Review
Endocrinology & Metabolism
Alexandra J. Brownstein, Michaela Veliova, Rebeca Acin-Perez, Marc Liesa, Orian S. Shirihai
Summary: Obesity results from an imbalance in energy homeostasis, with interest in exploiting thermogenic processes to counteract obesity. Mitochondrial uncoupling and other mechanisms can dissipate energy, with futile cycles such as lipolysis and calcium import/export cycle consuming energy. These cycles highlight the importance of mitochondrial oxidative function and ATP synthesis in thermogenic energy dissipation.
REVIEWS IN ENDOCRINE & METABOLIC DISORDERS
(2022)
Article
Biochemistry & Molecular Biology
Cuiyan Zhou, Wangsong Shang, Shan-Kai Yin, Haibo Shi, Weihai Ying
Summary: Our study revealed that aminooxyacetic acid (AOAA) inhibits LPS-induced neuroinflammation by modulating the malate-aspartate shuttle (MAS), suggesting AOAA as a new and effective drug. Furthermore, we found that MAS is a novel mediator of LPS-induced neuroinflammation due to its ability to modulate LPS-induced STAT3 phosphorylation, highlighting the critical role of NAD(+)/NADH metabolism in inflammation.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Milan Holecek
Summary: Aspartate-glutamate carrier 2 (AGC2) is a mitochondrial carrier that plays a crucial role in maintaining redox balance, mitochondrial respiration, and ATP synthesis. It is activated during starvation and muscle wasting disorders and is involved in the metabolism of aspartate and glutamate. Targeting AGC genes may offer a new therapeutic strategy against cancer.
Review
Biochemistry & Molecular Biology
Milan Holecek
Summary: Aspartate-glutamate carrier 2 (AGC2) is a mitochondrial carrier expressed in the liver that plays a crucial role in maintaining intracellular redox balance, mitochondrial respiration, and ATP synthesis. It is stimulated by catecholamines and glucagon during starvation, exercise, and muscle wasting disorders, and increases aspartate input to the urea cycle. Targeting AGC genes may provide a new therapeutic strategy to fight cancer.
Article
Microbiology
Fangying Li, Xiaozhe Fu, Xia Luo, Qiang Lin, Hongru Liang, Yinjie Niu, Lihui Liu, Ningqiu Li
Summary: Viruses rely on host cellular metabolism to complete their life cycle, and Siniperca chuatsi rhabdovirus (SCRV) has caused significant economic losses to the Chinese perch industry. This study investigated the role of asparagine metabolism in SCRV proliferation and found that key enzymes in the aspartate metabolic pathway were upregulated during SCRV infection. Addition of asparagine and glutamine restored SCRV replication, while inhibition of the aspartate-malate shuttle pathway and knockdown of key enzymes in the asparagine biosynthesis pathway reduced SCRV production. These findings provide insights into the pathogenic mechanism of SCRV through regulation of aspartate metabolism.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Olivia Vazquez-Martinez, Mauricio Diaz-Munoz, Fernando Lopez-Barrera, Rolando Hernandez-Munoz
Summary: This study explored the impact of isoproterenol-induced myocardial damage on mitochondrial function, specifically focusing on the malate-aspartate shuttle activity. The results showed minimal effects on endogenous shuttle activity, but significant enhancement in a reconstituted system during the post-infarction period, suggesting a compensatory response of cardiomyocytes to the metabolic consequences of myocardial infarction. These findings highlight the sequential biochemical and metabolic modifications within cardiomyocytes during heart damage associated with myocardial infarction, emphasizing the potential role of mitochondrial activity in controlling the redox state.
