desaturase, at low temperatures, which increases the ratio of unsaturated to saturated fatty acids. We further demonstrate that maintaining this increased fatty acid ratio is essential for protein homeostasis and longevity at low temperatures. Thus, the homeostasis of lipid composition by MDT-15 appears to be a limiting factor for C. elegans proteostasis and longevity at low temperatures. Our findings highlight the crucial roles of fat regulation in maintaining normal organismal physiology under different environmental conditions.

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“…Previously, our lab and others have developed methods to visualize lipogenic activities in living tissues by supplying deuterium-labeled fatty acids (D-FAs), such as palmitic acid, oleic acid, and arachidonic acid, and imaging C-D bonds in newly synthesized lipids [30][31][32][33] . However, DO-SRS is fundamentally different from those previous methods because D2O is a noninterfering probe that does not change native metabolism and is a non-carbon tracer that can probe activities of de novo lipogenesis.…”

Section: Optical Imaging Of De Novo Lipogenesis Via Do-srsmentioning

confidence: 99%

“…D2O is a better probe than D-FAs to analyze lipogenesis in C. elegans because of the following reasons. First, we directly compared CDL signals generated by D2O probing and D-FA supplementation (Supplementary Figure 3B and C) and found that although both labeled lipid droplets in similar patterns, 20% D2O treatment produced over two-fold stronger CDL signal than 4 mM deuterated palmitic acid, the highest concentration used in previous studies 31,33 . Second, D2O is able to track the ~14% lipids generated by de novo lipogenesis, whereas D-FA cannot.…”

Section: Do-srs Tracks Lipid Metabolism In C Elegansmentioning

confidence: 99%

Optical Imaging of Metabolic Dynamics in Animals

Shi

Zheng

Shen

et al. 2018

Preprint

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Direct visualization of metabolic dynamics in living tissues with high spatial and temporal resolution is essential to understanding many biological processes. Here we introduce a platform that combines deuterium oxide (D2O) probing with stimulated Raman scattering microscopy (DO-SRS) to image in situ metabolic activities. Enzymatic incorporation of D2O-derived deuterium into macromolecules generates carbondeuterium (C-D) bonds, which track biosynthesis in tissues and can be imaged by SRS in situ. Within the broad vibrational spectra of C-D bonds, we discovered lipid-, protein-, and DNA-specific Raman shifts and developed spectral unmixing methods to obtain C-D signals with macromolecular selectivity. DO-SRS enabled us to probe de novo lipogenesis in animals, image protein biosynthesis without tissue bias, and simultaneously visualize lipid and protein metabolism and reveal their different dynamics. DO-SRS, being noninvasive, universally applicable, and cost-effective, can be adapted to a broad range of biological systems to study development, tissue homeostasis, aging, and tumor heterogeneity. Results SRS imaging enables D2O to be a contrast agent for metabolic activitiesWater (H2O), the ubiquitous solvent of life, diffuses freely across cell and organelle membranes and participates in the vast majority of biochemical reactions. As an isotopologue of water, heavy water (D2O) can rapidly equilibrate with total body water in all cells within an organism and label cellular biomolecules with deuterium (D) by forming a variety of X-D bonds through non-enzymatic H/D exchange and enzymatic incorporation ( Figure 1A). The former is spontaneous and reversibly forms oxygen-deuterium (O-D), nitrogen-deuterium (N-D), and sulfur-deuterium (S-D) bonds on existing molecules, whereas the latter depends on enzyme-catalyzed chemical transformation that irreversibly breaks the O-D bond and forms C-D bonds on newly synthesized molecules 5 . Through such transformation, deuterium quickly labels the metabolic precursors, such as non-essential amino acids (NEAAs), acetyl-CoA, and deoxyribose, which are then slowly incorporated into proteins, lipids, and DNA,

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High-throughput screens using photo-highlighting discover BMP signaling in mitochondrial lipid oxidation

Cited by 48 publications

References 47 publications

CREB non-autonomously regulates Reproductive Aging through Hedgehog/Patched Signalling

CREB non-autonomously regulates Reproductive Aging through Hedgehog/Patched Signalling

C. elegans Mediator 15 permits low temperature-induced longevity via regulation of lipid and protein homeostasis

Optical Imaging of Metabolic Dynamics in Animals

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