Integration of cell signaling and cellular metabolism
The brain has a very high metabolic demand, and compelling evidence over the last years has evidenced that the source of energy that neurons and glial cells utilize contributes to shape neuronal function and survival. However, little is known on how brain cells adapt to changes in metabolic situations, such as “energy fuel” availability and other extracellular cues. Furthermore, how the utilization of select fuels contribute to modulate neuronal excitability and survival remains poorly understood.
Our current research focuses on understanding how signaling cascades regulate energy metabolism in the brain, with a special focus on mitochondria. Mitochondrial metabolism plays a key role in cellular physiology, which is underscored by the fact that mitochondrial dysfunction and metabolic decline have been linked to several neurological disorders. Our previous studies have shown that manipulation of the metabolic program in the brain constitutes a promising therapeutic strategy to treat disorders in which metabolic dysfunction is a central feature. Therefore, understanding the molecular mechanisms that modulate energy metabolism and mitochondrial function will contribute to gain insight into the underpinnings responsible for the pathogenesis of such diseases.
In particular, we are interested in:
- Identification and characterization of signaling mechanisms that regulate the choice of fuel in brain cells.
- Study the molecular underpinnings that link metabolic flow with neuronal function and viability.
- Ultimately, we plan to utilize this knowledge to design and evaluate potential therapeutic strategies against mitochondrial dysfunction-induced neurological disorders.
To address these questions, we use a multidisciplinary approach that combines cellular biology, metabolic flux analysis, biochemistry, proteomics, molecular biology and in vivo studies. Our ultimate goal is to identify integrative mechanisms of regulation of energy metabolism and to develop novel therapeutic strategies for neurological disorders in which aberrations in metabolism play a prominent role. In this regard, we conduct part of our research in close collaboration with the group of Dr. Javier Díaz Nido.
Nutrients and other metabolic clues impinge on neurons and crosstalk with signaling networks to modulate function and survival.
|Last name||Name||Laboratory||Ext.*||Professional category|
|Giménez Cassina Sendon||Alfredo||207||4594||agcassina(at)cbm.csic.es||Investigador|
- Katsu-Jiménez Y, Giménez-Cassina A, “Fibroblast Growth Factor-21 promotes ketone body utilization in neurons through AMP-dependent kinase activation” Mol Cell Neurosci, In press
- Katsu-Jimenez Y, Vázquez-Calvo C, Maffezzini C, Halldin M, Peng X, Freyer C, Wredenberg A, *Giménez-Cassina A, *Wedell A, *Arnér ESJ, “Absence of TXNIP in humans leads to lactic acidosis and low serum methionine linked to deficient respiration on pyruvate”, Diabetes, 2019, 68(4):709-723 (* AGC, AW & ESJ: Co-senior authors)
- Femenía T, Giménez-Cassina A, Codeluppi S, Fernández-Zafra T, Katsu-Jiménez Y, Terrando N, Eriksson LI, Gómez-Galán M. "Disrupted neuro-glial metabolic coupling after peripheral surgery", Journal of Neuroscience, 2018, 38(2):452-464
- Katsu-Jiménez Y, Alves RM, Giménez-Cassina A, "Food for thought: Impact of metabolism on neuronal excitability", Experimental Cell Research, 2017, 360(1):41-416
- Peng X., Giménez-Cassina A, Petrus P, Conrad M, Rydén M, Arnér ES, "Thioredoxin reductase 1 suppresses adipocyte differentiation and insulin responsiveness". Scientific Reports, 2016, 6:28080
- *Gimenez-Cassina A, Danial NN, “Regulation of mitochondrial nutrient and energy metabolism by BCL-2 proteins”, Trends in Endocrinology and Metabolism, 2015, 26(4):165-175 (*AGC: Corresponding author)
- Gimenez-Cassina A, Garcia-Haro L, Choi CS, Osundiji MA, Lane EA, Huang H, Yildirim MA, Szlyk B, Fisher JK, Polak K, Patton E, Wiwczar J, Robertson K, Godes M, Kim S, Kulkarni A, Distefano A, Samuel V, Cline G, Kim YB, Shulman GI, Danial NN, “Regulation of hepatic energy metabolism and gluconeogenesis by BAD”, Cell Metabolism, 2014, 19:272-284
- Gimenez-Cassina A, Martinez-François JR, Fisher JK, Szlyk B, Polak K, Wiwczar J, Tanner GF, Lutas A, Yellen G, Danial NN, "BAD-Dependent regulation of fuel metabolism and KATP channel activity confers resistance to epileptic seizures", Neuron, 2012, 74(4):719-730
- Gimenez-Cassina A, Wade-Martins R, Gomez-Sebastian S, Corona JC, Lim F, Diaz-Nido J, “Infectious delivery and long-term persistence of transgene expression in vivo by a 135 kb iBAC-FXN genomic DNA expression vector”, Gene Therapy, 2011, 18(10):1015-1019
- Gimenez-Cassina A, Danial NN. “Noxa: A Sweet Twist to Survival and More”, Molecular Cell, 2010, 40(5):687-688
- Gimenez-Cassina A, Lim F, Cerrato T, Palomo GM, Diaz-Nido J. “Mitochondrial Hexokinase II promotes neuronal survival and acts downstream of glycogen synthase kinase-3”. Journal of Biological Chemistry, 2009, 284(5):3001-3011
- Mauro Agrò (July 2019; Universidad Autónoma de Madrid; Co-supervisor. Main supervisor: Dr. Javier Díaz Nido)
- Ana Canerina Luis Amaro (expected: January 2020; Universidad de La Laguna; Co-supervisor. Main supervisor: Dr. Raquel Marín Cruzado)