Medicine and Translational Research, Physiology
Massachusetts General Hospital
Dr. Mootha is also a professor of systems biology and medicine at Harvard Medical School, an investigator in the Department of Molecular Biology at Massachusetts General Hospital, and an institute member of the Broad Institute.
Mitochondria: From Molecular Circuitry to Physiology and Disease
Mitochondria, the tiny organelles that are the power plants of the cell, have several quirks. They have their own small genome, separate from the DNA in the cell's nucleus. Their genome is passed down only from mother to child. And they likely originated as bacteria that were engulfed by—and eventually incorporated into—eukaryotic cells. Problems with mitochondria result in a suite of unusual disorders and diseases. This odd combination of biology, history, and disease captured the imagination of a young Vamsi Mootha during his first semester of medical school. He was finding his MD program at Harvard University in Boston nowhere near as stimulating as his undergraduate studies in applied math, statistics, and computational biology at Stanford University. Between the onset of winter and his displeasure at the need for rote memorization, the Texas-raised, California-educated Mootha says, "I felt like I was in a blizzard, both outside and inside."
Hiding from the snow, he began flipping through a borrowed book on mitochondria. It was as if the storm had lifted. "I knew then that's what I wanted to work on," he says.
After two years in medical school, Mootha took a year-long break to study the organelles' biochemistry as part of the HHMI-NIH Research Scholars Program at the National Institutes of Health in Bethesda. When he returned to medical school the following year, he saw his first patient with a mitochondrial disorder. "It had a profound impact on me. The patient was so sick, with no options," he says. "Some organs were severely impacted, while others worked just fine. It was puzzling."
Throughout the rest of his clinical training, Mootha paid close attention to research on mitochondrial disease. He realized that the field was highly focused—perhaps detrimentally—on mitochondrial DNA. "Mitochondrial DNA is maternally inherited, but most of these disorders aren't," he says. Mitochondrial DNA is just a tiny proportion of a cell's genetic material; most DNA is contained in a cell's nucleus and is equal proportions maternal and paternal. Despite the fact that mitochondrial DNA is inherited only from the mother, most mitochondrial disorders appear to follow the rules of classic Mendelian inheritance, which is controlled by nuclear DNA.
Mootha finished his residency in 2001, just when the last of the human genome sequence was coming online. It was a perfect confluence of events: Mootha was in Boston, at the hub of human genome research, with an extensive background in computer science. He landed an HHMI physician postdoctoral fellowship doing computational genomics at the Whitehead Institute for Biomedical Research under the mentorship of Eric Lander. There, he developed a novel computational tool to interpret genome-wide expression data and began characterizing mitochondrial proteins coded for by nuclear DNA.
In 2004, he started up his own lab with joint appointments at Harvard Medical School and Massachusetts General Hospital and soon received a MacArthur fellowship. His team has combined computation and genomics to build MitoCarta: a parts list of the 1,100 proteins—most encoded by the nuclear genome—that make up human mitochondria. His goal: to use MitoCarta to better understand how the nuclear genome controls mitochondria. "Having a parts list is really valuable," Mootha says. "If you have a patient with mitochondrial disease you can now sequence all of these components to figure out which ones are broken." He has identified more than a dozen nuclear genes that, when affected, result in rare but destructive mitochondrial diseases.
Mootha has also been working to characterize the tiny organelles' physiology. His lab discovered the molecular identity of the mitochondrial calcium uniporter, a major channel of communication between the mitochondrion and its cell. From here, he hopes to delve deeper into signaling pathways affected by disease to create a path to develop therapeutics.
He also plans to use his background in computational genomics and high-throughput biology to create wiring diagrams of mitochondria. "Our goal is to reverse-engineer the mitochondria to understand how all of their components work together," Mootha says. "A complete, molecular wiring diagram of their circuitry will help us understand why defects originating within mitochondria give rise to so many diverse and often puzzling symptoms." And because mild mitochondrial dysfunction is part of virtually all age-associated diseases, Mootha hopes to use that wiring diagram to develop therapeutics that can mitigate not just mitochondrial but all age-related diseases.
His team's work has already led to genetic diagnostics, prenatal screens, and a more complete understanding of these misunderstood organelles. But Mootha still sees hundreds of mitochondrial components waiting to be characterized, a multitude of genetic and cellular pathways to be described, and the potential to find cures for some devastating disorders. With this rich path before him, the New England winters seem much less bleak.