Dave Pagliarini

Settling the mysteries of the mitochondria

Dave Pagliarini

Dave Pagliarini

Director, Metabolism Research Group


As happens in science, my path to metabolic and mitochondrial research came from an unexpected discovery. Not knowing what to do next in my thesis work, I decided to determine where the protein I was studying “lived” in the cell. The strange, bright green pattern I stared at was unrecognizable to me then, but is now unmistakable—mitochondria! At that time, I knew very little about these tiny cellular machines. That is, I knew what everyone knows—that they are the “powerhouses of the cell.” It turned out that I had a bit of catching up to do.

Mitochondrial biology has undergone vast transformations unforeseen by the scientist that unlocked the mysteries of “oxidative phosphorylation” decades ago. It is certainly still true that the ten million billion mitochondria throughout our bodies (about 10 percent of our mass) produce nearly all of our cellular energy in the form of a molecule called ATP. But this simplistic concept of these organelles as discrete, kidney bean-shaped energy factories has given way to that of a cell-specific, dynamic network that fuses, divides and directs a vast array of functions central to cellular life, death and differentiation.

Importantly, it has also become clear that mitochondrial dysfunction underlies more than 50 inborn errors of metabolism, strongly contributes to a growing list of common disorders including type II diabetes, Parkinson’s disease and cancer, and is central to the aging process.

And yet, hundreds of mitochondrial genes still remain mere database entries with no known function, and an even greater number of patients live with mitochondrial disorders with no available treatment, or no known cause.

Since that fateful moment at the microscope, I have become a bona fide “mitochondriac.” I spent my remaining graduate years studying mitochondrial signaling proteins and how cells turn their functions on and off. If my doctoral work taught me how to leverage focused biochemistry to dig deeply into discrete aspects of a problem, my postdoctoral training taught me to employ the new tools of genomics and “systems biology” to see the all the moving parts.

At Harvard Medical School, I led an interdisciplinary study aimed at answering a surprisingly open question: What are mitochondria made of? Using state-of-the-art technology, high-powered computing, and old-fashioned biochemistry, we helped to identify hundreds of new mitochondrial proteins, to reveal how these organelles differ in tissues throughout our bodies, and to discover new mitochondrial proteins that are mutated in human disease.

The resource we developed, which we call the MitoCarta, now serves as the foundation for our work at Morgridge. My group and I are driven to understand the biochemical underpinnings of mitochondrial dysfunction in human diseases. If we can arrive at a clear, fundamental understanding of the obscure, disease-related processes that still elude our grasp, we have the potential to contribute to real cures.

Fearless Science

Science moves. It unlocks mysteries in medicine and opens new doors in human health. But science doesn’t thrive by asking safe questions. It moves when we push fearlessly into new frontiers. This Spring 2018 report explores science with the promise to move our lives.

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