Article
Chemistry, Medicinal
Ekaterina S. Kharechkina, Anna B. Nikiforova, Konstantin N. Belosludtsev, Tatyana Rokitskaya, Yuri N. Antonenko, Alexey G. Kruglov
Summary: Pioglitazone is an insulin-sensitizing antidiabetic drug that can affect glucose and lipid metabolism through mitochondrial targets. Research has shown that pioglitazone can decrease mitochondrial membrane potential, impact oxidative phosphorylation coupling, activate proton transport, among other effects, which play a crucial role in both therapeutic and adverse effects of the drug.
Article
Cardiac & Cardiovascular Systems
Hector Chapoy Villanueva, Jae Hwi Sung, Jackie A. Stevens, Michael J. Zhang, Peyton M. Nelson, Lalitha S. Denduluri, Feng Feng, Timothy D. O'Connell, DeWayne Townsend, Julia C. Liu
Summary: Transport of Ca2+ into mitochondria through the mitochondrial Ca2+ uniporter complex is essential for ATP production, but excessive Ca2+ can be detrimental. Short-term deletion of the regulatory protein EMRE in the heart resulted in impaired Ca2+ uptake, attenuated ATP production, and improved cardiac function in an I/R model. However, long-term EMRE loss led to similar impairment in Ca2+ handling and function, but loss of protection against I/R injury. These findings suggest that long-term absence of EMRE restores susceptibility to I/R, despite impaired bioenergetic response.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2023)
Review
Cell Biology
Elena Frigo, Ludovica Tommasin, Giovanna Lippe, Michela Carraro, Paolo Bernardi
Summary: This article introduces the formation of Ca2+-activated, high-conductance channels by F1FO (F)-ATP synthase and adenine nucleotide translocase (ANT) in the inner membrane of mitochondria from various eukaryotes. The permeability transition (PT), a Ca2+-dependent increase in permeability in the inner mitochondrial membrane, and its molecular mechanisms have been challenging for scientists for the past 70 years. The features of the PT (or lack thereof) in mammals, yeast, fruit flies, brine shrimp, and nematodes, as well as the intrinsic pathway of apoptosis and other forms of cell death, are discussed in this review.
Review
Biochemistry & Molecular Biology
Paolo Bernardi, Michela Carraro, Giovanna Lippe
Summary: The basis of mitochondrial permeability transition, a Ca2+-dependent permeability increase of the inner membrane, has been successfully defined, and it has been recognized as a regulator of mitochondrial ion homeostasis and a mechanism of cell death. However, there are still controversial mechanisms regarding the permeability transition that require further research for explanation.
Review
Biochemistry & Molecular Biology
Andrea Carrer, Claudio Laquatra, Ludovica Tommasin, Michela Carraro
Summary: The permeability transition (PT) involves increased permeation of the inner mitochondrial membrane due to the opening of the PT pore (PTP), which is a Ca2+-activated high conductance channel. Despite extensive exploration on PTP modulation, the lack of a clear understanding of its molecular nature complicates any target-based approach. Recent advancements indicate the existence of at least two mitochondrial permeability pathways mediated by the F-ATP synthase and the ANT, but the exact molecular mechanism leading to channel formation remains elusive for both.
Article
Cell Biology
Xavier R. Chapa-Dubocq, Jorge F. Garcia-Baez, Jason N. Bazil, Sabzali Javadov
Summary: This study investigates the modulation of mitochondrial metabolism and function by changes in matrix Ca2+. It identifies the main mechanism responsible for mitochondrial Ca2+ overload and proposes a potential role of adenine nucleotide translocator (ANT) in the gating of mitochondrial permeability transition pores (PTP).
CELL BIOLOGY AND TOXICOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Koichi Fujisawa
Summary: Adenylate kinase (AK) plays a crucial role in regulating adenine nucleotide metabolism and has been found to be associated with various diseases. This review article provides a summary of the physiological roles of AK isozymes, focusing on the symptoms caused by mutated AK isozymes in humans and phenotypic changes in animal models. The authors emphasize the importance of further research on intracellular, extracellular, and intercellular energy metabolism with a focus on AK for advancing new therapeutic approaches for diseases like cancer, lifestyle-related diseases, and aging.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Silvia Garcia-Catalan, Luis Gonzalez-Moreno, Araceli del Arco
Summary: Research has found two variants of ATP-Mg2+/Pi carriers in unicellular eukaryotes, with a common origin unrelated to ADP/ATP translocases, suggesting recurrent losses of the regulatory module in different phyla. These truncated variants of SCaMC are predominantly found in parasitic protists and green algae, indicating a potential relationship with specific lifestyles. Additionally, these variants exhibit intricate structural diversity that may be associated with their pathogenicity.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Biochemical Research Methods
Andrew S. Law, Paul S. Hafen, Jeffrey J. Brault
Summary: This study developed a UPLC method free of phosphate buffer to analyze adenine nucleotides using UV-Vis and mass spectrometry simultaneously. The method achieved successful separation and quantification of ATP-related compounds, as well as confirmation and identification of unknown peaks using UV-Vis and MS.