Review
Biochemistry & Molecular Biology
Beatriz Pardo, Eduardo Herrada-Soler, Jorgina Satrustegui, Laura Contreras, Araceli del Arco
Summary: AGC1/Aralar is a mitochondrial carrier involved in the transfer of redox power in neurons. Deficiency in AGC1/Aralar leads to a rare human disease and affects both neuronal and glial functions, resulting in various pathophysiological changes related to neuronal metabolism.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biotechnology & Applied Microbiology
Andy Wiranata Wijaya, Ralf Takors
Summary: Proper supply and regeneration of reduction equivalents such as NADH and NADPH are crucial for living cells. A study has identified a transhydrogenase-like mechanism in Chinese hamster ovary (CHO) cells, involving the adaptive interplay of different proteins to facilitate electron transfer and meet the cell's needs. This system utilizing malate and pyruvate as intermediary electron carriers shows flexibility and quick adaptation under different conditions.
BIOCHEMICAL ENGINEERING JOURNAL
(2021)
Review
Biochemistry & Molecular Biology
Paige K. Arnold, Lydia W. S. Finley
Summary: The tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, is a central metabolic pathway that oxidizes nutrients to support cellular energy production. Recent studies have shown that the TCA cycle is dynamic and can be utilized in cancer and other pathological states. This review provides a comprehensive overview of the TCA cycle, including its origins, discovery, requirements for sustained function, and regulatory nodes. It also discusses recent advances in understanding the flexibility and heterogeneity of TCA cycle activity in mammalian cells, emphasizing the importance of differential regulation and configuration to meet the specific requirements of distinct cell states.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Xia Fang, Pei Zhao, Shaoyong Gao, Dongmei Liu, Song Zhang, Mengtian Shan, Yuanyuan Wang, Joerg Herrmann, Qiang Li, Feilong Wang
Summary: Tumor cell-derived lactate has been identified as the main factor in the polarization of tumor-associated macrophages (TAMs). Previous studies have highlighted the importance of mitochondrial pyruvate carrier (MPC)-mediated transport in TAMs polarization. However, our genetic depletion study demonstrated that MPC is not necessary for lactate-induced macrophages polarization or tumor growth.It also had no impact on the stabilization of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and histone lactylation, which are both crucial for TAMs polarization. This suggests that lactate itself, rather than its downstream metabolites, is responsible for TAMs polarization.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biology
Takeshi Yoneshiro, Naoya Kataoka, Jacquelyn M. Walejko, Kenji Ikeda, Zachary Brown, Momoko Yoneshiro, Scott B. Crown, Tsuyoshi Osawa, Juro Sakai, Robert W. McGarrah, Phillip J. White, Kazuhiro Nakamura, Shingo Kajimura
Summary: This study investigates the role of mitochondrial BCAA carrier in regulating BCAA catabolism and adaptive response to fever, highlighting the significant enhancement of mitochondrial BCAA oxidation during fever and the essential role of MBC in BCAA deamination and thermogenesis.
Article
Neurosciences
Irene Perez-Liebana, Ines Juaristi, Paloma Gonzalez-Sanchez, Luis Gonzalez-Moreno, Eduardo Rial, Masa Podunavac, Armen Zakarian, Jordi Molgo, Ainara Vallejo-Illarramendi, Laura Mosqueira-Martin, Adolfo Lopez de Munain, Beatriz Pardo, Jorgina Satrustegui, Araceli del Arco
Summary: Calcium acts as an important secondary messenger in regulating the bioenergetic response in neurons. In glucose-utilizing embryonic mouse cortical neurons, calcium upregulates glycolysis, pyruvate levels, and respiration through the Aralar-MAS pathway, while not affecting glucose uptake. This calcium-dependent pathway plays a key role in tuning both glycolysis and oxidative phosphorylation in response to neuronal activation.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Endocrinology & Metabolism
Tobias Ackermann, Hidde R. Zuidhof, Christine Mueller, Gertrud Kortman, Martijn G. S. Rutten, Mathilde J. C. Broekhuis, Mohamad Amr Zaini, Gotz Hartleben, Cornelis F. Calkhoven
Summary: Cancer cells rely on glycolysis for energy production and growth. The transcription factor C/EBPλ-LIP promotes glycolysis and mitochondrial respiration in cancer cells. High expression of C/EBPλ-LIP increases vulnerability to glycolysis inhibition.
