Affinage

UQCRC2

Cytochrome b-c1 complex subunit 2, mitochondrial · UniProt P22695

Length
453 aa
Mass
48.4 kDa
Annotated
2026-06-10
17 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UQCRC2 encodes a core structural subunit of mitochondrial respiratory Complex III (ubiquinol-cytochrome c reductase) whose physical integration into the complex is essential for CIII dimerization, supercomplex (CI/CIII/CIV) assembly, and electron flux between Complex I and Complex III (PMID:23281071, PMID:33865955, PMID:37709555). The protein functions through a direct interaction with UQCRC1: mutations that disrupt this interface—such as p.Gly222Ala—cause accumulation of CIII subassemblies lacking UQCRC1, UQCRC2, and UQCRFS1, with degradation of both core subunits by the mitochondrial CLPP protease, and ectopic wild-type UQCRC2 restores respiration in patient cells (PMID:33865955). Pathogenic homozygous and compound heterozygous missense variants (p.Arg183Trp, p.Gly222Ala, and p.Gly397Arg/p.Phe146Ser) cause isolated mitochondrial Complex III deficiency, with p.Arg183Trp independently confirmed in a second unrelated patient (PMID:23281071, PMID:33865955, PMID:28275242). UQCRC2 expression is controlled at multiple levels: AMPK upregulates it transcriptionally via NFE2L2/NRF2 (PMID:33719895), TDP-43 maintains correct alternative splicing of its nuclear-encoded transcript (PMID:41761273), and SIRT5-mediated desuccinylation at lysine 250 promotes its cytoplasm-to-mitochondria translocation and enhances CIII activity (PMID:39892725). Through its control of mitochondrial respiration and ROS, UQCRC2 is required for PINK1/Parkin-mediated mitophagy and mitochondrial homeostasis; its loss elevates mitochondrial ROS, accelerates cellular senescence, exacerbates MLKL-dependent necroptosis, and modulates ferroptosis downstream of the iron transporter SLC25A28 (PMID:33719895, PMID:34774698, PMID:39707408, PMID:41456814).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2013 High

    Established UQCRC2 as a disease-relevant structural subunit by showing that a single interface mutation collapses Complex III function, answering whether UQCRC2 variants cause human mitochondrial disease.

    Evidence Whole-exome sequencing, structural modeling, and CIII activity/supercomplex assays in patient fibroblasts carrying p.Arg183Trp

    PMID:23281071

    Open questions at the time
    • Did not resolve the molecular partner whose binding is lost at the interface
    • No high-resolution structure of the mutant complex
  2. 2017 Medium

    Confirmed the causal essentiality of the R183 residue by independent replication, distinguishing a true pathogenic variant from a private finding.

    Evidence Sanger sequencing and clinical CIII activity measurement in a second unrelated patient

    PMID:28275242

    Open questions at the time
    • Biochemical confirmation only, no in vitro reconstitution in this report
  3. 2021 High

    Defined the molecular basis of CIII assembly failure by showing UQCRC2 must bind UQCRC1 to escape CLPP-mediated degradation, explaining how missense variants destabilize the complex.

    Evidence Patient fibroblast biochemistry, subassembly Western blots, CLPP quantification, respiratory flux, and wild-type rescue for p.Gly222Ala

    PMID:33865955

    Open questions at the time
    • Stoichiometry and structural detail of the UQCRC2–UQCRC1 interface not resolved
    • Whether CLPP degradation is the sole disposal route unaddressed
  4. 2021 Medium

    Placed UQCRC2 within a regulatory signaling axis by demonstrating transcriptional control via AMPK–NFE2L2 and a functional role in hepatic mitophagy, moving it beyond a static structural subunit.

    Evidence ChIP, luciferase reporter, knockdown/overexpression with PINK1/Parkin mitophagy readouts in hepatocytes

    PMID:33719895

    Open questions at the time
    • Whether NFE2L2 binds the UQCRC2 promoter directly versus indirectly
    • Mechanism linking CIII subunit level to mitophagy flux not defined
  5. 2021 Medium

    Connected UQCRC2 loss to regulated cell death by showing its knockdown sustains a ROS-dependent MLKL/RIPK necroptosis feedback loop in ethanol-stressed hepatocytes.