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Barbara Kutryb-Zajac, Ada Kawecka, Alicja Braczko, Marika Franczak, Ewa M. Slominska, Roberto Giovannoni, Ryszard T. Smolenski
Summary: Chronic hypoxia impairs vascular function through various mechanisms, including changes in mitochondrial respiration. Our study found that the hypoxia-mimetic agent CoCl2 reduces nitric oxide (NO) production, depletes intracellular ATP levels, and increases extracellular nucleotide and adenosine breakdown in endothelial cells (ECs). Supplementation of nucleotide precursors and inhibition of adenosine deaminase can restore ATP levels and protect endothelial function.
Article
Biology
Giampaolo Morciano, Natalia Naumova, Piotr Koprowski, Sara Valente, Vilma A. Sardao, Yaiza Potes, Alessandro Rimessi, Mariusz R. Wieckowski, Paulo J. Oliveira
Summary: This review summarizes the intriguing phenomenon of the mitochondrial permeability transition pore (mPTP) in cell biology. Despite almost 50 years of research, the mechanisms of mPTP are still not definitively understood. From initially being considered an in vitro artifact to now being recognized for its physiological and pathological implications, the journey of mPTP research has been long and complex.
BIOLOGICAL REVIEWS
(2021)
Article
Cell Biology
Corinne Bischof, Peter Mirtschink, Ting Yuan, Meiqian Wu, Chaonan Zhu, Jaskiran Kaur, Minh Duc Pham, Suam Gonzalez-Gonoggia, Marie Hammer, Eva-Maria Rogg, Rahul Sharma, Katharina Bottermann, Bettina Gercken, Eman Hagag, Corinne Berthonneche, Samuel Sossalla, Sebastian N. Stehr, Joachim Maxeiner, Maria Anna Duda, Mathieu Latreille, Nicola Zamboni, Fabio Martelli, Thierry Pedrazzini, Stefanie Dimmeler, Jaya Krishnan
Summary: Endoreplication, a type of growth mechanism in disease, is still poorly understood in terms of its metabolic basis and connection to morphologic growth. Studies have shown a direct coupling between endoreplication and hypertrophy in heart disease, revealing a new mechanism for pathologic overgrowth in failing myocardium.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Cell Biology
Maria A. A. Neginskaya, Sally E. E. Morris, Evgeny V. V. Pavlov
Summary: The mitochondrial permeability transition pore (mPTP) is a large, weakly selective pore that opens in response to increased Ca2+ concentration. mPTP activation is associated with cell death. The molecular identity of mPTP is not fully understood, but ATP synthase and adenine nucleotide translocase (ANT) are believed to be important components. Recent research showed that the interaction between ATP synthase and ANT is crucial for mPTP formation. Cells lacking the C subunit of ATP synthase can still undergo mPTP activation, indicating that ANT can form the pore independently but requires other components of ATP synthase.
Article
Biochemistry & Molecular Biology
Masami Koushi, Rei Asakai
Summary: The study demonstrates that in Saccharomyces cerevisiae, the PTP formation is mediated by AACs instead of ATP synthase dimers, suggesting a role of AAC-associated pore regulated by porin1/2 and Cpr3.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Cell Biology
Rene Endlicher, Zdenek Drahota, Katerina Stefkova, Zuzana Cervinkova, Otto Kucera
Summary: The mitochondrial permeability transition pore (MPTP) is a calcium-dependent, ion non-selective membrane pore with various functions. Its reversible opening protects cells from oxidative damage and allows Ca2+ ions efflux, while its irreversible opening leads to cell death. The sensitivity of the pore to Ca2+ ions changes with aging and plays a key role in disease pathogenesis.
