Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

List by Pablo Ranea Robles


Autophagy promotes cell and organismal survival by maintaining NAD(H) pools

Lucia Sedlackova, Elsje G. Otten, Filippo Scialo, David Shapira, Tetsushi Kataura, Bernadette Carroll, Elena Seranova, Yoana Rabanal-Ruiz, George Kelly, Rhoda Stefanatos, Glyn Nelson, Animesh Acharjee, Niall Kenneth, Sergey Trushin, Tong Zhang, Charles C. Bascom, Ryan Tasseff, Robert J. Isfort, John E. Oblong, Eugenia Trushina, Masaya Imoto, Shinji Saiki, Michael Lazarou, Manolis Papamichos Chronakis, Oliver D.K. Maddocks, Sovan Sarkar, Alberto Sanz, Viktor I. Korolchuk

Sedlackova et al. show in this preprint a new and essential role of autophagy in maintaining cellular NAD+ and NADH levels. They found that this function is well conserved from yeasts to humans and that NAD(H) boosters could serve as a therapy in human diseases associated with autophagy-dysfunction. This is an exciting new mechanistic link between autophagy and a critical mediator in cellular metabolism.

Cardiomyocyte-specific ACSL1 Deficiency Prevents Cardiac Lipotoxicity and Alleviates Heart Dysfunction in the ob/ob Model of Obesity

Florencia Pascual, Trisha J. Grevengoed, Liyang Zhao, Monte S. Willis, Rosalind A. Coleman

Pascual et al. show a potential target to improve obesity-related myocardial dysfunction. Lipid toxicity is associated with cardiac dysfunction and has been demonstrated in obese mice. Here, they report that ablation of an enzyme that activates free fatty acids to the CoA-conjugated form protected obese hearts and reversed triglyceride accumulation in those hearts.

Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3

Jessica A. Hall, Deepti Ramachandran, Hyun C. Roh, Joanna R. DiSpirito, Thiago Belchior, Peter-James H. Zushin, Colin J. Palmer, Shangyu Hong, Amir I. Mina, Bingyang Liu, Zhaoming Deng, Pratik Aryal, Christopher Jacobs, Danielle Tenen, Chester W. Brown, Julia F. Charles, Gerald I. Shulman, Barbara B. Kahn, Linus T.Y. Tsai, Evan D. Rosen, Bruce M. Spiegelman, Alexander S. Banks

PPAR-gamma agonist thiazolidinediones (TZDs) are potent insulin-sensitizing drugs. Still, their action is not only mediated by PPAR-gamma agonism, but also by reversal of Serine 273 phosphorylation of PPAR-gamma. However, the role of this PPAR-gamma phosphorylation had not been tested genetically until now. Hall et al. show here that mice with a mutation in that serine, so it can not be phosphorylated, are protected from insulin resistance and do not show typical TZDs side effects. They also propose a mediator of the diabetogenic role of PPAR-gamma S273 phosphorylation.

Atf-6 regulates lifespan through ER-mitochondrial calcium homeostasis

Kristopher Burkewitz, Sneha Dutta, Charlotte A. Kelley, Michael Steinbaugh, Erin J. Cram, William B. Mair

The role of different cell organelles in mammalian aging is well known, but there is much to know in the interplay between these organelles. In this preprint, Burkewitz et al. studied the interaction between mitochondria and the endoplasmic reticulum (ER) in the worm C. elegans. They uncovered that inhibition of a mediator of the unfolded protein response (UPR) modulates calcium homeostasis and signaling to the mitochondria. This metabolic rewiring increased lifespan in C. elegans via the ER calcium release channel.

Pioglitazone rescues mitochondrial lipid remodeling and pyruvate dehydrogenase hyperactivation in hepatic insulin resistance

Chris E. Shannon, Mukundan Ragavan, Juan Pablo Palavicini, Marcel Fourcaudot, Terry Bakewell, Eunsook S. Jin, Craig R. Malloy, Xianlin Han, Matthew E. Merritt, Luke Norton

Pioglitazone is an insulin-sensitizing drug prescribed for Type II Diabetes whose beneficial effects are usually associated to adipose tissue PPAR-gamma targeting. In this preprint, Shannon et al. investigated the effects of pioglitazone on hepatic mitochondrial remodeling. They found that the beneficial effects of pioglitazone in mice are dissociated from changes in TG and DAG levels in the liver. Instead, pioglitazone targeted mitochondrial lipids such as cardiolipin and inhibited PDH activation.

mTORC1-Plin3 pathway is essential to activate lipophagy and protects against hepatosteatosis

Marina Garcia-Macia, Adrián Santos-Ledo, Jack Leslie, Hanna Paish, Abigail Watson, Lee Borthwick, Jelena Mann, Fiona Oakley, Viktor I. Korolchuk, Derek A. Mann

Excess of lipids is accumulated in hepatocytes in the form of lipid droplets (LDs), but aberrant accumulation of LDs is detrimental and is involved in diseases like NAFLD. One way to relieve lipotoxicity is to degrade LDs by autophagy (lipophagy). Here, García-Macia et al. show that Plin3, a member of the perilipin family of proteins that coat LDs, is also involved in LD autophagy. They also show that mTORC1 phosphorylates and, surprisingly, activates Plin3 and lipophagy. Silencing of Plin3 inhibited lipophagy and induced lipid accumulation.

