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Neuro-Metabolism Research Lab

Deborah Chiabrando - PI

Deborah Chiabrando
Biographical Sketch

Assistant Professor, Dept. of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy

Main group members
Group Members
  • Diletta Isabella Zanin Venturini, PhD student
  • Raluca Elena Abalai, PhD student
  • Livia Metani, graduated student
  • Mia Carboni, master student
  • Elisa Lice, master student
  • Luca Gastaldi, undergraduate student

Research Activity

Mitochondria serve as the central hub for cellular metabolism, orchestrating energy production, nutrient utilization, and signaling pathways that are vital for maintaining proper cellular function and homeostasis. During neurodevelopment, mitochondria play a crucial role in regulating the proliferation, differentiation, migration, and survival of neuronal progenitors. In adulthood, maintaining proper metabolic control is essential to support the long-term survival of neurons, particularly those in the peripheral nervous system or the retina, which have high energy requirements.

Figure 2

Figure 1. Elucidating the mechanisms underlying FLVCR1-related disorders. FLVCR1-disorders encompass a group of genetic diseases due to mutations in the heme exporter FLVCR1. FLVCR1-related disorders include Posterior Column Ataxia and Retinitis Pigmentosa (RP) and Hereditary Sensory and Autonomic Neuropathies (HSAN). These disorders are characterized by the progressive degeneration of sensory neurons responsible for proprioception and nociception as well as degeneration of photoreceptors. The loss of these specific neuronal subtypes leads to sensory ataxia, pain insensitivity and vision loss. To study the molecular mechanisms underlying these disorders we developed several experimental models: (i) patients derived fibroblasts and lymphoblastoid cells (LCLs); (ii) patients derived induced pluripotent stem cells (iPSCs) that will be differentiated into specific neuronal types; (iii) murine and zebrafish models of the disease; (iv) murine primary sensory neurons. We plan to use a combination of genetic, metabolic, and proteomic approaches to elucidate the underlying molecular mechanisms and to identify therapeutic targets.

Figure 2

Figure 2. Spatiotemporal development of the cerebral cortex in mice. The cartoon illustrates the key steps in mouse cortical neurogenesis. On the right, a representative immunofluorescence performed on a E14,5 murine cortex section is shown. (Pax6=marker of neuronal progenitors; EdU=staining for proliferating cells; TbR2= marker of intermediate progenitors; Dapi=nuclei staining).

We are interested in rare neurodegenerative disorders linked to mitochondrial metabolism. Our current research focuses on a group of autosomal recessive disorders caused by FLVCR1 mutations. FLVCR1-related diseases include Posterior Column Ataxia and Retinitis Pigmentosa (PCARP), non-syndromic Retinitis Pigmentosa (RP) and Hereditary Sensory and Autonomic Neuropathies (HSAN). These disorders are characterized by the progressive degeneration of sensory neurons responsible for proprioception and nociception as well as degeneration of photoreceptors. The loss of these specific neuronal subtypes leads to sensory ataxia, pain insensitivity and vision loss. FLVCR1 has been implicated in the regulation of heme metabolism, choline uptake and overall energetic metabolism but the pathogenetic mechanisms underlying the diseases are still unclear. Our research aims to elucidate the role of FLVCR1 in the nervous system and to uncover the molecular mechanisms leading to sensory neurons and photoreceptors failure in FLVCR1-related diseases. To this end, we have developed several experimental models: (i) patients derived fibroblasts and lymphoblastoid cells (LCLs); (ii) patients derived induced pluripotent stem cells (iPSCs) that will be differentiated into specific neuronal types; (iii) murine and zebrafish models (iv) murine primary sensory neurons. We plan to use a combination of genetic, metabolic, and proteomic approaches to elucidate the underlying molecular mechanisms and to identify therapeutic targets (Fig.1). Our long-term goal is to discover a therapeutic entry point to effectively treat rare neurological disorders.

Our future research aims are: (1) to develop novel experimental models of FLVCR1-related disease; (2) to unravel the molecular mechanisms responsible for the degeneration of sensory neurons and photoreceptors in FLVCR1-related diseases; (3) to elucidate the role of heme trafficking during the development of the nervous system, with a particular focus on the pathogenesis of congenital hydrocephalus; (4) to get mechanistic insights into heme trafficking, by focusing on the role of different isoforms of the FLVCR1 gene.

2023-2025 Principal Investigator (PI) in the PRIN project entitled “Unlocking the structure and function of the heme transporter FLVCR1”. Grant number: 2022PX3SR3

2023-2025           Principal Investigator (PI) in the “Fondazione Telethon ETS” project, entitled “Posterior Column Ataxia and Retinitis Pigmentosa: new pathogenetic insights from the study of mitochondria-associated membranes”. Grant number: GMR22T1076

2021-2025          Co-PI in the project entitled “Defective heme transport in the development of congenital hydrocephalus”, supported by the National Institute of Health (NIH). Grant number: R01 NS123168-01 

Bertino F, Mukherjee D, Bonora M, Bagowski C, Nardelli J, Metani L, Zanin Venturini DI, Chianese D, Santander N, Salaroglio IC, Hentschel A, Quarta E, Genova T, McKinney AA, Allocco AL, Fiorito V, Petrillo S, Ammirata G, De Giorgio F, Dennis E, Allington G, Maier F, Shoukier M, Gloning KP, Munaron L, Mussano F, Salsano E, Pareyson D, di Rocco M, Altruda F, Panagiotakos G, Kahle KT, Gressens P, Riganti C, Pinton PP, Roos A, Arnold T, Tolosano E, Chiabrando D. Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus. Cell Rep Med. 2024 Jul 16;5(7):101647. doi: 10.1016/j.xcrm.2024.101647. PMID: 39019006

