Giovanni Manfredi, M.D., Ph.D.
Professor of Neuroscience, Mitochondria and Neurodegeneration Unit
Director, Neuroscience Graduate Program
Dr. Giovanni Manfredi directs the Mitochondria and Neurodegeneration Unit of the BMRI at Weill Cornell Medical College. His lab studies the alterations of mitochondrial metabolism in neurodegenerative disease, especially ALS and primary inherited mitochondrial diseases.
Assistant Research Professor: Dr. Marilena D’Aurelio,
Assistant Professor: Dr. Jordi Magrane
Instructor: Dr. Hibiki Kawamata.
Post doctoral fellows: Drs. Federica Valsecchi, Csaba Konrad, Gloria Palomo, Melis Inan
Graduate Student: Ms. Suzanne Burstein
Technical Assistants: Ms. Ifrah Shahi, Ms. Kathryne Kirk
The goals of the Mitochondria and Neurodegeneration Unit are to define the mechanisms of mitochondrial involvement in neurodegeneration and develop translational approaches to address mitochondrial impairment in ALS and other neurodegenerative conditions. The understanding of the molecular mechanisms underlying mitochondrial changes in neurodegeneration will allow designing targeted approaches to specific problems. We anticipate that signaling pathways and the protein machinery involved in mitochondrial quality control, i.e., mitochondrial transport, mitophagy, fusion and fission, will become increasingly interesting as potential therapeutic targets. Furthermore, approaches that stabilize mitochondrial function against stress and chronic damage will be sought. Genetic and pharmacological approaches to boost mitochondrial bioenergetics are under investigation and will be used to counteract mitochondrial insufficiency in neurodegeneration.
- Dr. Manfredi’s main scientific contributions are in the fields of mitochondrial biology and metabolic regulation in health and disease.
- The involvement of mitochondria in amyotrophic lateral sclerosis (ALS) is an area of research that his laboratory pioneered and developed.
- He demonstrated that mutant SOD1, which is one of the most common causes of familial ALS and originally considered to be exclusively a cytosolic protein, is accumulated and misfolded in mitochondria.
- He also pioneered the study of calcium handling dysregulation in mitochondria of mutant SOD1 mice and of the role that mitochondrial calcium handling plays in the gender differences in ALS.
- His work demonstrated the molecular mechanisms whereby SOD1 import in the mitochondrial intermembrane space is regulated under normal and pathological conditions.
- Dr. Manfredi with Dr. Magrane’ have developed new imaging tools to investigate mitochondrial axonal transport in ALS motor neurons, and showed that the dynamics of mitochondria is impaired in SOD1 mutant motor neurons in culture and in vivo in adult mice.
- By generating new transgenic mice, where SOD1 is specifically targeted to the mitochondrial intermembrane space, Dr. Manfredi has demonstrated that the mutant protein localized in mitochondria plays a direct role in causing neurodegeneration in vivo.
- Major contributions have been in the area of the pathogenic mechanisms of mitochondrial disorders caused by mutations in the mitochondrial DNA, using novel cybrid cell lines, which contain human mutant mtDNA transferred into mtDNA-less cells.
- In collaboration with Drs. Levin and Buck, in the Department of Pharmacology, Dr. Manfredi has discovered a novel regulatory pathway of oxidative phosphorylation in mammalian mitochondria. This pathway involves soluble adenylyl cyclase (sAC) localized in mitochondria that senses metabolic demands and activates, through cAMP, protein kinases, which then regulate the activities of mitochondrial enzymes.
- Kawamata H, Manfredi G*. (2008) Different regulation of wild-type and mutant Cu,Zn superoxide dismutase localization in mammalian mitochondria. Hum Mol Genet, 17, 3303-17.
- Acin-Perez, R., Salazar, E., Kamenetsky, M., Buck, J., Levin, L.R., and Manfredi, G. (2009). Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab 9, 265-276.
- Acin-Perez, R., Salazar, E., Brosel, S., Yang, H., Schon, E.A. and Manfredi, G*. (2009) Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects. EMBO Mol Med, 1, 392-406.
- Magrane, J., Hervias, I., Henning, M.S., Damiano, M., Kawamata, H. and Manfredi, G*. (2009) Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities.Hum Mol Genet, 18, 4552-4564.
- D'Aurelio, M., Vives-Bauza, C., Davidson, M.M. and Manfredi, G*. (2010) Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells. Hum Mol Genet, 19, 374-386.
- Kawamata, H., Tiranti, V., Magrané, J., Chinopoulos, C., Manfredi, G.* (2011) adPEO mutations in ANT1 impair ADP-ATP translocation in muscle mitochondria. Hum Mol 20, 2964-74.
- Acin-Perez, R., Gatti D.L., Bai, Y., Manfredi, G*. (2011) Protein phosphorylation and prevention of cytochrome oxidase inhibition by ATP: coupled mechanisms of energy metabolism regulation. Cell Metabolism 13, 712-719.
- Igoudjil A, Magrané J, Fischer LR, Kim HJ, Hervias I, DumontM, Cortez C, Glass JD, Starkov AA, Manfredi G* (2011). In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space J Neurosci (44):15826-37. PMID: 22049426
- Magrané J, Sahawneh MA, Przedborski S, Estévez AG, Manfredi G* (2012) Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci 4;32(1):229-42). PMID: 22219285
- Kim HJ, Magranè J, Starkov AA, Manfredi G*. (2012) The mitochondrial calcium regulator cyclophilin D is an essential component of estrogen-mediated neuroprotection in amyotrophic lateral sclerosis. Brain 135:2865-74. PMID: 22961554.
- 14. J. Magrane, C. Cortez, W. Gan, G. Manfredi. (2013) Abnormal Mitochondrial Transport and Morphology are Common Pathological Denominators in SOD1 and TDP43 ALS Mouse Models. Hum. Mol. Genet. PMID: 24154542.
- H. Kawamata, S. K. Ng, N. Diaz, S. Burstein, L. Morel, A. Osgood, B. Sider, H. Higashimori, P. G. Haydon, G. Manfredi, Y. Yang (2014) Abnormal Intracellular Calcium Signaling and SNARE-Dependent Exocytosis Contributes to SOD1G93A Astrocyte-Mediated Toxicity in Amyotrophic Lateral Sclerosis. J. Neurosci. 34, 2331-2348. PMID: 24501372
BMRI: Drs. Iadecola, Beal, and Zhou
Pharmacology: Drs. Levin, Buck, and Gross