Aoun 2015 Abstract MiP2015

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Cellular and animal models for the study of mitochondrial dysfunctions in Neurodegeneration with brain iron accumulation.


Aoun M, Acin-Perez R, Montorfano G, Rizzo A, Enriquez JA, Tiranti V (2015)

Event: MiP2015

β€œNeurodegeneration with brain iron accumulation” (NBIA) comprises a group of progressive neurodegenerative disorders characterized by high content of iron in the brain. Mutations in PANK2 gene, which encodes for the mitochondrial protein pantothenate kinase type 2, determine an autosomal recessive inborn error of CoA metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). The pathogenesis of PKAN, the most frequent form of NBIA, is still poorly understood. [1]

In our study, we are exploring a Pank2-KO mice model, which showed altered mitochondria membrane potential in neurons and defective respiration in the brain. Moreover, we have demonstrated that ketogenic diet, which stimulates lipid utilization by mitochondrial beta-oxidation, was able to reveal a clinical phenotype not present in Pank2-KO mice under standard diet [2]. These mitochondrial bioenergetics failure due to the absence of PANK2 protein may result from defects in mitochondrial membrane integrity and consequently in supercomplexes stabilization. Our first results showed a deficiency in complex IV activity in supercomplexes in the brain from Pank2-KO mice. In fact, PANK2 by synthesizing CoA required for membrane phospholipids remodeling and repair, indirectly contributes to the synthesis of cardiolipin implicated in supercomplexes stabilization. Thus, phospholipids metabolism could be an interesting target to better explore membrane homeostasis in vivo.

In parallel, we are conducting lipidomic analysis on NBIA patients fibroblasts and on PKAN patients red blood cells (RBC). The fibroblasts are an interesting tool to explore lipid metabolism in these diseases. Moreover, the complexity of the blood lipids profile establishes it as a rich source of molecules that can provide clues about human physiology and disease. Our first results showed a difference in fatty acids lipogenesis in fibroblasts and in phospholipids distribution in RBC membranes, mainly a decrease in phosphatidylcholine and sphingomyelin. Thus, lipidomic analysis in NBIA patients’ fibroblasts and RBC could provide a powerful biomarker in clinical medicine to understanding lipid biology in NBIA pathogenesis and monitoring therapeutic intervention.

Labels: MiParea: Respiration, mtDNA;mt-genetics, nDNA;cell genetics, Exercise physiology;nutrition;life style, Patients  Pathology: Neurodegenerative 

Organism: Human, Mouse  Tissue;cell: Nervous system, Blood cells, Fibroblast 

Event: A1, Poster  MiP2015 


1-Unit Molecular Neurogenetics, Foundation IRCCS Neurological Institute β€˜C Besta’, Milan, Italy; 2-Dept Cardiovascular Developm Repair, CNIC, Madrid, Spain; 3-Dept Biosystems applied molecular sciences, Univ degli Studi di Milano, Italy. -

References and acknowledgement

  1. Aoun M, Tiranti V (2015) Mitochondria: a crossroads for lipid metabolism defect in neurodegeneration with brain iron accumulation diseases. Int J Biochem Cell Biol 63:25-31.
  2. Brunetti D, Dusi S, Giordano C, Lamperti C, Morbin M, Fugnanesi V, Marchet S, Fagiolari G, Sibon O, Moggio M, d'Amati G, Tiranti V (2014) Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model. Brain 137:57-68.

The support of "Mitochondrial European Educational Training, MEET” project of the European Commission’s Seventh Framework Programme, FP7-PEOPLE-2012-ITN MARIE CURIE, grant agreement No. 317433 is gratefully acknowledged.

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