Article
Cell Biology
Sai Yuan, Tamara Korolnek, Byung-Eun Kim
Summary: Copper is an essential trace element for key biochemical reactions in the body. Recent studies have found that a small molecule compound called elesclomol can effectively treat Menkes disease in mice when administered orally. This compound facilitates copper delivery and can rescue copper deficiency in genetic models of mice and nematodes. These findings suggest that oral administration of elesclomol could be an optimal therapeutic approach for Menkes disease and other disorders related to copper insufficiency.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Cat McCann, Michael Quinteros, Ifeoluwa Adelugba, Marcos N. Morgada, Aida R. Castelblanco, Emily J. Davis, Antonio Lanzirotti, Sarah J. Hainer, Alejandro J. Vila, Juan G. Navea, Teresita Padilla-Benavides
Summary: This study reveals the important role of mitochondrial phosphate transporter PiC2 in copper transport and delivery to mitochondria, promoting the differentiation of primary myoblasts.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Sai-ya Zhu, Wen-qian Zhou, Yang-yang Niu, Chao Zheng, Xi Liu, Ying-ying Zhang, Chen Yu
Summary: Renal fibrosis development relies on proteins and cofactors, including copper, which is involved in renal microenvironment homeostasis. The accumulation of copper in mitochondria, rather than cytosol, leads to mitochondrial dysfunction, cell apoptosis, and renal fibrosis. Copper overload disrupts the activity of respiratory chain complex IV, impairs mitochondrial functions, and eventually leads to fibrosis development. COX17, the copper chaperone protein, plays a crucial role in maintaining mitochondrial copper homeostasis, restoring complex IV activity, and ameliorating renal fibrosis.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Neurosciences
Cortnie Hartwig, Gretchen Macias Mendez, Shatabdi Bhattacharjee, Alysia D. Vrailas-Mortimer, Stephanie A. Zlatic, Amanda A. H. Freeman, Avanti Gokhale, Mafalda Concilli, Erica Werner, Christie Sapp Savas, Samantha Rudin-Rush, Laura Palmer, Nicole Shearing, Lindsey Margewich, Jacob McArthy, Savanah Taylor, Blaine Roberts, Vladimir Lupashin, Roman S. Polishchuk, Daniel N. Cox, Ramon A. Jorquera, Victor Faundez
Summary: Rare genetic diseases affecting the nervous system are often caused by mutations in ATP7A and ATP7B genes, leading to disruptions in copper homeostasis. These disruptions can result in alterations in epidermis, aminergic, sensory, and motor neurons in Drosophila, with effects on mitochondrial content at synapses and synaptic morphology, transmission, and plasticity. The integrity of Golgi-dependent copper homeostasis mechanisms involving ATP7 and COG is crucial for maintaining mitochondrial function and synaptic localization.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Genetics & Heredity
Abhinav B. Swaminathan, Shivatheja Soma, Alison C. Vicary, Mohammad Zulkifli, Harman Kaur, Vishal M. Gohil
Summary: This study identified Coa4 as an essential protein in the copper delivery pathway to the Cu-B site of cytochrome c oxidase. It also revealed the involvement of Coa4 in cellular copper homeostasis.
Article
Multidisciplinary Sciences
Agnes Moe, Justin Di Trani, John L. Rubinstein, Peter Brzezinski
Summary: Energy conversion in aerobic organisms involves electron transfer from low-potential donors to dioxygen through the membrane-bound respiratory chain. The formation of supercomplex CIII2CIV1/2 facilitates electron transfer by two-dimensional diffusion of cyt. c, increasing QH(2):O-2 oxidoreductase activity and suggesting a regulatory role for supercomplex formation in the respiratory chain.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Paul A. Cobine, Stanley A. Moore, Scot C. Leary
Summary: Mitochondria accumulate copper through MCF proteins for the maturation of copper enzymes, involving transporters like Pic2 and SLC25A3. Copper and copper proteins play essential roles in regulating cellular copper balance and inter-organ communication, while matrix copper may also have a role in novel cell death pathway cuproptosis.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Plant Sciences
Aprajita Kumari, Vemula Chandra Kaladhar, Nidhi Yadav, Pooja Singh, Kishorekumar Reddy, Kapuganti Jagadis Gupta
Summary: The location of NO production in mitochondrial cytochrome c oxidase and its role in mitochondrial biogenesis were investigated in Arabidopsis seedlings under osmotic stress and recovery. Osmotic stress reduced growth and mitochondrial number while increasing NO production. Nitrite application stimulated NO production and mitochondrial number in a NO-deficient mutant. COX6b(-)3 and COA6-L subunits were induced during osmotic stress and mutants impaired in these subunits showed reduced NO production and mitochondrial biogenesis. The COX6b-3 and COA6-L subunits interacted with a VQ27 motif-containing protein in the presence of NO, and a vq27 mutant displayed impaired mitochondrial biogenesis.
