Gerald S Shadel, PhD

Professor of Pathology and of Genetics; Joseph A. and Lucille K. Madri Professor of Experimental Pathology; Director, Yale Center for Research on Aging (Y-Age)

Research Interests

Aging; Ataxia Telangiectasia; DNA Repair; DNA Replication; Genetics; Hearing Loss, Central; Immune System; Immunity, Innate; Mitochondria; Pathology; Saccharomyces cerevisiae; Transcription, Genetic; Protein Biosynthesis; Signal Transduction; Mice

Research Organizations

Pathology: Pathology Research | Shadel Lab

Cancer Center, Yale: Genomics, Genetics, and Epigenetics

Integrative Cell Signaling & Neurobiology of Metabolism (ICSNM)

Office of Cooperative Research

Research Summary

My research focuses on the important area of mitochondria in disease, aging and the immune system. My group has 1) made seminal contributions to the current understanding of mitochondrial gene regulation and mtDNA metabolism, 2) pioneered aging studies showing that mitochondrial respiration and ROS signaling are key components of conserved longevity pathways, and 3) developed and analyzed novel animal models of mitochondrial diseases and stress responses. For example, we identified mitochondrial dysfunction and oxidative-stress signaling as key elements of the multi-factorial, neurodegenerative disease Ataxia-Telangiectasia and developed the first mouse model of a human pathogenic mtDNA point mutation (a common cause of deafness). We also discovered that mtDNA stress is a trigger for the innate immune response and a cell-intrinsic antiviral signal that has implications for autoimmune diseases, cancer and age-related pathology. In total, my research has shown that the role of mitochondria in disease and aging transcends simple energetic decline and ROS damage and involves complex interactions with cellular stress pathways, where ROS (and other mediators) serve as context-dependent signaling molecules. The ultimate goal of our studies is to apply this new information on mitochondrial function and pathogenesis toward novel treatments for common human diseases and age-related pathology that involve deregulation of mitochondrial and metabolic pathways.

Specialized Terms: Mitochondria; mtDNA; Biogenesis; Mitochondrial Dysfunction; Human Disease; Aging; Transcription; Translation; Signal Tranduction; Cancer; Deafness; Immunity

Extensive Research Description

The studies in my laboratory have as their basis basic research into the mechanism of mitochondrial gene expression (i.e. mtDNA transcripiton, translation, ribosome biogenesis, RNA processing and replication/repair). Following this path also led me into novel ways that mitochondria contribute to disease, aging and the immune system. Below are four major areas of focus:


1. Role of mitochondria in disease pathology. Several important lines of investigation from my lab have led a greater understanding of the multiple ways mitochondria contribute to human disease pathology and leading to the general concept that mitochondrial dysfunction is remarkably tissue-specific and transcends simple reductions in energy metabolism. I will provide two salient examples. First, as part of our ongoing efforts to define factors required for human mtDNA expression, we cloned a mitochondrial ribosomal RNA methyltranferase called TFB1M that is an ortholog of a yeast mitochondrial transcription factor. Soon thereafter we found that cell lines derived from patients with the common deafness-associated mtDNA mutation A1555G have increased rRNA methylation by TFB1M that causes heightened susceptibility to apoptosis. Accordingly, we made a transgenic mouse that over-expresses TFB1M, hypothesizing that it would increase methylation at this site and cell death that underlies the deafness pathology in human patients and showed that these mice progressively lose their hearing due to specific pathology in tissues in the inner ear. This is the first mouse model of a inherited human pathogenic point mutation that recapitulates the tissue-specific pathology of the disease. A second example represents the translation into mammals of early yeast discovery studies in my lab showing that mtDNA stability is regulated by the yeast homologs of the mammalian DNA-damage response kinases ATM/ATR. Human cell lines from patients with the disease Ataxia-Telangiectasia (A-T), caused by loss of the ATM kinase, have depleted amounts of mtDNA due to deregulation of the enzyme ribonucleotide reductase. This study is broadly impactful because it was the first to show that mtDNA defects are part of this disease and that the de novo pathway of dNTP synthesis is involved in mtDNA replication/repair in mammalian cells. A-T is a multi-factorial disease involving neurodegeneration, cancer predisposition, sterility, and oxidative stress. Our studies and others have shown that mitochondrial dysfunction may underlie some of the diverse pathology of this disease. Finally, toward potential therapy, we have shown that reducing mitochondrial ROS in the mouse model of A-T delays their cancer and immunological phenotypes.


