Pere Puigserver, PhD

Institution: Dana-Farber Cancer Institute
Research: Control of Nutrient and Energy Metabolism
Grants & Publications: Harvard Catalyst
Categories: Dana-Farber

Nutrient Sensing and Diabetes: Mammalian cells sense nutrients signals to reprogram energetic metabolism and trigger tissue specific responses within the context of whole animal physiology. For example, nutrient fluctuations during fed/fasting or diabetic conditions define specific metabolic functions in central and peripheral tissues. We have used the family of PGC-1 coactivators, key proteins in remodeling glucose and lipid metabolism, as a “scaffold” bait to identify nutrient sensing components. We have identified a new regulatory nutrient/metabolite pathway that impinges on the hyperacetylation of PGC-1s. Central sensing components within this pathway include metabolite sensitive enzymes such as the acetyl transferase GCN5 (responds to Acetyl-CoA levels), the deacetylase SIRT1 (responds to NAD+ levels) and components of the canonical cAMP pathway, and insulin/amino acid cell cycle components (Lee et al. 2014). We have also identified small molecules that control “acetylation” components with anti-diabetic effects (Sharabi et al. 2017). In the context of cell cycle components linked to obesity/diabetes, we have recently identified a specific vulnerability (Cyclin D1/CDK4) in liver tumors formed in obese/diabetic conditions (Luo et al. 2020). We have also identified NADPH regulatory pathways that are controlled by metabolic enzymes such ME1 (Balsa et al. 2020). Studies in cells and mouse models have shown that manipulation of these pathways is dysregulated in type 2 diabetes linked to obesity.

Mitochondrial Biology and Energy Metabolism: Energy expenditure is a key component of energy balance that, at the cellular level, requires oxidative metabolism through mitochondrial respiratory activities. We are interested in defining the regulatory control of how mitochondrial mass is formed, assembled and activated to generate energy and heat dissipation. We use traditional approaches in biochemistry, cellular biology and physiology in combination with new screening technologies, genetic/epigenetic and disease models. We have applied bioinformatic and genetic/proteomic tools to identify transcription factors that are pivotal to mitochondrial biology including the zinc finger YY1 and the co-activator PGC-1s and signaling kinases including Clk2 (Verdeguer et al. 2015; Hattings et al. 2017) and PERK (Balsa et al 2019; Latorre-Muro et al. 2021). In addition, we uncouvered new mechanisms whereby tetracyclines and mitochondrial translation rescue mitochondrial dysregulation and mutations in cells and mouse pre-clinical models (Perry et al. 2021).