2. Academic Validation
  3. MARBL: A Live-Cell Method for Profiling Bioenergetic Heterogeneity by Noncanonical Methionine Labeling of the Cell Surface Proteome

MARBL: A Live-Cell Method for Profiling Bioenergetic Heterogeneity by Noncanonical Methionine Labeling of the Cell Surface Proteome

  • bioRxiv. 2026 Jun 2:2026.06.01.729353. doi: 10.64898/2026.06.01.729353.
Lillian R Delacruz 1 2,  Ming Ye 1 2,  Kendra A Libby 1 2,  Keran Han 1 2,  Chad J Munger 1 2,  Yunping Qiu 3 4,  Irwin J Kurland 3 4,  Alison E Ringel 1 2 5
Affiliations

Affiliations

  • 1 MIT Department of Biology, Cambridge, MA, USA 02139.
  • 2 Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA, USA 02139.
  • 3 Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism, Department of Medicine, Division of Endocrinology, Bronx, NY USA 10461.
  • 4 Stable Isotope and Metabolomics Core Facility, New York Regional Diabetes Research Center at the Albert Einstein College of Medicine, Bronx, NY, USA 10461.
  • 5 Koch Institute for Integrative Cancer Research, Cambridge, MA, USA 02139.
PMID: 42282597 DOI: 10.64898/2026.06.01.729353
Abstract

Heterogeneity is a hallmark of biological systems, where cell-to-cell variability supports adaptation to changing environments, but also enables maladaptive states such as drug resistance. Many sources of non-genetic variation, particularly bioenergetics and metabolism, remain difficult to measure in living cells and connect to functional outcomes. Here, we introduce MARBL (Methionine Analogues for Ratiometric Bioenergetics in Live cells), a method that encodes translationally-coupled energetic responses to metabolic stress as an internally normalized signal within the surface proteome of living cells. Applying MARBL to primary immune cells reveals that differences in baseline translational activity can underlie apparent metabolic vulnerabilities, underscoring the importance of ratiometric measurements. We demonstrate that MARBL can enrich pathogenic from non-pathogenic TH17 cells based on resilience to bioenergetic stress, which functionally distinguishes cells that produce IFNγ upon restimulation. Overall, MARBL offers a versatile platform to profile metabolic resilience in living cells and link bioenergetic state to cellular function.

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