    Evidence In vitro and in vivo knockdown, mitochondrial ROS measurement, and phospho-RIPK1/RIPK3/MLKL Western blots

    PMID:34774698

    Open questions at the time
    • Direct molecular link between CIII deficiency and MLKL activation unresolved
    • Generalizability beyond hepatocyte ethanol model untested
  6. 2024 Low

    Reinforced the structural-dimerization requirement of UQCRC2 by identifying additional compound heterozygous variants causing CIII deficiency.

    Evidence Whole-exome sequencing and clinical CIII activity for p.Gly397Arg/p.Phe146Ser

    PMID:37709555

    Open questions at the time
    • No in vitro functional reconstitution in this study
    • Variant-specific assembly defects not characterized
  7. 2024 Medium

    Demonstrated that UQCRC2-dependent respiration restrains cellular senescence, linking its bioenergetic function to a tissue homeostasis phenotype.

    Evidence Knockdown in 3D-cultured SCAPs with ROS, membrane potential, OCR, and senescence assays

    PMID:39707408

    Open questions at the time
    • Single cell model
    • Causal step between ROS rise and senescence program not dissected
  8. 2025 Medium

    Identified post-translational control of UQCRC2 localization, showing SIRT5 desuccinylation at K250 drives its mitochondrial translocation to tune CIII activity, ROS, and differentiation outcomes.

    Evidence Succinylation proteomics, Co-IP, SIRT5 gain/loss, OCR, ROS, and osteogenic differentiation assays in BM-MSCs

    PMID:39892725

    Open questions at the time
    • Mechanism of K250-dependent translocation not structurally explained
    • Whether cytoplasmic UQCRC2 has function before import unclear
  9. 2025 Medium

    Positioned UQCRC2 as a functional node in ferroptosis by showing SLC25A28-driven suppression of UQCRC2 disrupts CIII electron transport and triggers lipid peroxidation in colorectal cancer.

    Evidence Quantitative proteomics, knockdown/overexpression rescue, xenografts, and GPX4/lipid peroxidation assays

    PMID:41456814

    Open questions at the time
    • Mechanism by which SLC25A28 suppresses UQCRC2 expression undefined
    • Direct versus ROS-mediated contribution to ferroptosis not separated
  10. 2026 Medium

    Revealed splicing-level regulation by showing TDP-43 is required for correct UQCRC2 mRNA processing, providing a route by which TDP-43 dysfunction selectively impairs Complex III.

    Evidence TDP-43 knockdown with transcript splicing analysis, OXPHOS assembly, mitochondrial morphology, and respiration in HEK293T and SH-SY5Y cells