MOLECULAR METABOLISM
(2023)
Article
Multidisciplinary Sciences
Simone Nardin Weis, Jaques Miranda F. Souza, Juliana Bender Hoppe, Marina Firmino, Manfred Auer, Nassim N. Ataii, Leonardo Assis da Silva, Mariana Maier Gaelzer, Caroline Peres Klein, Alan R. Mol, Consuelo M. R. de Lima, Diogo Onofre Souza, Christianne G. Salbego, Carlos Andre O. Ricart, Wagner Fontes, Marcelo Valle de Sousa
Summary: Research has shown that there are fundamental sex-related differences in the proteome of organotypic hippocampal slice culture, with females exhibiting a greater prevalence of astrocytic metabolism and males showing significant neuronal metabolism. These differences manifest in preferences for glucose use, mitochondrial respiration subunits, and lipid metabolism between the sexes.
SCIENTIFIC REPORTS
(2021)
Article
Biology
Madeleine L. Hart, Evan Quon, Anna-Lena B. G. Vigil, Ian A. Engstrom, Oliver J. Newsom, Kristian Davidsen, Pia Hoellerbauer, Samantha M. Carlisle, Lucas B. Sullivan
Summary: The oxidative tricarboxylic acid (TCA) cycle is a crucial pathway for cell proliferation that involves the conversion of NAD+ to NADH and the production of aspartate. The loss of SDH, a component of the TCA cycle, is implicated in tumorigenesis, but the mechanism by which proliferating cells tolerate SDH loss is not well understood. This study identifies that SDH supports cell proliferation through aspartate synthesis and shows that concomitant inhibition of ETC complex I can restore aspartate production and cell proliferation in SDH-impaired cells. These findings highlight the metabolic mechanisms that cells use to maintain aspartate synthesis and reveal the impact of compartmentalized redox changes on cellular fitness.
Review
Endocrinology & Metabolism
Alexandra J. Brownstein, Michaela Veliova, Rebeca Acin-Perez, Marc Liesa, Orian S. Shirihai
Summary: Obesity results from an imbalance in energy homeostasis, with interest in exploiting thermogenic processes to counteract obesity. Mitochondrial uncoupling and other mechanisms can dissipate energy, with futile cycles such as lipolysis and calcium import/export cycle consuming energy. These cycles highlight the importance of mitochondrial oxidative function and ATP synthesis in thermogenic energy dissipation.
REVIEWS IN ENDOCRINE & METABOLIC DISORDERS
(2022)
Article
Endocrinology & Metabolism
Janos Steffen, Jennifer Ngo, Sheng-Ping Wang, Kevin Williams, Henning F. Kramer, George Ho, Carlos Rodriguez, Krishna Yekkala, Chidozie Amuzie, Russell Bialecki, Lisa Norquay, Andrea R. Nawrocki, Mark Erion, Alessandro Pocai, Orian S. Shirihai, Marc Liesa
Summary: Drp1 mitigates NASH by decreasing ER stress, preventing Oma1 activation, and exacerbation of ISR. The elevation in Gdf15 actions induced by NAG-Drp1si might represent an adaptive response decreasing the nutrient load to the liver when mitochondria are dysfunctional. Our study argues against blocking Drp1 in hepatocytes to combat NASH.
MOLECULAR METABOLISM
(2022)
Article
Multidisciplinary Sciences
Rhiannon B. Werder, Tao Liu, Kristine M. Abo, Jonathan Lindstrom-Vautrin, Carlos Villacorta-Martin, Jessie Huang, Anne Hinds, Nathan Boyer, Esther Bullitt, Marc Liesa, Edwin K. Silverman, Darrell N. Kotton, Michael H. Cho, Xiaobo Zhou, Andrew A. Wilson
Summary: This study used CRISPR interference to investigate the function of genes associated with COPD in induced pluripotent stem cell-derived type 2 alveolar epithelial cells. The results showed that these genes affect the differentiation, maturation, and proliferation of cells. Detailed characterization of the DSP gene revealed its role in regulating cell-cell junctions, proliferation, mitochondria function, and response to cigarette smoke-induced injury.