Review
Cell Biology
Celine Deneubourg, Mauricio Ramm, Luke J. Smith, Olga Baron, Kritarth Singh, Susan C. Byrne, Michael R. Duchen, Mathias Gautel, Eeva-Liisa Eskelinen, Manolis Fanto, Heinz Jungbluth
Summary: Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins has been recognized as an important cause of genetic disease. These disorders can present throughout life, with severe early-onset neurodevelopmental disorders and more common adult-onset neurodegenerative disorders. The overlap between congenital autophagy disorders and other multisystem diseases reflects the complex roles of proteins and suggests a promising area for future research.
Article
Cell & Tissue Engineering
Daisuke Araki, Jian Fei Fu, Heather Huntsman, Stefan Cordes, Fayaz Seifuddin, Luigi J. Alvarado, Patali S. Cheruku, Ayla Cash, Javier Traba, Yuesheng Li, Mehdi Pirooznia, Richard H. Smith, Andre Larochelle
Summary: Activation of NOTCH signaling using engineered DELTA-like ligand (DXI) under low oxygen tension culture conditions in human adult HSPCs can limit ER stress, increase the frequency of LTR-HSCs significantly, and help maintain undifferentiated phenotypes in cultured cells.
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)
Review
Cell Biology
Chih-Yao Chung, Gabriel E. Valdebenito, Anitta R. Chacko, Michael R. Duchen
Summary: Mutations in mitochondrial DNA have a significant impact on cellular energy homeostasis and signaling pathways, influencing disease presentation and progression.
TRENDS IN CELL BIOLOGY
(2022)
Article
Biology
Andres De la Rossa, Marine H. Laporte, Simone Astori, Thomas Marissal, Sylvie Montessuit, Preethi Sheshadri, Eva Ramos-Fernandez, Pablo Mendez, Abbas Khani, Charles Quairiaux, Eric B. Taylor, Jared Rutter, Jose Manuel Nunes, Alan Carleton, Michael R. Duchen, Carmen Sandi, Jean-Claude Martinou
Summary: Neuronal excitation relies on ATP from oxidative phosphorylation, and deficient oxidative phosphorylation can lead to hyperexcitability in neurons. Inhibiting GABA activity in mice with deficient mitochondrial pyruvate carrier (MPC) led to seizures and death, but providing ketone bodies restored energy and attenuated seizures. These findings provide insights into epilepsy and other neuropathologies associated with energy deficits.
Article
Biology
Liliana M. Almeida, Brigida R. Pinho, Michael R. Duchen, Jorge M. A. Oliveira
Summary: PERK plays a crucial role in responding to stress in the endoplasmic reticulum and mitochondria, regulating mitochondrial dynamics, metabolism, and quality control by activating multiple protective pathways. Pharmacological activation of PERK shows protective effects in neurodegenerative and metabolic diseases, while PERK inhibition exhibits protective effects in other disease models.
BIOLOGICAL REVIEWS
(2022)
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
Biochemistry & Molecular Biology
Araceli del Arco, Luis Gonzalez-Moreno, Irene Perez-Liebana, Ines Juaristi, Paloma Gonzalez-Sanchez, Laura Contreras, Beatriz Pardo, Jorgina Satrustegui
Summary: Calcium plays a crucial role in regulating cellular metabolism. It controls mitochondrial respiration and cellular energy production through calcium signaling. Recent studies have shown that cytosolic calcium signals, acting on mitochondrial NADH shuttles, are important in regulating cellular metabolism in neurons using glucose as fuel. Aralar/MAS pathway, regulated by cytosolic calcium, provides substrates and fuel for respiration, while mitochondrial calcium uptake does not contribute to this process. The activation of Aralar/MAS by small cytosolic calcium signals increases glycolysis and cytosolic pyruvate production, priming respiration as a feed-forward mechanism in response to workload. MCU and Aralar/MAS both contribute to the upregulation of oxidative phosphorylation, with Aralar/MAS playing a major role, particularly at small and submaximal workloads. These findings highlight the importance of calcium signaling and the Aralar/MAS pathway in cellular metabolism.