Affinage

CLUH

Clustered mitochondria protein homolog · UniProt O75153

Length
1309 aa
Mass
146.7 kDa
Annotated
2026-04-28
13 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLUH is a cytosolic RNA-binding protein that post-transcriptionally controls a specific subset of mRNAs encoding nuclear-encoded mitochondrial proteins, stabilizing these transcripts and promoting their translation near mitochondria to maintain oxidative phosphorylation, catabolic metabolism, and proper mitochondrial distribution (PMID:25349259, PMID:28188211, PMID:28424233). CLUH assembles into dynamic ribonucleoprotein granules that recruit mTOR kinase and G3BP1/2, coupling nutrient sensing to mTORC1 inhibition and mitophagy; loss of CLUH blocks mitophagy and causes mitochondrial clustering, phenotypes rescued by rapamycin or G3BP depletion (PMID:32149416). Through its TPR domain, CLUH also binds the SPAG5 mRNA and astrin-1 protein to coordinate mitochondrial metabolism with G1 cell growth and cell cycle progression (PMID:35559794, PMID:35012549). This conserved role in mitochondrial biogenesis and distribution is ancestral: yeast CLU1 and Drosophila Clu form analogous peri-mitochondrial granules and regulate polysome-associated translation of mitochondrial protein mRNAs (PMID:9601101, PMID:40623095).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1998 High

    Cross-species complementation established that the CLU gene family has an ancient, conserved role in mitochondrial distribution, answering whether the Dictyostelium cluA phenotype reflects a general eukaryotic function.

    Evidence Yeast CLU1 deletion caused mitochondrial clustering; CLU1 rescued Dictyostelium cluA- mutants

    PMID:9601101

    Open questions at the time
    • Molecular mechanism by which CLU1 controls mitochondrial positioning was unknown
    • No direct binding partners or substrates identified
    • Whether the protein acts on mRNA or directly on mitochondria was unresolved
  2. 2014 High

    RIP-seq revealed that mammalian CLUH functions as a cytosolic mRNA-binding protein with specificity for transcripts encoding nuclear-encoded mitochondrial proteins, resolving the molecular substrate of the CLU family.

    Evidence RIP-seq in human cells identified CLUH-bound mRNAs; CLUH knockdown reduced cognate protein levels and caused mitochondrial clustering

    PMID:25349259

    Open questions at the time
    • Whether CLUH controls mRNA stability, translation, or localization was not distinguished
    • The RNA-binding domain responsible for target selectivity was not mapped
    • In vivo physiological relevance not yet tested
  3. 2017 High

    Conditional knockout mice and CRISPR KO cells demonstrated that CLUH controls both stability and translation of target mRNAs, with loss causing OXPHOS deficiency, metabolic failure at the fetal-neonatal transition, and impaired starvation response — establishing CLUH as essential for metabolic adaptation in vivo.

    Evidence Cluh conditional KO mice with polysome profiling, mRNA stability assays, Seahorse respirometry, and metabolomics in KO cell lines

    PMID:28188211 PMID:28424233

    Open questions at the time
    • How CLUH distinguishes target from non-target mRNAs at a structural level was unknown
    • Whether CLUH acts co-translationally or post-translationally on mitochondrial import was unclear
    • Relationship between mRNA regulation and mitochondrial clustering phenotype not mechanistically linked
  4. 2020 High

    Discovery that CLUH forms RNP granules recruiting mTOR and G3BP1/2 revealed a signaling function: CLUH couples nutrient availability to mTORC1 inhibition and mitophagy, explaining the mitochondrial clustering phenotype as a mitophagy block.

    Evidence Co-IP, live-cell granule imaging, mTORC1 activity assays, mitophagy flux, rapamycin and G3BP1/2 siRNA rescue in primary hepatocytes

    PMID:32149416

    Open questions at the time
    • How CLUH granule assembly is triggered by metabolic signals was not defined
    • Whether mTOR recruitment is direct or mediated by adaptor proteins was not resolved
    • Structural basis of CLUH granule phase behavior was uncharacterized
  5. 2022 High

    Identification of CLUH–astrin-1 (SPAG5) interaction via both mRNA binding and protein–protein interaction demonstrated that CLUH integrates mitochondrial metabolism with cell cycle progression through G1 growth control and mTORC1 modulation.

    Evidence RIP, Co-IP, BioID proximity labeling, TPR domain mutants, cell cycle analysis, and metabolomics in CLUH KO cell lines

    PMID:35012549 PMID:35559794

    Open questions at the time
    • Whether astrin-1 is a co-regulator within CLUH granules or acts downstream was unclear
    • The precise mechanism linking CLUH-astrin to G1 growth remains uncharacterized
    • Whether CLUH–SPAG5 interaction is conserved beyond mammals was not tested
  6. 2023 Medium

    In macrophages, CLUH binds DRP1 and restrains mitochondrial fission; its loss amplifies inflammatory cytokine secretion by increasing mitochondrial ROS and impairing mitophagy/lysosomal function, extending CLUH function to innate immune regulation.

