David Pagliarini
Washington University in St Louis, MO·Biochemistry
Mitochondria, the cell's energy-producing compartments, run much of the cell's metabolism. When they fail, the result can be rare inherited disorders or common diseases such as type 2 diabetes, fatty liver disease, Parkinson's and cancer.
- Fields
Biochemistry
Biology
Genetics
- Topics
mitochondria
orphan proteins
MitoCarta
- Grants
- 3 known grants, through May 2029
What they work on
- Determine the chemical reactions catalyzed by ACAD10 and ACAD11, two enzymes that prepare 4-hydroxy fatty acids for fat burning, and test whether their kinase domain adds a phosphate group at the 4-hydroxy position, using enzymology and structural biology.
- Test whether ACAD10 converts shorter-chain 4-hydroxy fatty acids in mitochondria while ACAD11 handles longer-chain ones in peroxisomes, using microscopy and metabolite tracing in cells.
- Test whether losing ACAD10 or ACAD11 in worms and mice, or carrying ACAD10 variants in Akimel O'odham (Pima Indian) people, causes 4-hydroxy fatty acids to build up in the blood along with metabolic complications.
- Assign functions to orphan mitochondrial proteins by combining multi-omic profiling of yeast and human gene knockouts, deep mutational scanning, genetic screens and mass spectrometry, then studying selected proteins with mechanistic and structural methods.
- Define how coenzyme Q, a fat-soluble electron carrier and antioxidant, is made in mitochondria and moved through the cell, and design small molecules to manipulate the proteins involved.
- Establish how phosphorylation of targets of the phosphatases PPTC7 and HDHD5 affects branched-chain amino acid and fatty acid breakdown, building on phosphoproteomic data from CRISPRi knockdown of 10 mitochondrial phosphatases.
- Define how the phosphatase PGAM5 shapes mitochondrial inner-membrane folds (cristae) by controlling phosphorylation of MICOS, the protein complex that organizes cristae.
More about the research
Yet hundreds of mitochondrial proteins still have no known job, and that gap makes these conditions hard to diagnose or treat. This research program works out what these uncharacterized "orphan" proteins do. It studies three connected questions: how cells break down unusual fats, how mitochondria make and use coenzyme Q, and how chemical tags called phosphate groups switch mitochondrial proteins on and off.
Why it matters
Mitochondrial dysfunction is involved in about 350 rare inborn errors of metabolism and in common diseases such as type 2 diabetes, obesity, fatty liver disease, kidney disease, heart failure, Parkinson's and cancer. By assigning functions to orphan proteins, linking 4-hydroxy fatty acids to specific physiological problems, and identifying phosphatases that control mitochondrial activity, this work could point to new diagnostic clues and therapeutic targets for disorders of fat breakdown and mitochondrial disease.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Vincent Tagliabracci
University of Texas Southwestern Medical Center, TX·Biochemistry
Test whether mammalian ACAD10 and its related gene ACAD11 make ether lipids, building on the finding that ACAD10's kinase and phosphatase parts carry out missing steps of this pathway in C. elegans.
Christopher Radka
University of Kentucky, KY·Microbiology & Immunology·Early-career
Determine how oleate hydratase (OhyA), a bacterial enzyme, extracts unsaturated fatty acid substrates from cell membranes, using crystal structures of OhyA bound to liposomes and mapping of its membrane-targeting domains.
Yong-Xu Wang
University of Massachusetts Chan Medical School, MA·Physiology
Test whether a newly identified adipokine, a hormone released by fat tissue, resolves NASH and associated metabolic problems in two different NASH mouse models.
The school
Washington University in St Louis: 97 labs on PI Pages, $1.2B a year on research, 365 research doctorates a year.
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