Eric A. Schon, PhD
- Lewis P. Rowland Professor of Neurology (in Genetics and Development)
Mitochondria are unique among the constituents of the eukaryotic cell in that they are semi-autonomous organelles that contain their own genetic machinery. As such, they operate under the dual genetic controls of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Mitochondrial genetics differs markedly from mendelian genetics, because first, mitochondria are inherited exclusively from the mother, and second, there are hundreds or thousands of mitochondria (and mtDNAs) per cell. In addition, organellar division and mtDNA replication are stochastic processes unrelated to the cell cycle; and mtDNA gene organization, DNA replication, RNA transcription, and protein translation all have a prokaryotic "look" about them. This latter feature is no surprise, given that mitochondria were once bacteria that were taken up by the proto-eukaryotic cell early in evolution. Biochemically, the most relevant aspect of mitochondrial function is the production of oxidative energy via the respiratory chain and oxidative phosphorylation.
Mitochondria are semi-autonomous organelles that contain their own genetic machinery. As such, they operate under the dual genetic controls of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Mitochondrial genetics differs markedly from mendelian genetics, because first, mitochondria are inherited exclusively from the mother, and second, there are hundreds or thousands of mitochondria (and mtDNAs) per cell. Biochemically, the most relevant aspect of mitochondrial function is the production of oxidative energy via the respiratory chain and oxidative phosphorylation. There are maternally-inherited, mendelian-inherited, sporadic, and even environmentally-induced mitochondrial disorders, most of which are fatal. We are studying the molecular basis of a number of these diseases, often using cytoplasmic hybrids, or "cybrids," that contain known proportions of mutant or wild-type mtDNAs in clonal cell lines that have no contaminating mtDNA background. We have also begun a project on treating mtDNA-based disease using pharmacoligical approaches aimed at "shifting heteroplasmy" in order to restore respiratory function in patient-derived cells. Most recently we have become interested in the pathogenesis of Alzheimer disease, and have discovered that presenilin-1, presenilin-2, and gamma-secretase activity itself, are located predominantly in a specialized subcompartment of the ER that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAM). We have found that cells from AD patients have massively increased ER-mitochondrial communication, which may help explain many of the seemingly unrelated features of the disease. We believe that this hyperconnectivity plays a fundamental role in the pathogenesis of AD, with implications for both diagnosis and treatment of this devastating disorder.
- Department of Neurology
Division of Neuromuscular Medicine
Education & Training
- PhD, 1982 Biological Chemistry, University of Cincinnati College of Medicine
- H. Houston Merritt Center for Muscular Dystrophy and Related Disorders
College of Physicians and Surgeons (P&S)630 West 168th Street
4th Floor Merritt Center
New York, NY 10032
- (212) 305-3836
- (212) 305-3986
- Email: firstname.lastname@example.org
Honors & Awards1968: Phi Lambda Upsilon, honorary chemistry society. 1981: First place winner, University of Cincinnati College of Medicine Graduate Student Research Competition. 1986: Sponsor of the winner of the S. Weir Mitchell Award of the American Academy of Neurology: "Transthyretin: a choroid plexus-specific protein in human brain". 1986: Prize for Best Poster, International Symposium on Molecular and Genetic Aspects of Inherited Diseases of the Nervous System and Skeletal Muscle, Saint-Vincent, Italy: "Cytochrome c oxidase deficiency: a molecular genetic approach." 1989: Lamport Award for Excellence in Research, Columbia University. 1992: The Sigrid Juselius Lecture, "Analysis of pathogenic mitochondrial DNA mutations in a novel tissue culture system," presented at the 7th European Bioenergetics Conference, Helsinki, Finland. 1997: The Laura Dribin Lecture, "Molecular genetics of human mitochondrial disease," presented at Children's Hospital of Philadelphia, Philadelphia, PA.
- Mitochondrial genetics and the molecular basis of human mitochondrial disease
- Kevin R. Velasco, Technician
1. Gilkerson RW, Schon EA, Hernandez E, Davidson MM: (2008) Mitochondrial nucleoids maintain genetic autonomy but allow for functional complementation. J. Cell Biol. 181: 1117-1128
2. Area-Gomez E, de Groof AJC, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE, Yaffe MP, Pon LA, Schon EA: (2009) Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am. J. Pathol. 175: 1810-1816
3. Area-Gomez E, Lara Castillo MdC, Tambini MD, de Groof AJC, Madra M, Ikenouchi J, Umeda M, Bird TD, Sturley SL, Schon EA: (2012) Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J. 31: 4106-4123
4.Tambini MD, Pera M, Kanter E, Yang H, Guardia-Laguarta C, Holtzman DM, Sulzer D, Area-Gomez E, Schon EA* (2016). ApoE4 upregulates the activity of mitochondria-associated ER membranes. EMBO Rep. 17, 27-36.
5. Siegmund S, Yang H, Sharma R, Javors M, Skinner O, Mootha V, Hirano M, Schon EA* (2017). Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome. Hum. Mol. Genet. 26, 4588-4605.
6. Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Chan RB, Di Paolo G, Mehler MF, Perumal GS, Macaluso FP, Freyberg ZZ, Acin-Perez R, Enriquez JA, Schon EA, Area-Gomez E (2017). Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J. 36, 3356-3371.
For a complete list of publications, please visit PubMed.gov