Coordination of cell organelles to promote metabolon formation

Zhou Sha; Anthony M Pedley; Timothy D Iles; Shaoqing Zhang; Jack R Staub; Ruobo Zhou; Stephen J Benkovic

doi:10.1073/pnas.2532504123

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Coordination of cell organelles to promote metabolon formation

Journal article

Open access

Peer reviewed

Coordination of cell organelles to promote metabolon formation

Zhou Sha, Anthony M Pedley, Timothy D Iles, Shaoqing Zhang, Jack R Staub, Ruobo Zhou and Stephen J Benkovic

Proceedings of the National Academy of Sciences - PNAS, Vol.123(5), e2532504123

02/03/2026

DOI: 10.1073/pnas.2532504123

PMID: 41587318

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Abstract

The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5'-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.

Endoplasmic Reticulum - metabolism

Humans

Metabolome

Mitochondria - metabolism

Organelles - metabolism

Details

Title: Subtitle: Coordination of cell organelles to promote metabolon formation
Creators: Zhou Sha - Pennsylvania State University
Anthony M Pedley - University of Iowa
Timothy D Iles - University of Iowa
Shaoqing Zhang - Pennsylvania State University
Jack R Staub - Pennsylvania State University
Ruobo Zhou - Pennsylvania State University
Stephen J Benkovic - Pennsylvania State University
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.123(5), e2532504123
DOI: 10.1073/pnas.2532504123
PMID: 41587318
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: R35GM142973 / HHS | NIH (NIH) R35GM150481 / HHS | NIH (NIH) R01GM024129 / HHS | NIH (NIH)
Language: English
Date published: 02/03/2026
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9985132181002771

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