Assistant Professor of Biochemistry
B.S. Indiana University of Pennsylvania
Ph.D. Johns Hopkins University
Adam Hughes' Lab Page
Adam Hughes' PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
Organelle Communication and Disease, Cell Biology, Organelle Quality Control, Nutrient Sensing, Aging, Metabolic Stress
Cells spatially organize pathways, metabolites, proteins, and more into membrane-bound structures called organelles. Over the years, it has become clear that a breakdown in organelle integrity is a hallmark of aging, and linked to the development of numerous age-related and metabolic disorders. These disorders range from common disease such as cancer, neurodegeneration, and diabetes, to rare genetic diseases including inborn errors of metabolism, lysosomal storage disorders, and mitochondrial disease. Despite the clear link between organelle decline and disease, our understanding of why aging leads to organelle failure, how organelle collapse impacts cellular fitness, and the adaptive mechanisms cells use to maintain organelle health during times of stress is limited.
Recent studies from our lab have raised the possibility that organelle failure may drive aging and disease by disrupting the spatial organization of metabolites and proteins that are normally maintained in these compartments. Current projects in the lab are tackling how organelles communicate with one another, how alterations in cellular metabolite pools and mis-location of cellular proteins drive toxicity during aging and disease, and how cells maintain organelle homeostasis in times of stress. We use a combination of genetic, molecular, and biochemical approaches in both yeast and human disease models to answer these questions. All projects described below share important connections with both common and rare age-related and metabolic disorders, including cancer, diabetes, neurodegeneration, inborn errors of metabolism, mitochondrial disease, and lysosome storage disorders.
Organelle Communication in Aging and Disease
Organelles are not static, isolated structures within cells. Rather, they are dynamic, and form a highly elaborate, interconnected network with each other. We are interested in understanding how organelles are functionally connected within cells, and how these pathways of communication break down during times of stress. Current work in the lab is focused on untangling the crosstalk between mitochondria and lysosomes, two organelles that play major roles in metabolism and quality control, and whose interlinked functional decline underlies aging and numerous diseases. Working in both yeast and mammals, we have begun to elucidate the mechanism(s) linking the function of these organelles, and we hope the results of these studies will open new avenues by which the decline in the function of mitochondria and lysosomes drive diseases such as neurodegeneration, cancer, diabetes, and lysosomal storage disorders.
Metabolite Toxicity as a Driver of Aging and Disease
Amino acids are a basic building block of life, serving as precursors for protein biosynthesis and other cellular metabolites, and as metabolic fuel for cellular energy production. However, like many metabolites, elevated levels of amino acids can become toxic, and function as drivers of aging, and both common (diabetes) and rare (inborn errors of amino acid metabolism) metabolic disorders. It has become clear in recent years that cells have evolved mechanisms to spatially compartmentalize amino acids within organelles, and recent work from our lab suggests that a breakdown in the function of the lysosome—a major amino acid sequestering organelle—impacts cellular health by causing localized amino acid toxicity. How elevated intracellular levels of amino acids are toxic for cells, and what amino acids are problematic is currently unknown. We are pursuing projects in both yeast and mammals to dissect mechanisms of amino acid toxicity, and to elucidate how elevated levels of amino acids underlie the development of a host of metabolic disorders, including diabetes and rare genetic diseases associated with faulty amino acid metabolism.
Organelle Remodeling During Nutrient Stress
Cells are fantastic at adapting, and have evolved sophisticated mechanisms to maintain the health of their organelles in response to a variety of stressors. We are actively pursuing mechanisms by which cells maintain organelle function during amino acid stress. Our work in this area has led to our recent discovery of a new structure in cells called the Mitochondrial Derived Compartment, or MDC. MDCs are large, lumen containing compartments that form from mitochondria in response to nutrient stress. These structures are highly dynamic, and appear to function as sorting depots for selective removal of proteins from the mitochondrial network. MDCs are conserved from yeast to mammals, and our working hypothesis is that they help maintain optimal mitochondrial health in times of metabolic stress. Current work is focused on understanding the function of this pathway, elucidating the metabolic cues that regulate formation of these structures, and identifying the protein machinery that governs MDC formation.
Quality Control of Mis-localized Mitochondrial Proteins
In addition to metabolic perturbations, a breakdown in organelle function also influences cellular health by altering protein homeostasis within cells. Cells must synthesize, fold, and deliver proteins to their proper intracellular destination—failure to do so results in severe cellular toxicity, and also functions as a driver of aging and age-related disorders. A prime example of this comes from mitochondria. Almost all mitochondrial resident proteins are synthesized on cytosolic ribosomes, and imported into mitochondria co- or post-translationally. Cytosolic precursor proteins cannot be imported into dysfunctional mitochondria—thus, a major consequence of mitochondrial impairment in cells is the toxic accumulation of non-imported mitochondrial precursor proteins. Current work in our lab is focused on elucidating mechanisms by which cells combat stress caused by non-imported mitochondrial proteins, and understanding whether these toxic precursors function as a driver of age-related disorders. Our recent results suggest that other organelles serve as triage centers for non-imported mitochondrial precursors, and may play a key role in protecting the cell during times of mitochondrial impairment.
