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2 results on '"Carmela Piazzolla"'

1. Expanding the genetic and clinical spectrum of SLC25A42‐associated disorders and testing of pantothenic acid to improve CoA level in vitro

Author

Katharina Heckmann, Arcangela Iuso, Janine Reunert, Marianne Grüneberg, Anja Seelhöfer, Stephan Rust, Giuseppe Fiermonte, Eleonora Paradies, Carmela Piazzolla, Manoj Mannil, and Thorsten Marquardt

Subjects
cellular CoA, mitochondrial coenzyme transporter, mitochondrial respiration, pantothenic acid, SLC25A42, Diseases of the endocrine glands. Clinical endocrinology, RC648-665, Genetics, QH426-470
Abstract

Abstract SLC25A42 encodes the mitochondrial coenzyme A (CoA) transporter localized at the inner mitochondrial membrane. SLC25A42 deficiency leads to a congenital disease with a heterogeneous clinical presentation, including myopathy, developmental delay, lactic acidosis, and encephalopathy. Twenty‐one patients have been described so far. In the current study, we report on the identification of new biallelic variants in SLC25A42 in three siblings. Patients presented with symmetrical T2 hyperintensity of the putamen with minor volume depression at the brain MRI, elevated lactate, reduced oxygen consumption rates in muscle and fibroblasts, and reduced CoA levels in fibroblasts. Administration of pantothenic acid led to clinical stabilization and increased CoA levels in fibroblasts, thus confirming a role for SLC25A42 in energy metabolism and CoA homeostasis.

Published
2024
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2. KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth

Author

Vittoria Rago, Rocco Malivindi, Giuseppe E. De Benedetto, Isabella Pisano, Giuseppe Fiermonte, Francesco M. Lasorsa, Carmela Piazzolla, Christopher L. Riley, Angelo Vozza, Stephan J. Reshkin, Wolfgang Sommergruber, Gennaro Agrimi, Francesca Pezzuto, Rosa Angela Cardone, Simona N. Barile, Yuan Li, Pasquale Scarcia, Carlo M.T. Marobbio, Maria C. Vegliante, Ruggiero Gorgoglione, Edward M. Mills, Luigi Palmieri, Loredana Capobianco, Deborah Fratantonio, Susanna Raho, Maria Raffaella Greco, Francesco De Leonardis, Vincenza Dolce, Raho, Susanna, Capobianco, Loredana, Malivindi, Rocco, Vozza, Angelo, Piazzolla, Carmela, De Leonardis, Francesco, Gorgoglione, Ruggiero, Scarcia, Pasquale, Pezzuto, Francesca, Agrimi, Gennaro, Barile, Simona N., Pisano, Isabella, Reshkin, Stephan J., Greco, Maria R., Cardone, Rosa A., Rago, Vittoria, Li, Yuan, Marobbio, Carlo M. T., Sommergruber, Wolfgang, Riley, Christopher L., Lasorsa, Francesco M., Mills, Edward, Vegliante, Maria C., De Benedetto, Giuseppe E., Fratantonio, Deborah, Palmieri, Luigi, Dolce &amp, Vincenza, Fiermonte, Giuseppe, Raho, S., Capobianco, L., Malivindi, R., Vozza, A., Piazzolla, C., De Leonardis, F., Gorgoglione, R., Scarcia, P., Pezzuto, F., Agrimi, G., Barile, S. N., Pisano, I., Reshkin, S. J., Greco, M. R., Cardone, R. A., Rago, V., Li, Y., Marobbio, C. M. T., Sommergruber, W., Riley, C. L., Lasorsa, F. M., Mills, E., Vegliante, M. C., De Benedetto, G. E., Fratantonio, D., Palmieri, L., Dolce, V., and Fiermonte, G.

Subjects
endocrine system diseases, Endocrinology, Diabetes and Metabolism, Glutamine, Biological Transport, Active, Mice, SCID, Mitochondrion, Proto-Oncogene Proteins p21(ras), chemistry.chemical_compound, Mice, Cytosol, Physiology (medical), Cell Line, Tumor, Internal Medicine, Animals, Humans, Uncoupling Protein 2, oncogenic Kras, mitochondrial carrier, UCP2, human pancreatic ductal adenocarcinoma (PDAC), chemistry.chemical_classification, Reactive oxygen species, Aspartic Acid, Glutaminolysis, Cell growth, Animal, Pancreatic Neoplasm, Cell Biology, Xenograft Model Antitumor Assays, Cell biology, Mitochondria, Pancreatic Neoplasms, chemistry, Glutathione disulfide, Female, Aspartate transport, Reactive Oxygen Species, Reactive Oxygen Specie, Oxidation-Reduction, NADP, Carcinoma, Pancreatic Ductal, Human
Abstract

The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis1,2. Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production2. The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRASmut cell lines display decreased glutaminolysis, lower NADPH/NADP+ and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRASWT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRASmut PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRASmut rewired glutamine metabolism2, and thus it should be considered a key metabolic target for the treatment of this refractory tumour. UCP2 is shown in yeast and mammalian cells to transport aspartate out of mitochondria, thus enabling KRAS-mutated pancreatic ductal adenocarcinoma cells to perform glutaminolysis to support cancer growth.

Published
2020

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