Gerald S. Shadel, Ph.D.



Professor of Pathology and Genetics;
Director of Graduate Studies (DGS), Experimental Pathology Graduate Program.

Department of Pathology
Yale University School of Medicine
P.O. Box 208023
310 Cedar St., BML 371
New Haven, CT 06520-8023

Office: 203-785-2475
Lab: 203-785-2458
Fax: 203-785-2628

email: gerald.shadel@yale.edu


Training:
EDUCATION:

Postdoctoral Fellow, Stanford University, Palo Alto, CA

Ph.D. Biochemistry (1991), Texas A&M University, College Station, TX

B.S. Chemistry (1986), University of Nevada, Las Vegas

AWARDS:

2007 Amgen Outstanding Investigator/American Association for Investigative Pathology

2006 Glenn/AFAR Breakthroughs in Gerontology (BIG) Award

Damon Runyon-Walter Winchell Cancer Research Fund Postdoctoral Fellow (1992-1995)





Expertise:
Mitochondrial Diseases and Aging; Regulation of Mitochondrial Gene Expression and mtDNA Replication; Biochemical Mechanisms of Transcription Initiation; Genetic Analysis in Bacteria, Yeast and Mouse Model Systems; Mitochondrial DNA Damage and Repair Pathways; Signaling Pathways that Control Mitochondrial Biogenesis and Activity

Research Interests:
In humans, as in most animal cells, genetic information is housed not only in the nucleus, but also in mitochondria. Mitochondrial DNA (mtDNA) encodes thirteen essential proteins of the oxidative phosphorylation complexes as well as 22 tRNAs and 2 rRNAs required to translate these thirteen mRNAs in the mitochondrial matrix. Mutations in mtDNA cause maternally inherited neuromuscular disorders due to declines in cellular energy metabolism. In addition, mtDNA mutations accumulate in normal aging tissues, certain tumors, and have been implicated in late-onset diseases such a Alzheimer's, Parkinson's, and diabetes, indicating that the pathology of dysfunctional mitochondria is only beginning to be unraveled. The research in my laboratory is directed toward understanding the mechanism of gene expression in human mitochondria and its impact on human aging and disease. The ultimate goal is to understand the full impact of dysfunctional mitochondrial gene expression on human health and use this information to design specific interventions to treat mitochondria-based disease and age-related pathology.

Specifically, we focus on nucleus-encoded factors that are imported into the organelle to regulate transcription, translation, replication, and maintenance of mtDNA. We are also concerned with signaling pathways that connect the nuclear and mitochondrial genomes to coordinate gene expession patterns in both compartments. We use multiple approaches to this problem including the employment of mouse and yeast (S. cerevisiae) genetic model systems, biochemical characterization of mitochondrial transcription events and interactions, and in vivo approaches in cultured mammalian cells.


Professional Service:
Editorial Board of the journal "Mitochondrion" and managing editor "Mitomatters" section of the journal
American Association for the Advancement of Science (AAAS)
American Society for Biochemistry and Molecular Biology (ASBMB)
Mitochondrial Research Society (MRS)
American Society for Investigative Pathology (ASIP)
2008, Co-organizer, HHMI/Janelia Farm meeting on "New Frontiers in Mitochondrial Science: Integration into Cell Signaling"
2009, American Federation for Aging Research (AFAR) scientific review panel
2010, Co-organizer, ASIP meeting on the role of Mitochondria in Human Disease and Longevity

Other Links:

Shadel Lab
Mitochondrial Protein Database
Mitochondrial Research Society
Shadel Genetics Department Website
United Mitochondrial Disease Foundation (UMDF)
American Association for Investigative Pathology

Selected Publications:

Cotney J, McKay SE, Shadel GS. (2009) Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness. Human Molecular Genetics. 18:2670-82.

Pan, Y and Shadel, GS. (2009) Extension of chronological life span by reduced TOR signaling requires Sch9p and involves increased mitochondrial OXPHOS complex density. Aging. 1: 131-145. (see article and accompanying commentary at: http://www.impactaging.com/issues/v1/n1/contents.html).

Shadel, GS. (2008) Expression and maintenance of mitochondrial DNA: new insights into human disease pathology. American J. of Pathology. 172:1445-56. AMGEN OUTSTANDING INVESTIGATOR REVIEW.

Bonawitz ND, Chatenay-Lapointe M, Pan Y, Shadel GS. (2007) Reduced TOR Signaling Extends Chronological Life Span via Increased Respiration and Upregulation of Mitochondrial Gene Expression. Cell Metabolism 5:265-77. [see additional commentary by Bonawitz ND and Shadel GS. (2007) Rethinking the mitochondrial theory of aging: the role of mitochondrial gene expression in lifespan determination. Cell Cycle 6:1574-1578]

Eaton, JS et al. (2007) Ataxia-Telangiectasia Mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis. Journal of Clinical Investigation. 117:2723-2734.

Cotney J, Wang Z, Shadel GS. (2007) Relative abundance of the human mitochondrial transcription system and distinct roles for h-mtTFB1 and h-mtTFB2 in mitochondrial biogenesis and gene expression. Nucleic Acids Res. 2007;35(12):4042-4054.

Bonawitz ND, Clayton DA, Shadel (2006) Initiation and beyond: multiple functions of the human mitochondrial transcription machinery. Molecular Cell 24:813-25.

Reviews and Commentaries: Shadel, GS (2005) "Mitochondrial DNA, Aconitase wraps it up" Trends in Biochemical Sciences 30:294-296. Shadel GS (2004) "A dual-function mitochondrial transcription factor tunes out deafness" Molecular Genetics and Metabolism. 82:1-3. Shadel GS. (2004) Coupling the mitochondrial transcription machinery to human disease. Trends Genet. 2004 Oct;20(10):513-9.

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This page was last modified on: 08/25/2009