PLANT CELL AND ENVIRONMENT
(2023)
Review
Biochemistry & Molecular Biology
Abhinav B. Swaminathan, Vishal M. Gohil
Summary: Copper is essential for the stability and activity of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. The biogenesis of copper sites in CcO requires evolutionarily conserved proteins that form the mitochondrial copper delivery pathway. Mutations in some of these proteins have been shown to cause fatal infantile human disorders, emphasizing the biomedical significance of understanding copper delivery mechanisms to CcO.
Article
Biochemistry & Molecular Biology
Natalie M. Garza, Mohammad Zulkifli, Vishal M. Gohil
Summary: Copper and iron are essential cofactors for cellular enzymes, and disruption in their homeostasis can lead to severe human disorders. A study found that the investigational anticancer drug ES can deliver copper to mitochondrial cuproenzymes, potentially treating copper deficiency disorders. The study also revealed that ES treatment increases cellular and mitochondrial iron content, independent of the major cellular copper importer but dependent on the iron importer Ftr1 and its partner Fet3. The mechanism by which ES distributes copper in cells and influences iron homeostasis was further investigated.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Luke E. Formosa, Shadi Maghool, Alice J. Sharpe, Boris Reljic, Linden Muellner-Wong, David A. Stroud, Michael T. Ryan, Megan J. Maher
Summary: COA7 is a crucial assembly factor for the biogenesis of mitochondrial complex IV. It interacts with SCO1 and SCO2 to catalyze copper relay and reduction of disulfide bonds, which are important for complex IV assembly.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Md Yousuf Ali, Claudia R. Oliva, Susanne Flor, Prabhat C. Goswami, Corinne E. Griguer
Summary: This study identified the molecular mechanism of radioresistance in glioblastoma (GBM) as changes in the cellular labile iron pool (LIP) and the activity of cytochrome c oxidase (CcO). By manipulating CcO and LIP, the sensitivity of radioresistant GBM cells to radiation may be restored.
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Article
Cell Biology
Jia Shi, Yi Yang, Ya-Nan Wang, Qing Li, Xue Xing, An-Ying Cheng, Xiao-Na Zhan, Jie Li, Gang Xu, Fan He
Summary: This study reveals the association between metabolism and the progression of vascular calcification in chronic kidney disease (CKD). High phosphate and uremic serum enhance mitochondrial respiration capacity in vascular smooth muscle cells (VSMCs), while glycolysis level remains unchanged. Suppression of cytochrome c oxidase (COX) activity attenuates vascular calcification.
CELL DEATH & DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Michele Brischigliaro, Alfredo Cabrera-Orefice, Mattia Sturlese, Dei M. Elurbe, Elena Frigo, Erika Fernandez-Vizarra, Stefano Moro, Martijn A. Huynen, Susanne Arnold, Carlo Viscomi, Massimo Zeviani
Summary: The composition of cytochrome c oxidase (COX) is functionally conserved between vertebrate and invertebrate species, despite potential differences in individual structures.