Meeting Abstract
Biochemistry & Molecular Biology
Jennifer Ngo, Ilan Benador, Michaela Veliova, Rebeca Acin-Perez, Anton Petcherski, Alexandra Brownstein, Dong Wook Choi, Janos Steffen, Sheng-Ping Wang, Cris Beninca, Lucia Fernandez, Ajit Divakaruni, Alessandro Pocai, Marc Liesa, Nika Danial, Orian Shirihai
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
(2022)
Article
Cell Biology
Joseph E. Kaserman, Rhiannon B. Werder, Feiya Wang, Taylor Matte, Michelle I. Higgins, Mark Dodge, Jonathan Lindstrom-Vautrin, Pushpinder Bawa, Anne Hinds, Esther Bullitt, Ignacio S. Caballero, Xu Shi, Robert E. Gerszten, Nicola Brunetti-Pierri, Marc Liesa, Carlos Villacorta-Martin, Anthony N. Hollenberg, Darrell N. Kotton, Andrew A. Wilson
Summary: Individuals homozygous for the Zmutation in alpha-1 antitrypsin deficiency are at increased risk for liver disease. Heterozygous individuals also have a degree of risk. Lack of model systems has limited the study of the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. This study successfully derived syngeneic induced pluripotent stem cells (iPSCs) to investigate the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps), finding that MZ heterozygous iHeps exhibit an intermediate disease phenotype and share certain alterations with ZZ iHeps.
Article
Microbiology
Manuel Albert, Jesus Vazquez, Juan M. Falcon-Perez, Maria A. Balboa, Marc Liesa, Jesus Balsinde, Susana Guerra
Summary: This study reveals the role of ISG15 in regulating lipid metabolism in macrophages and its importance in the context of viral infections. The findings provide insights into macrophage immunometabolism and the interaction between poxviruses and the host.
MICROBIOLOGY SPECTRUM
(2022)
Article
Biochemistry & Molecular Biology
Rebeca Acin-Perez, Cristiane Beninca, Lucia Fernandez del Rio, Cynthia Shu, Siyouneh Baghdasarian, Vanessa Zanette, Christoph Gerle, Chimari Jiko, Ramzi Khairallah, Shaharyar Khan, David Rincon Fernandez Pacheco, Byourak Shabane, Karel Erion, Ruchi Masand, Sundeep Dugar, Cristina Ghenoiu, George Schreiner, Linsey Stiles, Marc Liesa, Orian S. Shirihai
Summary: The regulation of ATP synthesis and hydrolysis is crucial for cellular function. In this study, we investigate the hydrolytic activity of mitochondrial ATP synthase (CV) and its impact on cellular energetics. We identify a selective inhibitor of ATP hydrolysis, (+)-Epicatechin, that binds CV and prevents the binding of ATPase inhibitor (ATPIF1). By inhibiting CV hydrolytic activity, ATP content is restored in cells with respiratory chain defects or Duchenne Muscular Dystrophy, improving muscle force without increasing mitochondrial content. These findings highlight the potential of hydrolysis-selective inhibitors of CV in mitigating the effects of compromised mitochondrial respiration.
