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Showing ATP5PD — ATP5H is a alias.

ATP5PD

ATP synthase peripheral stalk subunit d, mitochondrial · UniProt O75947

Length
161 aa
Mass
18.5 kDa
Annotated
2026-06-09
67 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP5PD (ATP5H, subunit d) is a stator stalk subunit of the mitochondrial F1Fo-ATP synthase that is required for assembly of the holocomplex: its depletion blocks joining of the stator stalk to the rotor module, causing accumulation of separate F1-c-ring and b-e-g stator sub-intermediates (PMID:26297831). It directly contacts the F0 subunit ATP5F1, an interaction that is reduced in interfibrillar mitochondria of diabetic hearts in parallel with falling ATP synthase activity (PMID:23872101). Beyond its structural role, epigenetic silencing of ATP5H in tumor cells drives ROS accumulation and normoxic HIF-1α stabilization, conferring a stem-like, invasive, therapy-resistant phenotype that is reversed by antioxidant treatment (PMID:30124467), and its expression is regulated downstream of CaMKK2/NCLX signaling in liver cancer cells where it controls mitochondrial ATP production and cell migration (PMID:38020296). A model-organism study links loss of the ATP5H ortholog to enhanced amyloid-β proteotoxicity (PMID:28242297). No structural model of how subunit d bridges the stator and rotor modules has been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2013 Medium

    Established that subunit d physically engages another F0 subunit and that this contact is functionally coupled to enzyme output, framing ATP5H as a structural node within the membrane sector.

    Evidence Co-IP/pulldown plus ATP synthase activity assay in cardiac mitochondrial subpopulations from streptozotocin diabetic mice

    PMID:23872101

    Open questions at the time
    • Single lab, no reciprocal validation of the ATP5F1 interaction
    • Cardiolipin dependence of the interaction not directly tested here
    • Correlative link between reduced interaction and lower activity, not causal
  2. 2015 High

    Resolved the assembly role of ATP5H by showing its loss arrests holocomplex formation at defined sub-intermediates, establishing subunit d as the factor that joins the stator stalk to the rotor module.

    Evidence siRNA knockdown in human cells with native PAGE and immunoblotting, plus control knockdowns of mtDNA-encoded subunits

    PMID:26297831

    Open questions at the time
    • No structural model of the bridging interface
    • Order of subunit addition during assembly not fully resolved
    • Whether residual holocomplex retains activity untested
  3. 2017 Medium

    Connected ATP5H to neurodegeneration-relevant proteostasis by showing ortholog loss aggravates amyloid-β toxicity.

    Evidence RNAi knockdown of the C. elegans ortholog in a transgenic Aβ proteotoxicity model with phenotypic readout

    PMID:28242297

    Open questions at the time
    • Single method in a model organism
    • Mechanism linking ATP synthase function to Aβ toxicity unknown
    • No mammalian validation
  4. 2018 High

    Revealed a non-canonical consequence of ATP5H loss: epigenetic silencing triggers ROS-driven normoxic HIF-1α stabilization and a therapy-resistant stem-like state, reversible by antioxidants.

    Evidence Immune selection of murine and human tumor cells with epigenetic, ROS, HIF-1α assays and in vivo antioxidant rescue

    PMID:30124467

    Open questions at the time
    • Mechanism linking ATP synthase deficiency to ROS rise not fully dissected
    • Direct test of whether assembly defect causes the ROS phenotype absent
    • Generalizability across tumor types beyond models tested
  5. 2023 Medium

    Placed ATP5H downstream of a defined signaling axis by showing CaMKK2/NCLX controls its expression and thereby mitochondrial ATP output and cell motility.