    Evidence CRISPR KO macrophages, Co-IP of CLUH–DRP1, mitochondrial morphology imaging, ROS measurement, cytokine ELISA

    PMID:37140992

    Open questions at the time
    • CLUH–DRP1 interaction awaits reciprocal validation and independent replication
    • Whether CLUH regulates DRP1 via transcriptional versus post-translational mechanisms is ambiguous
    • Relevance to in vivo inflammatory disease models not established
  7. 2025 Medium

    Studies in Drosophila and yeast showed that Clu/Clu1 granules are dynamic, membraneless condensates that interact with polysomes independently of visible granule state, suggesting granules concentrate translating ribosomes rather than sequester silent mRNAs.

    Evidence Live-cell imaging of granule dynamics, polysome fractionation, ribosome co-sedimentation in Drosophila and yeast

    PMID:40623095

    Open questions at the time
    • Whether mammalian CLUH granules function identically to yeast/fly Clu granules needs direct comparison
    • The biophysical properties governing granule assembly/dissolution are uncharacterized
    • Relationship between polysome association and granule state is correlative

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of CLUH target mRNA selectivity, the mechanism by which CLUH granules sense metabolic signals to modulate phase behavior, and whether CLUH's mRNA-regulatory and signaling (mTORC1/mitophagy) roles are separable remain unresolved.
  • No high-resolution structure of CLUH or its TPR domain bound to target RNA
  • No reconstitution of CLUH granule formation in vitro
  • Whether mRNA stabilization and mTORC1 regulation are mechanistically coupled or parallel functions is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6
Localization
GO:0005829 cytosol 4 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 2 GO:0005634 nucleus 1 R-HSA-9612973 Autophagy 1
Partners
DNM1LG3BP1G3BP2MTORSPAG5
Complex memberships
CLUH-G3BP1/2-mTOR RNP granule

