Jerry Vockley, MD, PhD

  • Cleveland Family Endowed Chair in Pediatric Research, University of Pittsburgh
  • Professor of Human Genetics, University of Pittsburgh Graduate School of Public Health
  • Chief, Division of Medical Genetics, Children’s Hospital of Pittsburgh
  • Director, Center for Rare Disease Therapy, Children’s Hospital of Pittsburgh

Education & Training

  • Graduate School – University of Pennsylvania – PhD – Genetics
  • Medical School – University of Pennsylvania – MD
  • Residency – University of Colorado Health Sciences Center – Pediatrics
  • Fellowship – Yale University School of Medicine – Pediatrics & Human Genetics

Research Grants

NIH Grants:  R01, R13

Research Summary

The acyl-CoA dehydrogenases (ACDs) are a family of 1l mitochondrial enzymes involved in fatty acid and amino acid metabolism which catalyze the transfer of electrons from various acyl-CoA esters to electron transfer flavoprotein. Biochemical and immunological studies have identified 11 distinct members of the ACD enzyme family, each with a narrow substrate specificity. Long, medium and short chain acyl-CoA dehydrogenases (LCAD, MCAD and SCAD) catalyze the first step in the b-oxidation cycle with substrate optima of 16, 8 and 4 carbon chains, respectively. Isovaleryl-CoA dehydrogenase (IVD) and 2-methyl branched chain acyl-CoA dehydrogenase (2-meBCAD) catalyze the third step in leucine and isoleucine/valine metabolism, respectively. Each mature enzyme is a homotetramer and each monomer contains a non-covalently bound flavin molecule (FAD) as a prosthetic group. Deficiencies of all these enzymes except 2-meBCAD have been shown to cause disease in humans. One of these conditions (MCAD deficiency) may be the most common inborn error of metabolism in humans. My laboratory focuses on the use of molecular genetic techniques to investigate structure/function relationships in the ACD gene family at the molecular level and relate this information to mutations responsible for clinical deficiencies of these enzymes. I have a special focus on the structural aspects of mitochondrial proteins and their interactions to form protein complexes that function as coordinated metabons. Specific topics of interest in my lab include:

  1. Analysis of the complex pathway of ACD maturation, focusing on the process of assembly of the enzymes
  2. Expression analysis and computer-aided molecular modeling of mutant alleles from patients with deficiencies of these enzymes as a source of naturally occurring mutations of functional significance
  3. Characterization of structure/function relationships important in the active site, tetramerization, and interactions with other related mitochondrial proteins
  4. Novel therapy for deficiencies of these enzymes
  5. Functional and structural interactions of the three major pathways of mitochondrial energy pathway
  6. Contribution of energy dysfunction to common disease. We use metabolomic, proteomic, and structural biology approaches to study functional interactions of this family of proteins, molecular biology techniques to identify and characterize new disease-causing genes and mutations in know ones and apply our knowledge of these processes to design new drugs to treat inborn errors of metabolism.

I have an active clinical research program designing and participating in clinical projects to test the efficacy of novel treatments for metabolic disorders. I have mentored numerous graduate and MD, PhD students, medical students, post-doctoral fellows, and junior faculty. I am the founder and continue to lead the Society for Metabolic Disorders North American Metabolic Academy, a week-long course introduce the field of inborn errors of metabolis to medical genetics residents, and routinely teach in its European counterpart.

Representative Publications

  1. Ghaloul-Gonzalez L, Goldstein A, Walsh Vockley C, Dobrowolski SF, Biery A, Irani A, Ibarra J, Morton DH, Mohsen AW, Vockley J. (2016). Mitochondrial respiratory chain disorders in the Old Order Amish population. Mol Genet Metab. 118: 296-303. .
  2. Pena LD, van Calcar SC, Hansen J, Edick MJ, Walsh Vockley C, Leslie N, Cameron C, Mohsen AW, Berry SA, Arnold GL, Vockley J. (2016). Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 118: 272-81. PMC4970910.
  3. Bloom K, Mohsen AW, Karunanidhi A, El Demellawy D, Reyes-Mugica M, Wang Y, Ghaloul-Gonzalez L, Otsubo C, Tobita K, Muzumdar R, Gong Z, Tas E, Basu S, Chen J, Bennett M, Hoppel C, Vockley J. (2018). Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus. J Inherit Metab Dis. 41: 49-57. PMC5524623.
  4. Leipnitz G, Mohsen AW, Karunanidhi A, Seminotti B, Roginskaya VY, Markantone DM, Grings M, Mihalik SJ, Wipf P, Van Houten B, Vockley J. (2018). Evaluation of mitochondrial bioenergetics, dynamics, endoplasmic reticulum-mitochondria crosstalk, and reactive oxygen species in fibroblasts from patients with complex I deficiency. Sci Rep. 8: 1165. PMC5773529.
  5. McCalley S, Pirman D, Clasquin M, Johnson K, Jin S, Vockley J. (2019). Metabolic analysis reveals evidence for branched chain amino acid catabolism crosstalk and the potential for improved treatment of organic acidurias. Mol Genet Metab. In Press: Pending.
  6. Seminotti B, Leipnitz G, Karunanidhi A, Kochersperger C, Roginskaya VY, Basu S, Wang Y, Wipf P, Van Houten B, Mohsen AW, Vockley J. (2019). Mitochondrial energetics is impaired in very long-chain acyl-CoA dehydrogenase deficiency and can be rescued by treatment with mitochondria-targeted electron scavengers. Human Molecular Genetics. 28: 928-41. PMC6400046.
  7. Vockley J, Burton B, Berry GT, Longo N, Phillips J, Sanchez-Valle A, Tanpaiboon P, Grunewald S, Murphy E, Bowden A, Chen W, Chen CY, Cataldo J, Marsden D, Kakkis E. (2019). Results from a 78-week, single-arm, open-label phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders (LC-FAOD). J Inherit Metab Dis. 42: 169-77. PMC6348052.
  8. Wang Y, Palmfeldt J, Gregersen N, Makhov AM, Conway JF, Wang M, McCalley SP, Basu S, Alharbi H, St Croix C, Calderon MJ, Watkins S, Vockley J. (2019). Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex. Journal of Biological Chemistry. 294: 12380-91.PMC6699831.