Lischka A, Eggermann K, Record CJ, Dohrn MF, Laššuthová P, Kraft F, Begemann M, Dey D, Eggermann T, Beijer D, Šoukalová J, Laura M, Rossor AM, Mazanec R, Van Lent J, Tomaselli PJ, Ungelenk M, Debus KY, Feely SME, Gläser D, Jagadeesh S, Martin M, Govindaraj GM, Singhi P, Baineni R, Biswal N, Ibarra-Ramírez M, Bonduelle M, Gess B, Romero Sánchez J, Suthar R, Udani V, Nalini A, Unnikrishnan G, Marques W Junior, Mercier S, Procaccio V, Bris C, Suresh B, Reddy V, Skorupinska M, Bonello-Palot N, Mochel F, Dahl G, Sasidharan K, Devassikutty FM, Nampoothiri S, Rodovalho Doriqui MJ, Müller-Felber W, Vill K, Haack TB, Dufke A, Abele M, Stucka R, Siddiqi S, Ullah N, Spranger S, Chiabrando D, Bolgül BS, Parman Y, Seeman P, Lampert A, Schulz JB, Wood JN, Cox JJ, Auer-Grumbach M, Timmerman V, de Winter J, Themistocleous AC, Shy M, Bennett DL, Baets J, Hübner CA, Leipold E, Züchner S, Elbracht M, Çakar A, Senderek J, Hornemann T, Woods CG, Reilly MM, Kurth I. Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies. Brain. 2023 Dec 1;146(12):4880-4890. doi: 10.1093/brain/awad328. PMID: 37769650 Free PMC article.

Fiorito V, Allocco AL, Petrillo S, Gazzano E, Torretta S, Marchi S, Destefanis F, Pacelli C, Audrito V, Provero P, Medico E, Chiabrando D, Porporato PE, Cancelliere C, Bardelli A, Trusolino L, Capitanio N, Deaglio S, Altruda F, Pinton P, Cardaci S, Riganti C, Tolosano E. The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation. Cell R eports 2021 doi: 10.1016/j.celrep.2021.109252.

Chiabrando D, Fiorito V, Petrillo S, Bertino F, Tolosano E. HEME: a neglected player in nociception? Neuroscience and Biobehavioural Reviews 2021. doi: 10.1016/j.neubiorev.2021.01.011.

Bertino F, Firestone K, Bellacchio E, Jackson KE, Asamoah A, Hersh J, Fiorito V, Destefanis F, Gonser R, Tucker ME, Altruda F, Tolosano E and Chiabrando D. HEME AND SENSORY NEUROPATHY: INSIGHTS FROM NOVEL MUTATIONS IN THE HEME EXPORTER FLVCR1. PAIN, 2019  doi: 10.1097/j.pain.0000000000001675

Fiorito V*, Chiabrando D* and Tolosano E. MITOCHONDRIAL TARGETING IN NEURODEGENERATION: A HEME PERSPECTIVE. Pharmaceuticals, 2018  doi: 10.3389/fnins.2018.00712

Petrillo S, Chiabrando D, Genova T, Fiorito V, Ingoglia G, Vinchi F, Mussano F, Carossa S, Silengo L, Altruda F, Merlo GR, Munaron L and Tolosano E. HEME ACCUMULATION IN ENDOTHELIAL CELLS IMPAIRS ANGIOGENESIS BY TRIGGERING PARAPTOSIS. Cell Death and Differentiation, 2018  doi: 10.1038/s41418-017-0001-7

Castori M, Morlino S, Ungelenk M, Pareyson D, Salsano E, Grammatico P, Tolosano E, Kurth I and Chiabrando D. POSTERIOR COLUMN ATAXIA WITH RETINITIS PIGMENTOSA COEXISTING WITH SENSORY-AUTONOMIC NEUROPATHY AND LEUKEMIA DUE TO A RECURRENT FLVCR1 MUTATION. Am Journal Medical Genetics B, 2017 doi: 10.1002/ajmg.b.32570

Chiabrando D, Castori M, di Rocco M, Ungelenk M, Gießelmann S, Di Capua M, Madeo A, Grammatico P, Bartsch S, Hübner CA, Altruda F, Silengo L, Tolosano E, Ingo Kurth. MUTATIONS IN THE HEME EXPORTER FLVCR1 CAUSE SENSORY NEURODEGENERATION WITH LOSS OF PAIN PERCEPTION. PLOS Genetics, 2016. doi: 10.1371/journal.pgen.1006461

Chiabrando D, Vinchi F, Fiorito V, Mercurio S and Tolosano E. HEME IN PATHOPHYSIOLOGY: A MATTER OF SCAVENGING, METABOLISM AND TRAFFICKING ACROSS CELL MEMBRANES. Frontiers in Pharmacology, 2014. doi: 10.3389/fphar.2014.00061

Vinchi F, Ingoglia G, Chiabrando D, Mercurio S, Turco E, Silengo L, Altruda F and Tolosano E. HEME EXPORTER FLVCR1A REGULATES HEME SYNTHESIS AND DEGRADATION AND CONTROLS ACTIVITY OF CYTOCHROMES P450. Gastroenterology, 2014.  doi: 10.1053/j.gastro.2014.01.053

Chiabrando D, Marro S, Mercurio S, Giorgi C, Petrillo S, Vinchi F, Fiorito V, Fagoonee S, Camporeale A, Turco E, Merlo GR, Silengo L, Altruda F, Pinton P and Tolosano E. THE MITOCHONDRIAL HEME EXPORTER FLVCR1B MEDIATES ERYTHROID DIFFERENTIATION. Journal of Clinical Investigation, 2012.  doi: 10.1172/JCI62422

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