2. Mitochondrial ROS signaling in aging and longevity. With the dramatic shift toward an older human population demographic and a corresponding rise in age-related diseases, there is currently heightened interest in understanding molecular mechanisms underlying the aging process because of the potential to unlock interventions to effect healthy aging (i.e. to increase healthspan). Mitochondria have long been implicated in aging, being central to the long-held “mitochondrial” and “free radical” theories that suggest functional declines in energy metabolism and increased ROS-mediated damage are causative. However, recent advances, including those I will summarize here from my lab, have redefined how mitochondria fit into the major longevity pathways and influence aging by novel mechanisms. Reduced signaling through the mechanistic target of rapamycin (mTOR) pathway is a conserved, anti-aging mechanism, most recently demonstrated by the ability of rapamycin to extend murine lifespan. The nutrient-sensing, mechanistic target of rapamycin (mTOR) pathway was discovered in yeast and we used this model system to probe the mechanism of longevity regulation mediated by reduced signaling through mTOR complex 1 (mTORC1). We found that reduced mTORC1 signaling extends yeast chronological lifespan by flipping a switch in metabolism toward mitochondrial respiration. It does this by increasing mitochondrial translation and OXPHOS complex density as opposed to increasing mitochondrial biogenesis. Even more intriguing, we eventually uncovered that that this resulted from a burst of mitochondrial ROS that cause via signaling (not damage) adaptive changes in nuclear gene expression and increased stress resistance. Specifically, we found that mitochondrial ROS signal through the yeast homolog of ATM (Tel1p) to epigentically silence subtelomeric chromatin by inactivating a histone H3K36 demethylase called Rph1p. Our yeast studies, in combination with studies by others in C. elegans and mice, has led to a paradigm shift in our thinking about mitochondrial stress in aging, where mitochondrial stress signals like ROS activate adaptive pro-longevity responses (sometimes referred to as “mitohormesis”). Ongoing efforts in my lab are directed toward translating these exciting studies into mammals to understanding how mitochondrial stress impacts aging and age-related disease.


3. Mitochondria and mtDNA in the immune system. The role of mitochondria in regulating the immune system is a burgeoning and exciting area. In this context, mitochondria are not only needed for the high proliferation capacity and specialized metabolism of specific immune cell types, but also for novel functions in pathogen recognition (e.g. through the mitochondrial antiviral protein MAVS), antiviral signaling and inflammatory responses that are areas of intense interest currently. Through several active collaborations with members of the Yale Immunobiology Department, I entered this field several years ago and am now pursuing it as a primary area of investigation in my lab. The major advances I have made in this area so far include 1) in collaboration with Susan Kaech, we showed that there is a burst of mitochondrial biogenesis during T cell receptor activation in CD8+ T cells that involves mTOR and AMP kinase signaling, and that there are memory T cell defects in the disease Ataxia-telangiectasia, 2) in collaboration with Sankar Ghosh, we demonstrated that mitochondrial ROS are involved directly in killing bacteria, mediated by recruitment of the TLR signaling protein TRAF6 to mitochondria, where it interacts with and ubiquitinates the mitochondrial complex I protein ECSIT to increase the rate of mitochondrial ROS production, 3) In collaboration with Akiko Iwasaki, we showed that mitochondrial ROS are involved in antiviral RLR signaling, and 4) we made the exciting discovery that mtDNA stress primes the innate immune system. Specifically, we showed that certain DNA viruses attack mtDNA, which leads to activation of interferon stimulated gene activation and enhanced type 1 interferon production. This is mediated by reduced expression of the mtDNA-binding protein TFAM, hyper-fusion of mitochondria, and release of mtDNA into the cytoplasm, where it activated the DNA-sensor, cGAS. I believe that the multi-faceted roles of mitochondria in the immune system and inflammatory responses will turn out to be a key element in how mitochondria are involved in human disease pathology and aging and hence I am actively pursuing this concept.


4. Mechanism of mitochondrial gene expression. This is the general area that I have worked in for >20 years. Mitochondrial DNA (mtDNA) encodes thirteen essential proteins of the oxidative phophorylation system, as well as two rRNAs and 22 tRNAs needed to translate these on dedicated mitochondrial ribosomes. The circular mtDNA molecule is transcribed in both directions to generate polycistronic primary transcripts that need to be extensively processed to liberate the mature RNA species. The machinery required for all of these events is encoded by nuclear genes and imported into the organelle, but remain far from fully defined or understood. Furthermore, the mechanism of mitochondrial gene expression has features of bacterial, viral, and nuclear systems that have been challenging to unravel. My lab has made many breakthroughs in this area that are summarized as follows: 1) my lab cloned the first mammalian homolog of the essential yeast transcription factor Mtf1p, called mtTFB1 (or TFB1M) and showed it was evolutionarily related to bacterial rRNA methyltransferases. Mammals have two paralogs of this class of proteins, TFB1M and TFB2M that we have shown have cooperative functions in transcription and translation, with TFB1M having a more prominent role in the latter and involved in maternally inherited deafness. 2) We have shown that the other major transcription factor in mitochondria TFAM is a context-dependent activator of transcription (as opposed to a requisite core component of the initiation complex), and can even directly repress transcription at one of the mtDNA promoters (work we did in collaboration with Craig Cameron at Penn State). 3) We have uncovered that mitochondrial RNA polymerase (Rpo41p in yeast, POLRMT in mammals) is involved in additional molecular interactions that regulate transcription, couple additional activities to transcription, or mediate transcription-independent functions.

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