Article
Neurosciences
Benjamin R. Troutwine, Taylor A. Strope, Edziu Franczak, Colton R. Lysaker, Laylan Hamid, Clayton Mansel, Julia A. Stopperan, Cynthia M. Gouvion, Mohammad Haeri, Russell H. Swerdlow, Heather M. Wilkins
Summary: The study found that Alzheimer's disease (AD) patients have mitochondrial dysfunction, specifically reduced brain cytochrome oxidase (COX) function and complex II Vmax. APOE epsilon 4 carriers also have deficits in COX, complex II, and III. These results suggest a dysregulated relationship between brain mitochondrial function and A beta pathology in AD.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Natalie M. Garza, Aaron T. Griffin, Mohammad Zulkifli, Chenxi Qiu, Craig D. Kaplan, Vishal M. Gohil
Summary: This study identified novel genetic regulators of mitochondrial copper homeostasis through a genome-wide screen, including subunits of the AP-3 complex and components of the cellular pH-sensing pathway. These genes impact vacuolar acidity, which in turn perturbs mitochondrial copper homeostasis and CcO function. The study provides insights into how vacuolar pH affects mitochondrial respiration through copper homeostasis.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Donna M. Iadarola, Alaumy Joshi, Cameron B. Caldwell, Vishal M. Gohil
Summary: Phosphatidylethanolamine (PE) is essential for mitochondrial respiration in yeast, while phosphatidylcholine (PC) can largely be replaced. Choline (Cho) has been shown to rescue respiratory growth of PE-deficient yeast by replenishing mitochondrial PE levels. This rescue mechanism involves the conversion of Cho to PC via the Kennedy pathway and the involvement of enzyme Psd2 in PE biosynthesis.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Sagnika Ghosh, Mohammad Zulkifli, Alaumy Joshi, Manigandan Venkatesan, Allen Cristel, Neelanjan Vishnu, Muniswamy Madesh, Vishal M. Gohil
Summary: This study demonstrates the importance of mitochondrial phospholipid cardiolipin in the stability and activity of the mitochondrial calcium uniporter (MCU) complex regulatory subunit MICU1 in Barth syndrome patients. The decrease in MICU1 levels disrupts mitochondrial calcium uptake kinetics, leading to the impairment of pyruvate dehydrogenase activation and reducing equivalents generation, ultimately affecting mitochondrial bioenergetics. Defects in mitochondrial calcium signaling may contribute to cardiac and skeletal muscle pathologies in Barth syndrome patients, highlighting a potential therapeutic target for this disorder.
HUMAN MOLECULAR GENETICS
(2022)
Review
Biochemistry & Molecular Biology
Abhinav B. Swaminathan, Vishal M. Gohil
Summary: Copper is essential for the stability and activity of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. The biogenesis of copper sites in CcO requires evolutionarily conserved proteins that form the mitochondrial copper delivery pathway. Mutations in some of these proteins have been shown to cause fatal infantile human disorders, emphasizing the biomedical significance of understanding copper delivery mechanisms to CcO.
Article
Biochemistry & Molecular Biology
Natalie M. Garza, Mohammad Zulkifli, Vishal M. Gohil
Summary: Copper and iron are essential cofactors for cellular enzymes, and disruption in their homeostasis can lead to severe human disorders. A study found that the investigational anticancer drug ES can deliver copper to mitochondrial cuproenzymes, potentially treating copper deficiency disorders. The study also revealed that ES treatment increases cellular and mitochondrial iron content, independent of the major cellular copper importer but dependent on the iron importer Ftr1 and its partner Fet3. The mechanism by which ES distributes copper in cells and influences iron homeostasis was further investigated.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Genetics & Heredity
Abhinav B. Swaminathan, Shivatheja Soma, Alison C. Vicary, Mohammad Zulkifli, Harman Kaur, Vishal M. Gohil
Summary: This study identified Coa4 as an essential protein in the copper delivery pathway to the Cu-B site of cytochrome c oxidase. It also revealed the involvement of Coa4 in cellular copper homeostasis.
Editorial Material
Cell Biology
Michal Wasilewski, Vishal M. Gohil, Oleh Khalimonchuk
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Endocrinology & Metabolism
Natalie M. Garza, Abhinav B. Swaminathan, Krishna P. Maremanda, Mohammad Zulki Fli, Vishal M. Gohil
Summary: Copper is an essential micronutrient that plays a crucial role in mitochondrial energy metabolism. Copper enters cells through transporters and is distributed to cuproenzymes by chaperones. Mutations in copper transporters and chaperones disrupt copper homeostasis in mitochondria, leading to genetic disorders. Elesclomol, a copper ionophore, shows therapeutic potential for copper deficiency disorders.
