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History recording and content mapping of inter-organelle contacts in living systems via CLAP-ID

ABSTRACT: Organelles dynamically interact to coordinate cellular functions, yet existing methods fail to record interaction histories or resolve contact-specific molecular compositions. Here, we introduce CLAP-ID, a light-gated method for tagging and profiling contacting organelles in living cells. Using a light-activated biotin ligase targeted to one organelle, CLAP-ID biotinylates adjacent organelles during transient contacts, enabling their subsequent isolation and multi-omic analysis. Validating CLAP-ID on mitochondria-ER interactions, we identified metabolites and proteins enriched in ER-proximal mitochondria. Furthermore, bidirectional CLAP-ID mapping of mitochondria-endolysosome contacts revealed that SNX3 on endolysosomes regulates mitochondrial morphology and that calcium-binding proteins rapidly relocalize from mitochondria-lysosome contacts upon lysosomal damage. CLAP-ID quantified contact extent across over 20 organelle pairs and uncovered new peroxisome-stress granule contacts mediating protein transfer. It also resolved distinct, contact-dependent mitochondrial subtypes within mouse tumor tissues and hippocampal neurons. By enabling organelle classification based on interaction history, CLAP-ID provides a versatile tool for dissecting contact-dependent organelle regulation.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Wei Qin

PROVIDER: PXD074226 | iProX | Sat Feb 07 00:00:00 GMT 2026

REPOSITORIES: iProX

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