Oxidative phosphorylation (OXPHOS) refers to the cell's core biochemical pathway for generating ATP. During the past 20 years, it's become abundantly evident that both inborn errors of metabolism as well as common, degenerative diseases stem from OXPHOS dysfunction. How defects in a single pathway transmit to other biochemical pathways to give rise to so many different syndromes and diseases is not clear. Moreover, diagnosing the inborn errors of mitochondrial metabolism is incredibly challenging. We hypothesize that a variety of biochemical pathways are conditionally activated in response to OXPHOS dysfunction, to permit the cell to adapt to the disease state. Using emerging """"""""metabolomics"""""""" technologies, we propose to systematically identify such coupled biochemical pathways. We will utilize cells in culture as well as humans with known OXPHOS genetic diseases and profile cellular and plasma metabolites to determine how cellular metabolism adapts to defects in OXPHOS. The biochemical networks we uncover may shed insights into disease pathogenesis, may be targeted for therapy, and may immediately provide a biomarker for OXPHOS disease. The current study should lay the foundation for better understanding the role of OXPHOS in a number of common human diseases.

Public Health Relevance

We have recently discovered a key cellular pathway that is altered in metabolic disorders such as diabetes. Using novel measurement technologies, we hope to better understand how alterations in these pathways give rise to disease in cells as well as in humans. If successful, our research could assist in the diagnosis of metabolic diseases, and also help motivate the design of novel therapies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Castle, Arthur
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Delaney, Nigel F; Sharma, Rohit; Tadvalkar, Laura et al. (2017) Metabolic profiles of exercise in patients with McArdle disease or mitochondrial myopathy. Proc Natl Acad Sci U S A 114:8402-8407
Bao, Xiaoyan Robert; Ong, Shao-En; Goldberger, Olga et al. (2016) Mitochondrial dysfunction remodels one-carbon metabolism in human cells. Elife 5:
Thompson Legault, Julie; Strittmatter, Laura; Tardif, Jessica et al. (2015) A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome Cell Rep 13:981-9
Lennerz, Belinda S; Vafai, Scott B; Delaney, Nigel F et al. (2015) Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans. Mol Genet Metab 114:73-9
Strittmatter, Laura; Li, Yang; Nakatsuka, Nathan J et al. (2014) CLYBL is a polymorphic human enzyme with malate synthase and ?-methylmalate synthase activity. Hum Mol Genet 23:2313-23
Nilsson, Roland; Jain, Mohit; Madhusudhan, Nikhil et al. (2014) Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun 5:3128
McCormack, S E; Shaham, O; McCarthy, M A et al. (2013) Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents. Pediatr Obes 8:52-61
Jain, Mohit; Nilsson, Roland; Sharma, Sonia et al. (2012) Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336:1040-4
Leoni, Valerio; Strittmatter, Laura; Zorzi, Giovanna et al. (2012) Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations. Mol Genet Metab 105:463-71
Shaham, Oded; Slate, Nancy G; Goldberger, Olga et al. (2010) A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells. Proc Natl Acad Sci U S A 107:1571-5

Showing the most recent 10 out of 14 publications