Feil Family Brain & Mind Research Institute

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D’Aurelio, Marilena - Manfredi Laboratory

Marilena D’Aurelio, Ph.D.
Assistant Research Professor of Neuroscience

 

Overview 

My research attempts to identify the pathogenic mechanisms of mitochondrial diseases, focusing on mitochondrial dysfunction, oxidative stress, and altered cell metabolism. My hypothesis is that mitochondrial disease pathogenesis depends on the blockage of crucial steps of the inter-organ amino acid metabolism. We have utilized a new compelling metabolomics technology to identify previously unrecognized defects in glutamine metabolism in mitochondrial DNA mutant cells associated with human mitochondrial diseases. We were able to rescue the defective pathway by supplementing the cells with compounds that bypass the enzymatic blockages. The ultimate goal is to bypass the metabolic blockages in vivo in a new mouse model of mitochondrial disease using dietary supplementation, thus identifying novel strategies for metabolism-based therapy.To achieve this goal I will work with excellent collaborators within the Weill Medical College. My expertise in mitochondrial bioenergetics and molecular genetics will be also available for collaborative mitochondrial related research projects. The goal is to extend the metabolic study to neurodegenerative diseases and to identify new therapeutic targets

 

Achievements & Publications 

One novel discovery, using the cybrid cell model, has been the demonstration of heterologous recombination in mitochondrial DNA as a potential mechanism of DNA repair during oxidative stress and aging. A meaningful finding has been that the respiratory chain supercomplexes are functional units and that supercomplex assembly is a necessary step for mitochondrial respiration. Another important finding is that mtDNA background plays an important role in modulating the biochemical phenotype of mitochondrial diseases and can explain the phenotypic differences among individuals harboring the same mutation and the phenotypic similarities shared among individuals carrying different mtDNA mutations.

  • G. Lenaz, A. Baracca, V. Carelli, M. D'Aurelio, G. Sgarbi, G. Solaini. Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim Biophys Acta. 2004 Jul 23; 1658(1-2):89-94. Review. PMID:15282179 
  • M. D’Aurelio, C.D. Gajewski, M.T. Lin, W.M. Mauck, L.Z. Shao, G. Lenaz, C.T. Moraes and G. Manfredi. Heterologous mitochondrial DNA recombination in human cells. Hum Mol Genet. 2004 Dec 15; 13(24):3171-9. PMID:15496432
  • G. Deleonardi, A. Biondi, M. D’Aurelio, M.M. Pich, K. Stankov, A. Falasca, G. Formiggini, C. Bovina, G. Romeo, G. Lenaz. Plasma membrane oxidoreductase activity in cultured cells in relation to mitochondrial function and oxidative stress. Biofactors. 2004; 20(4):251-8. PMID:15706061
  • K. Stankov, A. Biondi, M. D’Aurelio, G. Gasparre, A. Falasca, G. Romeo, G. Lenaz. Mitochondrial activities of a cell line derived from thyroid hurthle cell tumors. Thyroid. 2006 Apr; 16(4):325-31. PMID:16646677
  • M. D’Aurelio, C.D. Gajewski, G. Lenaz, G.Manfredi. Respiratory chain supercomplexes set the threshold for respiration defects in human mtDNA mutant cybrids. Hum Mol Genet. 2006 Jul 1; 15: 2157-69. PMID:16740593
  • Y. Li*, M. D'Aurelio*, J. Deng, J. Park, G. Manfredi, P. Hu, J. Lu, and Y. Bai. An Assembled Complex IV Maintains the Stability and Activity of Complex I in Mammalian Mitochondria. J. Biol. Chem., 2007 Jun 15; 282(24):17557-17562. PMID:17452320
  • M. D'Aurelio, C. Vives-Bauza, MM. Davidson,  G. Manfredi. Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells. Hum Mol Genet. 2010 Jan 15; 19(2):374-86. PMID:19875463
  • P. Zhou, L. Qian, M. D'Aurelio, S. Cho, G. Wang, G. Manfredi, V. Pickel, C. Iadecola. Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities. J.Neurosci. 2012 Jan 11; 32(2):583-92. PMID:22238093
  • F. Gonzalvez*, M. D'Aurelio*, M. Boutant, A. Moustapha, J. P. Puech, T. Landes, L. Arnaure, G. Vial, N. Talleux, C. Slomianny, R. J. Wanders, R. H. Houtkooper, P. Belenger, I. M. Moller, E. Gottlieb, F. M. Vaz, G. Manfredi, P. X. Petit. Barth syndrome: Cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin gene mutation. Biochim Biophys Acta 2013 Mar 20. PMID: 23523468
  • M. Damiano, E. Diguet, C. Malgorn, M. D'Aurelio, L. Galvan, F. Petit, L. Benhaim, M. Guillermier, D. Houitte, N. Dufour, P. Hantraye, JM. Canals, J. Alberch, T. Delzescaux, N. Déglon, MF. Beal, E. Brouillet. A role of mitochondrial complex II defects in genetic models of Huntington's disease expressing N-terminal fragments of mutant huntingtin. Hum Mol Genet. 2013 Jun 5.PMID:23720495

 

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