Integrated proteomic and metabolomic analyses of the mitochondrial neurodegenerative disease MELAS

Authors

Haorong Li, Department of Chemistry, The George Washington University, Science and Engineering Hall, 800 22nd St., NW, Washington, DC 20052, USA. linghao@gwu.edu.
Martine Uittenbogaard, Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Ryan Navarro, Department of Chemistry, The George Washington University, Science and Engineering Hall, 800 22nd St., NW, Washington, DC 20052, USA. linghao@gwu.edu.
Mustafa Ahmed, Department of Chemistry, The George Washington University, Science and Engineering Hall, 800 22nd St., NW, Washington, DC 20052, USA. linghao@gwu.edu.
Andrea Gropman, Division of Neurogenetics and Neurodevelopmental Pediatrics, Children's National Medical Center, Washington, DC 20010, USA.
Anne Chiaramello, Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Ling Hao, Department of Chemistry, The George Washington University, Science and Engineering Hall, 800 22nd St., NW, Washington, DC 20052, USA. linghao@gwu.edu.

Document Type

Journal Article

Publication Date

1-4-2022

Journal

Molecular omics

DOI

10.1039/d1mo00416f

Abstract

MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is a progressive neurodegenerative disease caused by pathogenic mitochondrial DNA variants. The pathogenic mechanism of MELAS remains enigmatic due to the exceptional clinical heterogeneity and the obscure genotype-phenotype correlation among MELAS patients. To gain insights into the pathogenic signature of MELAS, we designed a comprehensive strategy integrating proteomics and metabolomics in patient-derived dermal fibroblasts harboring the ultra-rare MELAS pathogenic variant m.14453G>A, specifically affecting the mitochondrial respiratory complex I. Global proteomics was achieved by data-dependent acquisition (DDA) and verified by data-independent acquisition (DIA) using both Spectronaut and the recently launched MaxDIA platforms. Comprehensive metabolite coverage was achieved for both polar and nonpolar metabolites in both reverse phase and HILIC LC-MS/MS analyses. Our proof-of-principle MELAS study with multi-omics integration revealed OXPHOS dysregulation with a predominant deficiency of complex I subunits, as well as alterations in key bioenergetic pathways, glycolysis, tricarboxylic acid cycle, and fatty acid β-oxidation. The most clinically relevant discovery is the downregulation of the arginine biosynthesis pathway, likely due to blocked argininosuccinate synthase, which is congruent with the MELAS cardinal symptom of stroke-like episodes and its current treatment by arginine infusion. In conclusion, we demonstrated an integrated proteomic and metabolomic strategy for patient-derived fibroblasts, which has great clinical potential to discover therapeutic targets and design personalized interventions after validation with a larger patient cohort in the future.

APA Citation

Li, Haorong; Uittenbogaard, Martine; Navarro, Ryan; Ahmed, Mustafa; Gropman, Andrea; Chiaramello, Anne; and Hao, Ling, "Integrated proteomic and metabolomic analyses of the mitochondrial neurodegenerative disease MELAS" (2022). GW Authored Works. Paper 410.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/410

Department

Anatomy and Regenerative Biology