TRENDS IN ENDOCRINOLOGY AND METABOLISM
(2023)
Article
Biochemistry & Molecular Biology
Alaumy Joshi, Vishal M. Gohil
Summary: Barth syndrome is a debilitating disorder caused by mutations in the TAFAZZIN gene, which is involved in maintaining normal levels of cardiolipin in mitochondrial membranes. A recent study found that in addition to calcium, the levels of magnesium are significantly reduced in Barth syndrome patients. This study also identified a decrease in the abundance of the mitochondrial magnesium influx channel MRS2 in various models of Barth syndrome. The researchers attributed this reduction to the increased turnover of MRS2 in models with cardiolipin deficiency. These findings suggest that perturbation of mitochondrial magnesium homeostasis may contribute to the pathology of Barth syndrome.
HUMAN MOLECULAR GENETICS
(2023)
Review
Cell Biology
Alaumy Joshi, Travis H. Richard, Vishal M. Gohil
Summary: Studies on mitochondrial phospholipids have revealed their crucial role in mitochondrial bioenergetics and human health. The composition and function of these phospholipids have been highly conserved, and recent advances in understanding their transport mechanisms have further enhanced our understanding of mitochondrial phospholipid homeostasis. Additionally, disruptions in mitochondrial phospholipid biosynthesis have been linked to various genetic diseases, and promising therapeutic strategies are being developed for these disorders.
JOURNAL OF CELL SCIENCE
(2023)
Article
Medicine, Research & Experimental
Kimberly A. Jett, Zakery N. Baker, Amzad Hossain, Aren Boulet, Paul A. Cobine, Sagnika Ghosh, Philip Ng, Orhan Yilmaz, Kris Barreto, John DeCoteau, Karen Mochoruk, George N. Ioannou, Christopher Savard, Sai Yuan, Osama H. M. H. Abdalla, Christopher Lowden, Byung-Eun Kim, Hai-Ying Mary Cheng, Brendan J. Battersby, Vishal M. Gohil, Scot C. Leary
Summary: We identified a copper-linked signaling circuit activated by disrupted mitochondrial function, resulting in atrophy of the spleen and thymus and a deficiency in peripheral white blood cells. The leukopenia was caused by alpha-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. The upregulation of alpha-fetoprotein in stressed tissue may suppress the immune system, contributing to recurrent or chronic infections in mitochondrial diseases or other disorders with secondary mitochondrial dysfunction.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Biochemistry & Molecular Biology
Steven W. Wall, Lilia Sanchez, Kelly Scribner Tuttle, Scott J. Pearson, Shivatheja Soma, Garhett L. Wyatt, Hannah N. Carter, Ramsey M. Jenschke, Lin Tan, Sara A. Martinez, Philip L. Lorenzi, Vishal M. Gohil, Monique Rijnkels, Weston W. Porter
Summary: Researchers discovered that a metabolism-related protein plays a crucial role in stabilizing breast cancer cell growth, providing insight for the development of treatments to block cancer progression.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Mohammad Zulkifli, Adriana U. Okonkwo, Vishal M. Gohil
Summary: Ferredoxins (FDXs) are a class of iron-sulfur (Fe-S) proteins that function as electron transfer proteins in various metabolic pathways. This study demonstrates the essential role of FDX1 in mitochondrial respiration and energy production in rat cardiomyocyte cells. FDX1 knockout leads to reduced mitochondrial respiration by decreasing the abundance and assembly of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. FDX1 is also involved in heme a biosynthesis and acts upstream of COX15 in CcO biogenesis.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Review
Oncology
Eva J. Ge, Ashley I. Bush, Angela Casini, Paul A. Cobine, Justin R. Cross, Gina M. DeNicola, Q. Ping Dou, Katherine J. Franz, Vishal M. Gohil, Sanjeev Gupta, Stephen G. Kaler, Svetlana Lutsenko, Vivek Mittal, Michael J. Petris, Roman Polishchuk, Martina Ralle, Michael L. Schilsky, Nicholas K. Tonks, Linda T. Vahdat, Linda Van Aelst, Dan Xi, Peng Yuan, Donita C. Brady, Christopher J. Chang
Summary: Copper is a essential nutrient with both beneficial and toxic properties to cells. Recent progress in transition metal signaling has led to new connections between researchers from different disciplines, with potential for translating basic research into clinical therapies for diseases. The relationship between copper and cancer is particularly important, with opportunities for leveraging disease vulnerabilities through copper-dependent signaling pathways.
NATURE REVIEWS CANCER
(2022)