    Evidence CaMKK2 overexpression and NCLX siRNA in HepG2/HuH-7 cells with expression, ATP probe, and migration/invasion assays

    PMID:38020296

    Open questions at the time
    • Single lab, mechanism of transcriptional/translational regulation unresolved
    • Direct binding of regulators to ATP5H locus not shown
    • Contribution of ATP5H specifically to migration vs. bystander effect

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the assembly defect, ATP5F1/cardiolipin interaction, and the downstream ROS/HIF-1α and signaling phenotypes mechanistically connect into a single causal chain remains unresolved.
  • No structural model of subunit d at the stator-rotor interface
  • Causal link between assembly failure and ROS accumulation untested
  • Cardiolipin dependence of the ATP5F1 contact not directly demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 2
Partners
ATP5F1
Complex memberships
F1Fo-ATP synthase

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Epigenetic loss of ATP5H (ATP synthase subunit d) in tumor cells leads to ROS accumulation and HIF-1α stabilization under normoxia, conferring a stem-like and invasive phenotype and cross-resistance to immunotherapy, chemotherapy, and radiotherapy. In vivo antioxidant delivery reversed these phenotypic changes and resensitized tumor cells to therapy. Sequential in vitro/in vivo immune selection of murine and human tumor cells, followed by molecular analysis of epigenetic changes, ROS measurement, HIF-1α stabilization assays, and in vivo antioxidant rescue experiments The Journal of Clinical Investigation High 30124467
2013 ATP5H (subunit d of the ATP synthase F0 complex) directly interacts with ATP5F1 (another F0 subunit), and both interactions are significantly decreased in interfibrillar mitochondria (IFM) of type 1 diabetic hearts, coinciding with decreased ATP synthase activity. Co-immunoprecipitation/pulldown to identify novel direct interactions between ATP synthase F0 subunits; Western blot quantification; ATP synthase activity assay in cardiac mitochondrial subpopulations from streptozotocin-induced diabetic FVB mice Life Sciences Medium 23872101
2015 Knockdown of the d-subunit (ATP5H/ATP5PD) in human cells prevents formation of the ATP synthase holocomplex; instead, two separate subcomplexes accumulate: one containing the central rotor shaft plus catalytic subunits (F1-c-ring) and one containing stator stalk components (b-e-g complex), establishing that ATP5H is required for final assembly of the stator stalk with the rotor module. siRNA knockdown of d-subunit expression in human cells, followed by analysis of subcomplex accumulation by native PAGE and immunoblotting; additional knockdowns of mtDNA-encoded a-subunit and A6L to confirm F1-c-ring formation FEBS Letters High 26297831
2017 Knockdown of C. elegans ortholog of ATP5H is associated with increased amyloid-β toxicity in a transgenic C. elegans Aβ proteotoxicity model, placing ATP5H in a pathway relevant to Aβ-mediated neurodegeneration. RNA interference (RNAi) knockdown of ATP5H C. elegans ortholog in a transgenic C. elegans Aβ proteotoxicity model; phenotypic readout of Aβ toxicity Alzheimer's & Dementia Medium 28242297
2023 Dihydroartemisinin (DHA) reduces ATP5H protein and mRNA expression in liver cancer cells via the CaMKK2/NCLX signaling pathway; knockdown of NCLX reproduced CaMKK2-mediated downregulation of ATP5H, placing ATP5H downstream of CaMKK2/NCLX in regulation of mitochondrial ATP production and cell migration/invasion. Western blotting and RT-qPCR for ATP5H expression; CaMKK2 overexpression and NCLX siRNA knockdown in HepG2 and HuH-7 cells; ATP fluorescent probe measurement; wound healing and Transwell invasion assays Oncology Letters Medium 38020296
2021 ATP5H (ATP5PD) protein abundance is elevated in spermatozoa from patients with repetitive fertilization failure after ICSI compared to controls with normal fertilization rates, suggesting altered mitochondrial function associated with fertilization failure. 2D-LC-MS/MS quantitative proteomics of individual sperm samples; Western blot validation of selected proteins; JC-1 staining for mitochondrial membrane potential Andrology Low 33615715
2012 ATP5H is detected in both mitochondrial and nuclear fractions of MCF7 breast cancer cells, indicating dual subcellular localization of this oxidative phosphorylation subunit. Concurrent proteomics analysis of isolated nuclei and mitochondria from MCF7 cells; protein identification by mass spectrometry Journal of Proteome Research Low 23051583
2021 In a FACS-based workflow, ATP5H (nuclear-encoded mitochondrial protein) protein levels are used as a reference for mitochondrial content, and the ratio of MTCO1 (mtDNA-encoded) to ATP5H fluorescence intensity reports on mtDNA genomic stability, since MTCO1 is selectively depleted when mtDNA is damaged. FACS-based simultaneous measurement of ATP5H and MTCO1 protein levels by intracellular antibody staining; downstream qPCR for mtDNA copy number validation BioChem Low 35937039