- Schuler MH and Hughes AL. (2020). OPA1 and Angiogenesis: Beyond the Fusion Function. Cell Metabolism 31, 886-887.
- English AM, Kornmann B, Shaw JM, and Hughes AL. (2020). ER-Mitochondria Contacts Promote Mitochondrial-Derived Compartment Biogenesis. bioRxiv, doi: https://doi.org/10.1101/2020.03.13.991133.
Schuler MH, English AM, Campbell TJ, Shaw JM, and Hughes AL. (2020). Mitochondrial-Derived Compartments Facilitate Cellular Adaptation to Amino Acid Stress. bioRxiv doi: https://doi.org/10.1101/2020.03.13.991091
- Hughes CE, Coody TK, Jeong M, Berg JA, Winge DR, and Hughes AL. (2020). Cysteine toxicity drives age-related mitochondrial decline by altering iron homoeostasis. Cell 180, 296-310.
- English AM and Hughes AL. (2020). Knowing When to Let Go: Lysosomes Regulate Inter-Mitochondrial Tethering. (2020). Developmental Cell 50, 259-260.
Goodrum JM, Lever AR, Coody TK, Gottschling DE, and Hughes AL. (2019) Rsp5 and Mdm30 reshape the mitochondrial network in response to age-induced vacuole stress. Mol Biol Cell. May 29 mbcE19020094. doi: 10.1091/mbc.E19-02-0094.
Coody TK and Hughes AL. (2018). Advancing the aging biology toolkit. Elife 7, pii: e42976.
- Carmona-Gutierrez D, Hughes AL, Madeo F, Ruckenstuhl C. (2016). The crucial impact of lysosomes in aging and longevity. Review. Ageing Res Rev, 2016 Apr 26. pii:S1568-1637(16)30066-6. doi: 10.1016/j.arr.2016.04.009. [Epub ahead of print]
- Hughes AL, Hughes CE, Henderson KA, Yazvenko N, Gottschling DE. (2016). Selective sorting and destruction of mitochondrial membrane proteins in aged yeast. Elife, 5. pii: e13943. doi: 10.7554/eLife.13943.
- Rutter J and Hughes AL. (2015). Power(2): the power of yeast genetics applied to the powerhouse of the cell. Trends Endocrinol Metab, 26, 59-68.
- Henderson KA, Hughes AL, and Gottschling DE. (2104). Mother-daughter asymmetry of pH underlies aging and rejuvenation in yeast. Elife, 3:e03504.
- Hughes AL and Gottschling DE. (2012). An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature, 492, 261-265.
- Burg JS, Powell DW, Chai R, Hughes AL, Link AJ, and Espenshade PJ. (2008). Insig regulates HMG-CoA Reductase by controlling enzyme phosphorylation in fission yeast. Cell Metabolism 8, 522-531.
- Hughes AL, Stewart EV, and Espenshade PJ. (2008). Identification of 23 mutations in fission yeast Scap that constitutively activate SREBP: A comparative analysis with hamster Scap. J of Lipid Research 49, 2001-2012.
- Espenshade PJ and Hughes AL. (2007). Regulation of sterol synthesis in eukaryotes. Annu Rev Genetics 41, 401-427.
- Hughes AL, Lee CS, Bien CM, and Espenshade PJ. (2007). 4-Methyl sterols regulate fission yeast SREBP-Scap under low oxygen and cell stress. J Biol Chem 282, 24388-24396.
- Lee H, Bien CM, Hughes AL, Espenshade PJ, Kwon-Chung KJ, and Chang YC. (2007). Cobalt chloride, a hypoxia-mimicking agent, targets sterol synthesis in the pathogenic fungus Cryptococcus neoformans. Molecular Microbiology 65, 1018-1033.
- Hughes AL, Powell DW, Bard M, Eckstein J, Barbuch R, Link AJ, and Espenshade PJ. (2007). Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes. Cell Metabolism 5, 143-149.
- Todd BL, Stewart EV, Burg JS, Hughes AL, and Espenshade PJ. (2006). Sterol regulatory element binding protein is a principal regulator of anaerobic gene expression in fission yeast. Mol Cell Biol 26, 2817-31.
- Hughes AL, Todd BL, and Espenshade PJ. (2005). SREBP pathway responds to sterols and functions as an oxygen sensor in fission yeast. Cell 120, 831-42.
- Warren CD, Eckley DM, Lee MS, Hanna JS, Hughes A, Peyser B, Jie C, Irizarry R, and Spencer FA. (2004). S-phase checkpoint genes safeguard high-fidelity sister chromatid cohesion. Mol Biol Cell 15, 1724-35.