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, and nutrient sensing
We study the basic cell biology of organelles. These remarkable structures are a necessary
evil for eukaryotic cells. On one hand, they provide important compartmentalization
of diverse cellular activities such as DNA replication, metabolite synthesis and storage,
and proteolytic degradation. On the other, the division of cellular activities into
distinct compartments requires intricate pathways of organelle crosstalk and quality
control that are essential for cells to maintain organelle homeostasis in various
environments. It has become increasingly clear in recent years that failure to maintain
organelle integrity is a hallmark of the aging process across species, and serves
as the underlying molecular basis for a number of age-associated diseases including
Parkinson’s, Alzheimer’s, diabetes, and lysosomal storage disorders.
We are interested in identifying mechanisms cells use to achieve organelle homeostasis, and understanding how failure to maintain organelle integrity contributes to aging and the development of age-associated diseases. More specifically, we are working to identify and characterize new pathways of organelle crosstalk and quality control, and determine how aging and metabolic state impact organelle function and integrity. Our work is primarily carried out in budding yeast, utilizing a variety of genetic, cell biological, and biochemical approaches. The pathways we study in yeast are relevant to human disease, and our goal is to eventually translate our results from yeast into mammalian systems. Our current work focuses on three projects centered around two organelles with important roles in aging and metabolism: the mitochondria and lysosome (vacuole in yeast).
Mitochondrial Quality Control
Mitochondrial dysfunction is a hallmark of the aging process across organisms. Cells are equipped with quality control mechanisms to detect and respond to mitochondrial stress, including the recently characterized PINK1/Parkin pathway, which regulates mitochondrial dynamics to promote clearance of dysfunctional mitochondria by autophagy. Mutations in this pathway prevent turnover of dysfunctional mitochondria and lead to the development of juvenile-onset Parkinson’s disease, which illustrates the importance of organelle dysfunction in age-associated diseases. Although yeast have no obvious sequence homologs of PINK1 or Parkin, we recently discovered a pathway functionally similar to the PINK1/Parkin pathway in yeast that is activated by age-induced mitochondrial dysfunction. We are currently using microscopy-based screens alongside in vitro reconstitution assays to identify new genes required for this pathway and to understand mechanistically how mitochondria are degraded by autophagy at a genome-wide level.
Lysosomes play an important role in protein turnover and metabolite storage, and lysosomal dysfunction has been linked to aging and age-associated diseases such as Parkinson’s and Alzheimer’s disease. In a screen designed to identify causes of mitochondrial dysfunction in aged yeast cells, we uncovered a metabolic connection between the yeast lysosome-like vacuole and mitochondria that regulates the aging process. We found that loss of lysosomal function compromises mitochondrial function during aging, and our current hypothesis is that failure to store amino acids in dysfunctional lysosomes is what leads to mitochondrial problems with age. We are currently conducting genetic screens and using metabolite profiling to identify the metabolite(s) and mechanism(s) responsible for lysosome-regulation of mitochondrial function.
Nutrient Regulation of Lysosomal Acidity
Lysosomes are acidic organelles, and this acidity is required for their ability to degrade proteins and store metabolites. As part of our characterization of age-related changes to lysosome function and lysosome-mitochondria crosstalk in yeast, we discovered that lysosomal acidity (pH) is regulated by glucose, and showed that glucose regulation of lysosomal pH is a critical part of the mechanism through which calorie restriction extends lifespan, a phenomenon widely conserved across organisms. We are now working to determine the molecular mechanisms through which glucose regulates lysosomal pH in yeast, and also examining metabolic regulation of lysosomal acidity in mammalian cells. Understanding how nutrients regulate lysosomal function will likely have important implications for understanding how nutrients regulate aging and age-associated diseases.
- 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.