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 ATP5H/KCTD2 locus is associated with Alzheimer's disease risk. Molecular psychiatry 58 23857120
2016 Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease. Annals of neurology 55 26913989
2018 Mitochondrial respiratory chain complex abnormal expressions and fusion disorder are involved in fluoride-induced mitochondrial dysfunction in ovarian granulosa cells. Chemosphere 52 30342406
2010 Characterization of the N-ATPase, a distinct, laterally transferred Na+-translocating form of the bacterial F-type membrane ATPase. Bioinformatics (Oxford, England) 51 20472544
2013 Changes in the transcriptome of the human endometrial Ishikawa cancer cell line induced by estrogen, progesterone, tamoxifen, and mifepristone (RU486) as detected by RNA-sequencing. PloS one 45 23874806
2018 Understanding the regulatory mechanisms of milk production using integrative transcriptomic and proteomic analyses: improving inefficient utilization of crop by-products as forage in dairy industry. BMC genomics 44 29843597
2018 Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance. The Journal of clinical investigation 41 30124467
2016 Ataxin-1 regulates the cerebellar bioenergetics proteome through the GSK3β-mTOR pathway which is altered in Spinocerebellar ataxia type 1 (SCA1). Human molecular genetics 40 27466200
2011 Quantitative proteomic analysis of dexamethasone-induced effects on osteoblast differentiation, proliferation, and apoptosis in MC3T3-E1 cells using SILAC. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 37 21060993
2010 Differentially expressed proteins during fat accumulation in bovine skeletal muscle. Meat science 37 20667664
2010 Analysis of differentially expressed mitochondrial proteins in chromophobe renal cell carcinomas and renal oncocytomas by 2-D gel electrophoresis. International journal of biological sciences 35 20440404
2020 Circ-ATP5H Induces Hepatitis B Virus Replication and Expression by Regulating miR-138-5p/TNFAIP3 Axis. Cancer management and research 34 33173336
2017 ATP5J and ATP5H Proactive Expression Correlates with Cardiomyocyte Mitochondrial Dysfunction Induced by Fluoride. Biological trace element research 34 28261761
2016 Transcriptional profiles of type 2 diabetes in human skeletal muscle reveal insulin resistance, metabolic defects, apoptosis, and molecular signatures of immune activation in response to infections. Biochemical and biophysical research communications 34 27847319
2017 Systems biology approach to late-onset Alzheimer's disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments. Alzheimer's & dementia : the journal of the Alzheimer's Association 33 28242297
2018 Mitochondrial Molecular Abnormalities Revealed by Proteomic Analysis of Hippocampal Organelles of Mice Triple Transgenic for Alzheimer Disease. Frontiers in molecular neuroscience 31 29593495
2012 Spatial distribution of cellular function: the partitioning of proteins between mitochondria and the nucleus in MCF7 breast cancer cells. Journal of proteome research 31 23051583
2013 Evaluation of the cardiolipin biosynthetic pathway and its interactions in the diabetic heart. Life sciences 30 23872101
2015 Assembly of human mitochondrial ATP synthase through two separate intermediates, F1-c-ring and b-e-g complex. FEBS letters 29 26297831
2016 Fatal familial insomnia: mitochondrial and protein synthesis machinery decline in the mediodorsal thalamus. Brain pathology (Zurich, Switzerland) 22 27338255
2018 Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: implication for Alzheimer's disease. Archives of toxicology 19 29383422
2021 Current Molecular Biology and Therapeutic Strategy Status and Prospects for circRNAs in HBV-Associated Hepatocellular Carcinoma. Frontiers in oncology 18 34277444