    PMID:41761273

    Open questions at the time
    • Specific mis-spliced isoform and its fate not fully characterized
    • Direct binding of TDP-43 to UQCRC2 pre-mRNA not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs on UQCRC2 (transcription, splicing, succinylation) are integrated, and the structural basis of its dimerization role, remain unresolved.
  • No high-resolution structure of UQCRC2 within human CIII
  • Cross-talk among AMPK/NFE2L2, TDP-43, and SIRT5 regulation untested
  • Whether senescence, necroptosis, and ferroptosis phenotypes share a common ROS mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
SIRT5UQCRC1UQCRFS1
Complex memberships
CI/CIII/CIV supercomplexMitochondrial respiratory Complex III (ubiquinol-cytochrome c reductase)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 A homozygous missense mutation p.Arg183Trp in UQCRC2 disrupts the hydrophobic core at the subunit interface of the core protein II homodimer (structural modeling), causing mitochondrial Complex III deficiency and impaired assembly of the CI/CIII/CIV supercomplex, as demonstrated in patient fibroblasts. Whole-exome sequencing, structural modeling, in vitro biochemical assays in patient fibroblasts (CIII activity, supercomplex assembly) Human mutation High 23281071
2021 A homozygous missense mutation p.Gly222Ala in UQCRC2 impairs specific protein-protein interactions, leading to accumulation of CIII subassemblies that lack UQCRC1, UQCRC2, and UQCRFS1. Mutant UQCRC2 fails to interact with UQCRC1, causing degradation of both subunits by mitochondrial CLPP protease. This reduces available CIII for supercomplex formation, diminishes CI levels, and impairs electron flux between CI and CIII. Ectopic wild-type UQCRC2 expression rescued maximal respiration rate in patient cells. Patient fibroblast biochemistry, Western blot for subunit and subassembly levels, CLPP protease quantification, respiratory flux measurements, ectopic wild-type UQCRC2 rescue experiment Biochimica et biophysica acta. Molecular basis of disease High 33865955
2021 AMPK indirectly upregulates UQCRC2 protein levels by activating NFE2L2/NRF2, which enhances UQCRC2 gene transcription. UQCRC2 knockdown impairs mitophagy, while UQCRC2 overexpression increases mitophagy and attenuates alcohol-induced liver injury, defining an AMPK–NFE2L2–UQCRC2 signaling axis in hepatic mitophagy regulation. UQCRC2 knockdown/overexpression in hepatocytes, RNA-seq, chromatin immunoprecipitation (ChIP) assay, luciferase reporter assay, co-immunoprecipitation, mitophagy flux measurements (LC3, PINK1/Parkin), OCR measurement Autophagy Medium 33719895
2021 UQCRC2 is required for PINK1/Parkin-mediated mitophagy in ethanol-exposed hepatocytes; UQCRC2 knockdown reduces the capacity to clear impaired mitochondria, increases mitochondrial ROS, and exacerbates MLKL-mediated necroptosis by sustaining the ROS-dependent positive feedback between p-MLKL and RIPK1/RIPK3. In vitro UQCRC2 knockdown in ethanol-treated hepatocytes, mitophagy flux assays, mitochondrial ROS measurement, Western blot for RIPK1/RIPK3/MLKL phosphorylation, in vivo UQCRC2 knockdown Free radical biology & medicine Medium 34774698
2025 SIRT5-mediated desuccinylation of UQCRC2 at lysine 250 promotes translocation of UQCRC2 from the cytoplasm to mitochondria, enhancing mitochondrial respiratory complex III activity, increasing mitochondrial ROS, accelerating cellular senescence, and inhibiting osteogenic differentiation of BM-MSCs. Succinylation proteomics, Co-immunoprecipitation, SIRT5 overexpression/knockdown, OCR measurement, mitochondrial ROS assay, osteogenic differentiation assays (Alizarin red staining, Western blot for Runx2/osteocalcin) Cellular signalling Medium 39892725
2024 UQCRC2 plays a role in dimerization of mitochondrial Complex III; novel compound heterozygous variants (p.Gly397Arg and p.Phe146Ser) cause Complex III deficiency with metabolic phenotype, confirming the structural requirement of UQCRC2 for CIII function. Whole-exome sequencing, clinical biochemistry (Complex III activity), variant pathogenicity assessment Cold Spring Harbor molecular case studies Low 37709555
2026 TDP-43 regulates alternative splicing of the nuclear-encoded UQCRC2 transcript; TDP-43 knockdown causes aberrant mis-splicing of UQCRC2 mRNA leading to decreased UQCRC2 protein, selective disruption of Complex III activity, and impaired mitochondrial morphology and respiratory capacity. This was observed in both HEK293T and SH-SY5Y cells. TDP-43 knockdown, transcript analysis (alternative splicing), OXPHOS complex assembly assay, mitochondrial morphology imaging, respiratory capacity measurement Biology direct Medium 41761273
2024 UQCRC2 knockdown in 3D-cultured SCAPs increases mitochondrial ROS, decreases mitochondrial membrane potential, and reduces the oxygen consumption rate for oxidative phosphorylation, accelerating cellular senescence, demonstrating that UQCRC2-mediated mitochondrial homeostasis is required for delaying senescence. UQCRC2 knockdown in 3D-cultured SCAPs, mitochondrial ROS measurement, mitochondrial membrane potential assay, OCR measurement, senescence assays Journal of translational medicine Medium 39707408
2025 SLC25A28 (mitochondrial iron transporter) specifically suppresses UQCRC2 expression downstream of baicalin treatment, disrupting Complex III electron transport, increasing mitochondrial ROS, and triggering ferroptosis in colorectal cancer cells. UQCRC2 knockdown exacerbated ferroptosis, while UQCRC2 overexpression conferred protection, confirming UQCRC2 as a functional mediator in the SLC25A28–UQCRC2–ETC ferroptosis axis. Quantitative proteomics, genetic knockdown/overexpression, pharmacological inhibition, xenograft models, lipid peroxidation and glutathione/GPX4 assays Free radical biology & medicine Medium 41456814
2013 UQCRC2 is required for normal sperm function; reduced UQCRC2 protein levels in mouse spermatozoa (induced by nutlin-3a) are associated with decreased intracellular ATP production, impaired sperm motility, reduced capacitation and acrosome reaction, and poor fertilization rates in vitro. In vitro mouse spermatozoa treatment with nutlin-3a, Western blotting for UQCRC2, ATP assay, CASA (computer-assisted sperm analysis), CTC staining, IVF PloS one Low 24130818
2017 The same UQCRC2 p.Arg183Trp mutation identified in the first family causes isolated Complex III deficiency when present in a second unrelated patient, confirming that this residue is functionally essential for CIII activity. Sanger sequencing, clinical biochemistry (Complex III activity measurement in patient tissue) Journal of human genetics Medium 28275242