Transcriptomic Profiling of Skeletal Muscle Adaptations to Exercise and Inactivity

Nicolas J. Pillon, Brendan M. Gabriel, Lucile Dollet, Jonathon A. Smith, Laura Sardón Puig, Javier Botella, David J. Bishop, Anna Krook, Juleen R. Zierath

To better understand the transcriptomic changes underlying the adaptations in skeletal muscle to exercise and sedentarism Pillon et al. integrated data from 66 published datasets. This extensive compilation of transcriptomics data revealed different pathways activated by inactivity, different types of exercise and different modes of training. NR4A3 (Nor1) was identified as one of the most responsive genes to exercise and inactivity. They also provide an online interface to explore the database.

PHGDH supports liver ceramide synthesis and sustains lipid homeostasis

Yun Pyo Kang, Aimee Falzone, Min Liu, James J. Saller, Florian A. Karreth, Gina M. DeNicola

D-3-phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step of de novo biosynthesis of L-serine. PHGDH has been proposed as an attractive target for cancer therapy since PHGDH activity is consistently high in many cancers. In this work, Kang et al. knocked down PHGDH in non-CNS adult murine tissues with a PHGDH shRNA under the control of a doxycycline-inducible promoter. There was no overt phenotype in adult tissues after PHGDH depletion. Moreover, serum and hepatic ceramide levels were decreased and triglycerides with longer and unsaturated acyl chains were increased. This work suggest that PHGDH inhibitors could be well tolerated for cancer therapy.

Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation

Natasha H. J. Ng, Sara M. Willems, Juan Fernandez, Rebecca S. Fine, Eleanor Wheeler, Jennifer Wessel, Hidetoshi Kitajima, Gaelle Marenne, Jana K. Rundle, Xueling Sim

Little et al. show here a method to integrate cellular metabolism studies with SeaHorse together with fluorescent dyes that allow to add information about mitochondrial dynamics and mitochondrial function.

ER stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

Nurulain Ho, Haoxi Wu, Jiaming Xu, Jhee Hong Koh

This preprint shed light on the mechanism of insulin resistance and its relation to hyperinsulinemia in muscle cells. They show that insulin receptor (Insr) levels were negatively correlated to insulin levels in muscle cells and mouse skeletal muscle, which suggest that hyperinsulinemia causes insulin resistance rather than being a compensatory mechanism.

mTORC1 signaling is not essential for the maintenance of muscle mass and function in adult sedentary mice

Alexander S Ham, Kathrin Chojnowska, Lionel A Tintignac, Shuo Lin, Alexander Schmidt, Daniel J Ham, Michael Sinnreich, Markus A Ruegg

Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of protein homeostasis in the muscle. Rapamycin, an mTOR inhibitor, is widely used but its effect on muscle mass are not well known yet. To elucidate the role of mTORC1 in maintaining muscle mass in adulthood, Ham et al. inhibited mTORC1 signaling in the skeletal muscle of adult mice. They inhibited mTORC1 by ablating Raptor, a regulator of mTORC1 signaling. They found that muscle mass and function were not affected at 5 months of age, suggesting that muscle maintenance in sedentary mice does not require mTORC1 activity.

Lecithin:Retinol Acyl Transferase (LRAT) induces the formation of lipid droplets

Martijn R. Molenaar, Tsjerk A. Wassenaar, Kamlesh K. Yadav, Alexandre Toulmay

Seamet, a new metabolomics method to measure metabolites in seawater using GC/MS is described in this preprint. This method overcomes the limitations of salt in marine metabolomics.

Housing temperature influences exercise training adaptations in mice

Steffen H. Raun, Carlos H. Henriquez-Olguin, Iuliia Karavaeva, Mona Ali, Lisbeth L.V. Moller, Witold Kot, Josue L. Castro Mejia, Dennis Sandris Nielsen, Zach Gerhart-Hines, Erik A. Richter, Lykke Sylow

Another report on different physiological response of rodents under different housting temperatures.  Raun et al. show here that exercise-induced metabolic adaptations were blunted when mice were housed in thermoneutral conditions (30 °C).

Exercise does not induce browning of WAT at thermoneutrality and induces an oxidative, myogenic signature in BAT

Peter Aldiss, Jo E Lewis, Irene Lupini, David J Boocock, Amanda K Miles, Francis J P Ebling, Helen Budge, Michael E Symonds

Rodents are usually housed below their thermoneutral zone, but studies done at thermoneutrality show that their physiology is completely different, because brown adipose tissue (BAT) is hyperactive below thermoneutrality. Aldiss et al. show here that exercise does not induce browing of white adipose tissue (WAT) and a different response in BAT in rats housed at thermoneutrality (28 °C).

Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

Chi-Lun Chang, Aubrey V. Weigel, Maria S. Ioannou, H. Amalia Pasolli, C. Shan Xu, David R. Peale, Gleb Shtengel, Melanie Freeman, Herald F. Hess, Craig Blackstone, Jennifer Lippincott-Schwartz

Peroxisomes interact with other organelles within the cell, but how they do it remain largely unknown. Here Chang et al. describe a tether between peroxisomes and lipid droplets that transfer fatty acids.

Presynaptic boutons that contain mitochondria are more stable

Robert M. Lees, James D. Johnson, Michael C. Ashby

Mitochondria are crucial for energy generation in the central nervous system and their dysfunction is related to multiple neurodegenerative diseases. Here, Lees et al. show that presynapses with more mitochondria are more stable, which open new avenues of research on the role of cellular metabolism and bioenergetics on synaptic structural plasticity.

Categories: biochemistry , cell biology , pathology , physiology

Tags: lipid , metabolism , mitochondria , peroxisome

Posted on: 21st May 2019 , updated on: 19th February 2020

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