2020 Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models. International journal of molecular sciences 18 33053689
2019 Comparative proteomic analysis of Tibetan pig spermatozoa at high and low altitudes. BMC genomics 18 31291894
2015 Proteomic analysis of hepatocellular carcinoma HepG2 cells treated with platycodin D. Chinese journal of natural medicines 18 26412427
2014 Proteome alterations in cortex of mice exposed to fluoride and lead. Biological trace element research 17 25529766
2018 Ca2+ metabolic disorder and abnormal expression of cardiac troponin involved in fluoride-induced cardiomyocyte damage. Chemosphere 16 29533806
2014 Bleomycin hydrolase and hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis. Amino acids 15 24633403
2023 Meta-analysis of brain samples of individuals with schizophrenia detects down-regulation of multiple ATP synthase encoding genes in both females and males. Journal of psychiatric research 14 36640659
2021 Altered mitochondrial function in spermatozoa from patients with repetitive fertilization failure after ICSI revealed by proteomics. Andrology 14 33615715
2016 Insights into the potential of picoplanktonic marine cyanobacteria strains for cancer therapies - Cytotoxic mechanisms against the RKO colon cancer cell line. Toxicon : official journal of the International Society on Toxinology 13 27242042
2015 Nicotine mediates expression of genes related to antioxidant capacity and oxidative stress response in HIV-1 transgenic rat brain. Journal of neurovirology 13 26306689
2024 Multi-omics revealed anti-fatigue property of polyphenol from areca nut. Phytomedicine : international journal of phytotherapy and phytopharmacology 12 38964153
2021 Sodium butyrate modulates chicken macrophage proteins essential for Salmonella Enteritidis invasion. PloS one 12 33909627
2016 Mechanisms of propofol attenuation of ketamine-induced neonatal brain injury. European review for medical and pharmacological sciences 11 26813465
2022 Expression of actin- and oxidative phosphorylation-related transcripts across the cortical visuospatial working memory network in unaffected comparison and schizophrenia subjects. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 10 35034100
2021 Effects of Edible Insect Tenebrio molitor Larva Fermentation Extract as a Substitute Protein on Hepatosteatogenesis and Proteomic Changes in Obese Mice Induced by High-Fat Diet. International journal of molecular sciences 9 33807173
2024 Single-cell sequencing combined with transcriptomics and in vivo and in vitro analysis reveals the landscape of ferroptosis in myocardial ischemia-reperfusion injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 39520298
2020 mPTP Proteins Regulated by Streptozotocin-Induced Diabetes Mellitus Are Effectively Involved in the Processes of Maintaining Myocardial Metabolic Adaptation. International journal of molecular sciences 7 32283821
2014 Paraoxonase 1 and dietary hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis. Acta biochimica Polonica 7 25347084
2024 Proteomic analysis of laser captured tubular tissues reveals complement activation and mitochondrial dysfunction in autoimmune related kidney diseases. Scientific reports 6 39164435
2023 Particulate matter 10 induces oxidative stress and apoptosis in rhesus macaques skin fibroblast. PeerJ 6 38130933
2019 Close association between abnormal expressed enzymes of energy metabolism and diarrhea-predominant irritable bowel syndrome. Chinese medical journal 6 30614852
2019 Amorphous silica nanoparticles induce tumorigenesis via regulating ATP5H/SOD1-related oxidative stress, oxidative phosphorylation and EIF4G2/PABPC1-associated translational initiation. PeerJ 6 30863671
2019 Ultrasonic-assisted extraction and digestion of proteins from solid biopsies followed by peptide sequential extraction hyphenated to MALDI-based profiling holds the promise of distinguishing renal oncocytoma from chromophobe renal cell carcinoma. Talanta 6 31514886