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Ilio Vitale, Federico Pietrocola, Emma Guilbaud, Stuart A. Aaronson, John M. Abrams, Dieter Adam, Massimiliano Agostini, Patrizia Agostinis, Emad S. Alnemri, Lucia Altucci, Ivano Amelio, David W. Andrews, Rami Aqeilan, Eli Arama, Eric H. Baehrecke, Siddharth Balachandran, Daniele Bano, Nickolai A. Barlev, Jiri Bartek, Nicolas G. Bazan, Christoph Becker, Francesca Bernassola, Mathieu J. M. Bertrand, Marco E. Bianchi, Mikhail V. Blagosklonny, J. Magarian Blander, Giovanni Blandino, Klas Blomgren, Christoph Borner, Carl D. Bortner, Pierluigi Bove, Patricia Boya, Catherine Brenner, Petr Broz, Thomas Brunner, Rune Busk Damgaard, George A. Calin, Michelangelo Campanella, Eleonora Candi, Michele Carbone, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Guo-Qiang Chen, Quan Chen, Youhai H. Chen, Emily H. Cheng, Jerry E. Chipuk, John A. Cidlowski, Aaron Ciechanover, Gennaro Ciliberto, Marcus Conrad, Juan R. Cubillos-Ruiz, Peter E. Czabotar, Vincenzo D'Angiolella, Mads Daugaard, Ted M. Dawson, Valina L. Dawson, Ruggero De Maria, Bart De Strooper, Klaus-Michael Debatin, Ralph J. Deberardinis, Alexei Degterev, Giannino Del Sal, Mohanish Deshmukh, Francesco Di Virgilio, Marc Diederich, Scott J. Dixon, Brian D. Dynlacht, Wafik S. El-Deiry, John W. Elrod, Kurt Engeland, Gian Maria Fimia, Claudia Galassi, Carlo Ganini, Ana J. Garcia-Saez, Abhishek D. Garg, Carmen Garrido, Evripidis Gavathiotis, Motti Gerlic, Sourav Ghosh, Douglas R. Green, Lloyd A. Greene, Hinrich Gronemeyer, Georg Haecker, Gyorgy Hajnoczky, J. Marie Hardwick, Ygal Haupt, Sudan He, David M. Heery, Michael O. Hengartner, Claudio Hetz, David A. Hildeman, Hidenori Ichijo, Satoshi Inoue, Marja Jaeaettelae, Ana Janic, Bertrand Joseph, Philipp J. Jost, Thirumala-Devi Kanneganti, Michael Karin, Hamid Kashkar, Thomas Kaufmann, Gemma L. Kelly, Oliver Kepp, Adi Kimchi, Richard N. Kitsis, Daniel J. Klionsky, Ruth Kluck, Dmitri Krysko, Dagmar Kulms, Sharad Kumar, Sergio Lavandero, Inna N. Lavrik, John J. Lemasters, Gianmaria Liccardi, Andreas Linkermann, Stuart A. Lipton, Richard A. Lockshin, Carlos Lopez-Otin, Tom Luedde, Marion MacFarlane, Frank Madeo, Walter Malorni, Gwenola Manic, Roberto Mantovani, Saverio Marchi, Jean-Christophe Marine, Seamus J. Martin, Jean-Claude Martinou, Pier G. Mastroberardino, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Gerry Melino, Sonia Melino, Edward A. Miao, Ute M. Moll, Cristina Munoz-Pinedo, Daniel J. Murphy, Maria Victoria Niklison-Chirou, Flavia Novelli, Gabriel Nunez, Andrew Oberst, Dimitry Ofengeim, Joseph T. Opferman, Moshe Oren, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M. Penninger, Francesca Pentimalli, David M. Pereira, Shazib Pervaiz, Marcus E. Peter, Paolo Pinton, Giovanni Porta, Jochen H. M. Prehn, Hamsa Puthalakath, Gabriel A. Rabinovich, Krishnaraj Rajalingam, Kodi S. Ravichandran, Markus Rehm, Jean-Ehrland Ricci, Rosario Rizzuto, Nirmal Robinson, Cecilia M. P. Rodrigues, Barak Rotblat, Carla Rothlin, David C. Rubinsztein, Thomas Rudel, Alessandro Rufini, Kevin M. Ryan, Kristopher A. Sarosiek, Akira Sawa, Emre Sayan, Kate Schroder, Luca Scorrano, Federico Sesti, Feng Shao, Yufang Shi, Giuseppe S. Sica, John Silke, Hans-Uwe Simon, Antonella Sistigu, Anastasis Stephanou, Brent R. Stockwell, Flavie Strapazzon, Andreas Strasser, Liming Sun, Erwei Sun, Qiang Sun, Gyorgy Szabadkai, Stephen W. G. Tait, Daolin Tang, Nektarios Tavernarakis, Carol M. Troy, Boris Turk, Nicoletta Urbano, Peter Vandenabeele, Tom Vanden Berghe, Matthew G. Vander Heiden, Jacqueline L. Vanderluit, Alexei Verkhratsky, Andreas Villunger, Silvia von Karstedt, Anne K. Voss, Karen H. Vousden, Domagoj Vucic, Daniela Vuri, Erwin F. Wagner, Henning Walczak, David Wallach, Ruoning Wang, Ying Wang, Achim Weber, Will Wood, Takahiro Yamazaki, Huang-Tian Yang, Zahra Zakeri, Joanna E. Zawacka-Pankau, Lin Zhang, Haibing Zhang, Boris Zhivotovsky, Wenzhao Zhou, Mauro Piacentini, Guido Kroemer, Lorenzo Galluzzi
Summary: Apoptosis is a regulated cell death process involving caspase family proteases. Inhibiting or delaying apoptosis experimentally through pharmacological and genetic strategies has demonstrated its importance in embryonic development, tissue homeostasis, and the pathogenesis of various human disorders. Defects in apoptotic cell death machinery impair development and promote oncogenesis, while inappropriate activation of apoptosis contributes to cell loss and tissue damage in neurological, cardiovascular, renal, hepatic, infectious, neoplastic, and inflammatory conditions.
