David J. Pagliarini, PhD

Urbauer Professor and BJC Investigator, Cell Biology & Physiology

Research Interests

Metabolic Regulation

Category(ies) of Research

Basic

Descriptor of Research

Mitochondria are iconic structures in biology, recognizable as the cellular “powerhouses” to most anyone who has taken a high school science curriculum. However, this familiarity deceptively implies that these organelles are simple, fully defined cellular machines. In reality, mitochondria possess hundreds of uncharacterized ‘orphan’ proteins; their classic bioenergetic pathways rely on countless unidentified enzymes, chaperones, and transporters; half of all diagnosed mitochondrial diseases are unresolved; and there are no FDA-approved drugs to treat mitochondrial dysfunction, which underlies hundreds of rare diseases and common metabolic and neurodegenerative disorders. These profound facts form the basis of my research program. Our goal is to understand mitochondrial metabolism holistically and at sufficient mechanistic depth to devise new rationale molecular therapies that will alleviate human disease. Our philosophy is that the greatest leaps forward toward this goal will come from a deliberate exploration of the dark, unexplored corners of this organelle. Our approach is thus to intentionally target orphan proteins, confident that with a blend of clever large-scale profiling and sound mechanistic biochemistry we can reveal their activities, integrate them into established pathways and processes, connect their dysfunction to unresolved diseases, and manipulate them through customized small molecule interventions.

PubMed