Article
Biochemistry & Molecular Biology
Jennifer Ngo, Dong Wook Choi, Illana A. Stanley, Linsey Stiles, Anthony J. A. Molina, Pei-Hsuan Chen, Ana Lako, Isabelle Chiao Han Sung, Rishov Goswami, Min-young Kim, Nathanael Miller, Siyouneh Baghdasarian, Doyeon Kim-Vasquez, Anthony E. Jones, Brett Roach, Vincent Gutierrez, Karel Erion, Ajit S. Divakaruni, Marc Liesa, Nika N. Danial, Orian S. Shirihai
Summary: Changes in mitochondrial morphology, specifically fragmentation and elongation, have been found to impact fatty acid oxidation (FAO) rates. Fragmentation increases FAO, while elongation decreases FAO. The induction of fragmentation also mimics specific biological functions related to enhanced FAO in different cell types. The downstream effector of mitochondrial morphology in regulating FAO is identified as carnitine O-palmitoyltransferase 1 (CPT1). Mechanistically, fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition.
Article
Multidisciplinary Sciences
Jialiu Zeng, Rebeca Acin-Perez, Essam A. Assali, Andrew Martin, Alexandra J. Brownstein, Anton Petcherski, Lucia Fernandez-del-Rio, Ruiqing Xiao, Chih Hung Lo, Michael Shum, Marc Liesa, Xue Han, Orian S. Shirihai, Mark W. Grinstaff
Summary: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. This study synthesizes acid-activated acidifying nanoparticles to restore lysosomal function and reverse fasting hyperglycemia and hepatic steatosis in NAFLD. In high fat diet mouse models, treatment with these nanoparticles restores autophagy and mitochondrial function to lean, healthy levels, showing the potential therapeutic use for NAFLD.
NATURE COMMUNICATIONS
(2023)
Article
Biology
Lucia Fernandez-del-Rio, Cristiane Beninca, Frankie Villalobos, Cynthia Shu, Linsey Stiles, Marc Liesa, Ajit S. Divakaruni, Rebeca Acin-Perez, Orian S. Shirihai
Summary: Mitochondrial depolarization can lead to ATP depletion through the reversal activity of ATP synthase. However, studying ATP hydrolysis as a parameter has been limited due to current methods requiring the isolation of mitochondria and the introduction of detergents. In this study, a new approach is described that allows the assessment of maximal ATP hydrolytic capacity and respiratory capacity in frozen cell lysates, PBMCs, and tissue homogenates, with the potential to be used in clinical samples and explore ATP hydrolysis as a drug target for disease treatment.
LIFE SCIENCE ALLIANCE
(2023)
Article
Biochemistry & Molecular Biology
Brandon R. Desousa, Kristen K. O. Kim, Anthony E. Jones, Andrea B. Ball, Wei Y. Hsieh, Pamela Swain, Danielle H. Morrow, Alexandra J. Brownstein, David A. Ferrick, Orian S. Shirihai, Andrew Neilson, David A. Nathanson, George W. Rogers, Brian P. Dranka, Anne N. Murphy, Charles Affourtit, Steven J. Bensinger, Linsey Stiles, Natalia Romero, Ajit S. Divakaruni
Summary: Oxidative phosphorylation and glycolysis are the main ATP-generating pathways in mammalian metabolism, and their balance can be shifted in response to cell-specific functions. However, current methods for measuring these metabolic switches are mostly qualitative, making it difficult to differentiate between healthy changes and compensatory responses due to metabolic dysfunction. In this study, we present a method to accurately calculate ATP production rates from oxidative phosphorylation and glycolysis using Seahorse XF Analyzer data. We applied this method to study various cell types and experimental conditions, and observed significant changes in bioenergetics that were not detectable using steady-state ATP measurements. This method provides a valuable tool for studying energy metabolism in live cells.
Article
Biochemical Research Methods
Thomas Belmas, Marc Liesa, Michael Shum
Summary: This article presents a protocol for assessing mitochondrial redox state and unconjugated bilirubin levels in primary hepatocytes from obese mice, using sensitive techniques to quantify H2O2 and antioxidants in live cells.
Meeting Abstract
Oncology
Adrian Schwarzer, Matheus Oliveira, Marc-Jens Kleppa, Andy Anantha, Alan Cooper, Todd Hembrough, Jedd Levine, Michael Luther, Michael Stocum, Marc Liesa-Roig, Matt Kostura