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy. Autophagy 113 33719895
2013 Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation. Human mutation 73 23281071
2021 Activation of UQCRC2-dependent mitophagy by tetramethylpyrazine inhibits MLKL-mediated hepatocyte necroptosis in alcoholic liver disease. Free radical biology & medicine 40 34774698
2017 UQCRC2 mutation in a patient with mitochondrial complex III deficiency causing recurrent liver failure, lactic acidosis and hypoglycemia. Journal of human genetics 30 28275242
2013 Nutlin-3a decreases male fertility via UQCRC2. PloS one 27 24130818
2021 Homozygous missense mutation in UQCRC2 associated with severe encephalomyopathy, mitochondrial complex III assembly defect and activation of mitochondrial protein quality control. Biochimica et biophysica acta. Molecular basis of disease 25 33865955
2021 Knockdown of circ-UQCRC2 ameliorated lipopolysaccharide-induced injury in MRC-5 cells by the miR-326/PDCD4/NF-κB pathway. International immunopharmacology 18 33895481
2020 The miR-370/UQCRC2 axis facilitates tumorigenesis by regulating epithelial-mesenchymal transition in Gastric Cancer. Journal of Cancer 14 32742452
2022 UQCRC2-related mitochondrial complex III deficiency, about 7 patients. Mitochondrion 13 36509339
2020 Artesunate alleviates schistosomiasis-induced liver fibrosis by downregulation of mitochondrial complex Ⅰ subunit NDUFB8 and complex Ⅲ subunit UQCRC2 in hepatic stellate cells. Acta tropica 13 33264632
2021 Circ-UQCRC2 aggravates lipopolysaccharide-induced injury in human bronchial epithelioid cells via targeting miR-495-3p/MYD88-mediated inflammatory response and oxidative stress. Autoimmunity 9 34499003
2024 3D culture inhibits replicative senescence of SCAPs via UQCRC2-mediated mitochondrial oxidative phosphorylation. Journal of translational medicine 5 39707408
2024 Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment. Cold Spring Harbor molecular case studies 2 37709555
2025 SIRT5 -mediated desuccinylation of UQCRC2 attenuates osteogenic differentiation of aged BM-MSCs through impairing mitochondrial homeostasis. Cellular signalling 1 39892725
2026 TDP-43-driven alternative splicing of UQCRC2 modulates mitochondrial bioenergetics. Biology direct 0 41761273
2026 Reversible Metabolic and Liver Disease in Complex III Deficiency: Novel Variants Expand the Reported UQCRC2-Associated Phenotype. Cells 0 41972687
2025 Baicalin triggers ferroptosis to suppress colorectal cancer via SLC25A28-UQCRC2-regulated electron transport chain disruption. Free radical biology & medicine 0 41456814

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