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 CLUH is a cytosolic mRNA-binding protein that specifically binds a subset of mRNAs encoding nuclear-encoded mitochondrial proteins, as determined by RNA immunoprecipitation followed by next-generation sequencing (RIP-seq). Loss of CLUH decreased levels of proteins translated by target transcripts and caused mitochondrial clustering. A fraction of CLUH colocalizes with tyrosinated tubulin and can be detected close to mitochondria. RNA immunoprecipitation + next-generation sequencing (RIP-seq), CLUH knockdown with protein-level readouts, immunofluorescence colocalization The Journal of cell biology High 25349259
2017 CLUH controls the stability and translation of its target mRNAs encoding mitochondrial proteins. In the absence of CLUH, mitochondria are depleted of key enzymes involved in oxidative phosphorylation and catabolic energy-converting pathways, leading to impaired glucose homeostasis and metabolic failure at the fetal-neonatal transition and loss of starvation response in adult liver. Cluh conditional knockout mouse model, polysome profiling/translation assays, mRNA stability assays, metabolic and respiratory function measurements The Journal of cell biology High 28188211
1998 The S. cerevisiae CLU1 gene is a functional homolog of Dictyostelium cluA; deletion of CLU1 causes condensation of the mitochondrial reticulum to one side of the cell, and CLU1 can rescue cytokinesis and mitochondrial distribution defects in cluA- Dictyostelium mutants, establishing a conserved role in mitochondrial morphology and distribution. Yeast gene deletion, complementation of Dictyostelium cluA- mutants with CLU1, fluorescence microscopy of mitochondria Journal of cell science High 9601101
2020 CLUH coalesces into specific ribonucleoprotein granules in primary hepatocytes that control the translational fate of target mRNAs (e.g., Pcx, Hadha, Hmgcs2). CLUH granules recruit mTOR kinase and the RNA-binding proteins G3BP1 and G3BP2. Upon starvation, CLUH inhibits mTORC1 activation and promotes mitochondrial turnover (mitophagy); in the absence of CLUH, a mitophagy block causes mitochondrial clustering rescued by rapamycin or G3BP1/2 depletion. Immunoprecipitation, live-cell imaging of granules, translation assays, mTORC1 activity measurements, rapamycin treatment, G3BP1/2 siRNA knockdown, mitophagy flux assays The EMBO journal High 32149416
2017 CLUH-knockout cells generated by CRISPR/Cas9 show mitochondrial clustering associated with decreased abundance of respiratory complexes, OXPHOS defects, impaired mitochondrial translation, and a metabolic shift toward glucose dependency, with metabolomic evidence of dysfunctional Krebs cycle and fatty acid oxidation. CRISPR/Cas9 knockout, Seahorse respirometry, mitochondrial translation assay, mass spectrometry metabolomics, electron microscopy Journal of cell science High 28424233
2022 CLUH interacts stably and RNA-independently with itself and with SPAG5 (astrin's co-localizing partner) in cytosolic granular structures. CLUH also shows proximity to mitochondrial proteins and their cognate mRNAs in the cytosol during active translation, dependent on the CLUH TPR domain. Co-immunoprecipitation, BioID proximity labeling, RNase treatment controls, domain mutant analysis (TPR domain), mass spectrometry interactome BMC biology High 35012549
2022 CLUH binds both the SPAG5 mRNA and its protein product astrin-1, controlling synthesis and stability of the full-length astrin-1 isoform. CLUH interacts with astrin-1 specifically during interphase. Loss of CLUH decreases astrin levels, increases mTORC1 signaling, impairs anaplerotic/anabolic pathways, and causes cells to fail to grow during G1 and to progress faster through the cell cycle. RIP (RNA immunoprecipitation), Co-immunoprecipitation, cell cycle analysis by flow cytometry, mTORC1 activity assays, metabolomics, CLUH knockout cell lines eLife High 35559794
2023 CLUH binds to DRP1 (dynamin-related protein 1) and regulates DRP1 transcription in human macrophages. In CLUH-knockout macrophages stimulated with TLR ligands, loss of CLUH enhances DRP1 availability for mitochondrial fission, producing a smaller dysfunctional mitochondrial pool that increases mitochondrial ROS, reduces mitophagy, and impairs lysosomal function, causing enhanced secretion of pro-inflammatory cytokines IL-6 and TNF-α. CLUH knockout (CRISPR), Co-immunoprecipitation (CLUH-DRP1), mitochondrial morphology imaging, ROS measurement, mitophagy/lysosomal flux assays, cytokine ELISA JCI insight Medium 37140992
2019 CLUH depletion during adipogenesis reduces stability of mRNAs encoding mitochondrial proteins and impairs mitochondrial respiration, blocking adipocyte differentiation and specifically preventing induction of brown adipocyte-specific genes (Ucp1, Cidea, Cox7a1). siRNA knockdown of Cluh, qRT-PCR for mRNA stability, Seahorse respirometry, lipid droplet staining, adipogenic marker gene expression Scientific reports Medium 31048716
2023 Musashi-2 (MSI2) destabilizes CLUH mRNA as a direct downstream target; overexpression of CLUH rescues MSI2-induced mitochondrial dysfunction and cardiac hypertrophy, establishing CLUH mRNA as a direct target of MSI2-mediated destabilization. RNA-binding protein target identification, AAV9-mediated overexpression in mice, rescue experiments with CLUH overexpression, global proteomics, Seahorse, transmission electron microscopy Basic research in cardiology Medium 37923788
2016 CLUH, normally a cytoplasmic protein, is translocated to the nucleoplasm or SC35-positive speckles by influenza viral proteins PB2 and M1, respectively. CLUH depletion disrupts subnuclear transport of viral ribonucleoprotein (vRNP) and abolishes vRNP nuclear export without affecting viral RNA or protein expression. siRNA knockdown, immunofluorescence localization, nuclear export assays, viral replication assays Nature microbiology Medium 27573102
2025 Drosophila Clu and yeast Clu1 form dynamic, membraneless, mRNA-containing granules adjacent to mitochondria in response to metabolic changes. Clu1 regulates translation of nuclear-encoded mitochondrial proteins by interacting with polysomes (independently of granule state), suggesting that granules concentrate ribosomes engaged in translating target mRNAs. Live-cell fluorescence imaging of granule formation, polysome fractionation, ribosome co-sedimentation, RIP, genetic manipulation in Drosophila and yeast PLoS genetics Medium 40623095

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 CLUH regulates mitochondrial biogenesis by binding mRNAs of nuclear-encoded mitochondrial proteins. The Journal of cell biology 106 25349259
2017 CLUH regulates mitochondrial metabolism by controlling translation and decay of target mRNAs. The Journal of cell biology 69 28188211
1998 The S. cerevisiae CLU1 and D. discoideum cluA genes are functional homologues that influence mitochondrial morphology and distribution. Journal of cell science 68 9601101
2020 CLUH granules coordinate translation of mitochondrial proteins with mTORC1 signaling and mitophagy. The EMBO journal 48 32149416
2017 CLUH couples mitochondrial distribution to the energetic and metabolic status. Journal of cell science 34 28424233
2022 The interactome of CLUH reveals its association to SPAG5 and its co-translational proximity to mitochondrial proteins. BMC biology 19 35012549
2023 CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis. JCI insight 15 37140992
2022 CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression. eLife 15 35559794
2019 Cluh plays a pivotal role during adipogenesis by regulating the activity of mitochondria. Scientific reports 14 31048716
2016 The host protein CLUH participates in the subnuclear transport of influenza virus ribonucleoprotein complexes. Nature microbiology 12 27573102
2023 Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA. Basic research in cardiology 10 37923788
2022 Plant mitochondrial FMT and its mammalian homolog CLUH controls development and behavior in Arabidopsis and locomotion in mice. Cellular and molecular life sciences : CMLS 2 35652974
2025 Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions. PLoS genetics 0 40623095