CELL DEATH AND DIFFERENTIATION
(2023)
Editorial Material
Biochemistry & Molecular Biology
Gabriel E. Valdebenito, Anitta R. Chacko, Michael R. Duchen
Summary: The mitochondrial F1Fo-ATP synthase can both synthesize ATP and pump protons, with potential implications for diseases. In a recent study, Acin-Perez et al. identified (+)-epicatechin as a compound that selectively inhibits ATP hydrolysis without affecting ATP synthesis. They found that this compound has significant benefits for cell and tissue function in disease models, suggesting a novel therapeutic approach for mitochondrial disease.
Article
Genetics & Heredity
Luis Gonzalez-Moreno, Andrea Santamaria-Cano, Alberto Paradela, Maria Luz Martinez-Chantar, Miguel A. Martin, Mercedes Perez-Carreras, Alberto Garcia-Picazo, Jesus Vazquez, Enrique Calvo, Gloria Gonzalez-Aseguinolaza, Takeyori Saheki, Araceli del Arco, Jorgina Satrustegui, Laura Contreras
Summary: The deficiency of CITRIN, the liver mitochondrial aspartate-glutamate carrier (AGC), is the cause of four human clinical phenotypes. A potential therapy for this condition is the expression of aralar, the AGC present in brain, to replace citrin. To explore the significance of AGC replacement in human therapy, the relative levels of citrin and aralar in mouse and human liver were studied. The results support the benefit of increasing aralar expression to improve the redox balance capacity of human liver, as an effective therapy for CITRIN deficiency.
MOLECULAR GENETICS AND METABOLISM REPORTS
(2023)
Article
Cell Biology
Sonia Dominguez-Zorita, Ines Romero-Carraminana, Fulvio Santacatterina, Pau B. B. Esparza-Molto, Carolina Simo, Araceli del-Arco, Cristina Nunez de Arenas, Jorge Saiz, Coral Barbas, Jose M. Cuezva
Summary: ATPase Inhibitory Factor 1 (IF1) regulates mitochondrial ATP synthase activity and its expression is variable in differentiated human and mouse cells. Overexpression of IF1 protects intestinal cells against colon inflammation. A conditional IF1-knockout mouse model was developed to investigate the role of IF1 in mitochondrial function and tissue homeostasis. Results showed that lack of IF1 led to increased ATP synthase/hydrolase activities, mitochondrial dysfunction, and a pro-inflammatory phenotype in mice.
CELL DEATH & DISEASE
(2023)
Article
Cell Biology
Kim Han, Komudi Singh, Allison M. Meadows, Rahul Sharma, Shahin Hassanzadeh, Jing Wu, Haley Goss-Holmes, Rebecca D. Huffstutler, Heather L. Teague, Nehal N. Mehta, Julian L. Griffin, Rong Tian, Javier Traba, Michael N. Sack
Summary: NAD+ boosting can modulate adaptive immunity by reducing IFNg and IL-17 secretion, enhancing Th17 polarization, and reducing inflammation in psoriasis through activation of Nrf2 and increased antioxidant defenses.
CELL REPORTS MEDICINE
(2023)
Article
Physiology
Aurea Oliva, Carolina Merono, Javier Traba
Summary: Mitochondria have a crucial role in the activation of the immune system, regulating cell metabolism and immune pathways. Dysregulation of mitochondria can lead to human diseases.
CURRENT OPINION IN PHYSIOLOGY
(2022)