2023 Dihydroartemisinin inhibits liver cancer cell migration and invasion by reducing ATP synthase production through CaMKK2/NCLX. Oncology letters 5 38020296
2013 Glucocorticoid receptor is involved in the breed-dependent transcriptional regulation of mtDNA- and nuclear-encoded mitochondria genes in the liver of newborn piglets. BMC veterinary research 5 23618392
2024 Gene crosstalk between COVID-19 and preeclampsia revealed by blood transcriptome analysis. Frontiers in immunology 4 38259479
2024 Deregulation of oxidative phosphorylation pathways in embryos derived in vitro from prepubertal and pubertal heifers based on whole-transcriptome sequencing. BMC genomics 4 38914933
2024 Dihydroartemisinin inhibits ATP6 activity, reduces energy metabolism of hepatocellular carcinoma cells, promotes apoptosis and inhibits metastasis via CANX. Oncology letters 4 39161338
2019 Candidate genes mediated by estrogen-related receptor γ in pancreatic β cells. Journal of biochemical and molecular toxicology 4 31478280
2025 The chimeric gene orf610a reduces cotton pollen fertility by impairing the assembly of ATP synthase. Plant biotechnology journal 3 40333481
2025 Maternal polystyrene nanoplastics suppress zebrafish offspring development and locomotion through mitochondrial dysfunction. Environmental pollution (Barking, Essex : 1987) 3 40912539
2024 Upregulation of Oxidative Phosphorylation Genes in Cumulus Cells of The Polycystic Ovary Syndrome Patients with or without Insulin Resistance. Cell journal 3 38736407
2020 Selection and validation of reference genes for RT-qPCR in adipose and longissimus dorsi muscle tissues of buffalo. Animal biotechnology 3 32862779
2025 Differential Proteomic Analysis of DEN-induced Hepatocellular Carcinoma in Male and Female Balb/c Mice Reveals Novel Sex-Specific Markers. Cancer genomics & proteomics 2 41151867
2024 Analysis of Sigma-1 Receptor Antagonist BD1047 Effect on Upregulating Proteins in HIV-1-Infected Macrophages Exposed to Cocaine Using Quantitative Proteomics. Biomedicines 2 39335448
2025 Auxin signaling related to H+-ATPase synthesis and antioxidant enzyme activities regulates fluoranthene uptake by ryegrass roots. Ecotoxicology and environmental safety 1 39919594
2025 High-fructose diet induces depressive-like behaviors and short-term memory deficits through hippocampal neurogenesis impairment via neural stem cell dysfunction. Nutrition & metabolism 1 41331761
2024 Developing a comprehensive molecular subgrouping model for cervical cancer using machine learning. American journal of cancer research 1 39005664
2022 An Integrated Bioinformatics Approach to Identify Network-Derived Hub Genes in Starving Zebrafish. Animals : an open access journal from MDPI 1 36230465
2012 An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3. BMC medical genetics 1 22436252
2026 Mitochondrial dysfunction in muscle cells induced by snoring vibrations. Mitochondrion 0 42235782
2026 Mass spectrometry-based proteomic profiling of human tauopathy brains suggests mitochondria-associated alterations. Frontiers in molecular neuroscience 0 42254865
2025 Proteomic Screening for Cellular Targets of the Duck Enteritis Virus Protein VP26 Reveals That the Host Actin-Myosin II Network Regulates the Proliferation of the Virus. International journal of molecular sciences 0 41009665
2024 Consensus gene co-expression analysis across multiple intestinal tissues to identify key genes and pathways associated with abdominal fat deposition in broilers. British poultry science 0 39466128
2021 A Novel FACS-Based Workflow for Simultaneous Assessment of RedOx Status, Cellular Phenotype, and Mitochondrial Genome Stability. BioChem 0 35937039

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