Details for: ATP5MC3

Gene ID: 518

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: ATP5MC3

Ensembl ID: ENSG00000154518

Description: ATP synthase membrane subunit c locus 3

Selected Context(s):  Retina + Healthy

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • ON-bipolar cell CL0000749
    CSI 133.75
    rCSI 90.03%
    PRS 10.58
  • retinal rod cell CL0000604
    CSI 110.04
    rCSI 84.68%
    PRS 3.49
  • retinal cone cell CL0000573
    CSI 89.63
    rCSI 67.64%
    PRS 3.32
  • retinal ganglion cell CL0000740
    CSI 77.82
    rCSI 92.81%
    PRS 22.96

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Analyzed for its expression specificity (**CSI Z-SCORE**), [ATP5MC3](/details-gene/518) is identified not as a cell-type-specific marker but as a ubiquitously expressed 'housekeeping' gene. Its fundamental role as a subunit of the mitochondrial ATP synthase complex is consistent with its broad, non-specific expression pattern in metabolically active cells. Variants in [ATP5MC3](/details-gene/518) are associated with neurological disorders, highlighting its critical importance in tissues with high energy demands. ## Cellular Roles and Expression Landscape The expression profile of [ATP5MC3](/details-gene/518) in the **Retina + Healthy** context is characterized by a notable lack of cell-type specificity. This is evidenced by statistically non-significant **CSI (Z-SCORE)** values of 0.00 and correspondingly low Percentile Rank Scores (PRS) across all top-expressing cell types, including [ON-bipolar cell](/details-cell/CL0000749), [retinal rod cell](/details-cell/CL0000604), [retinal cone cell](/details-cell/CL0000573), and [retinal ganglion cell](/details-cell/CL0000740). This expression pattern strongly suggests that [ATP5MC3](/details-gene/518) is not a gene that defines the unique identity of these cells. Instead, its consistent presence underscores its essential 'housekeeping' function in maintaining cellular energy homeostasis. The high metabolic activity required for phototransduction and neural signaling in retinal neurons necessitates robust mitochondrial function, making the abundant expression of ATP synthase components like [ATP5MC3](/details-gene/518) a biological prerequisite for their survival and operation. Its role is therefore fundamental rather than specific. ## Pathways and Molecular Function The functional annotations for [ATP5MC3](/details-gene/518) align perfectly with its observed ubiquitous expression pattern. As a core component of the proton-transporting ATP synthase complex ([GO:0045263](https://www.ebi.ac.uk/QuickGO/term/GO:0045263)), it is localized to the mitochondrial inner membrane ([GO:0005743](https://www.ebi.ac.uk/QuickGO/term/GO:0005743)) and is indispensable for proton motive force-driven ATP synthesis ([GO:0015986](https://www.ebi.ac.uk/QuickGO/term/GO:0015986)). Its involvement in high-level Reactome pathways such as '[Metabolism](/details-pathway/R-HSA-1430728)', '[Formation of atp by chemiosmotic coupling](/details-pathway/R-HSA-163210)', and '[Mitochondrial biogenesis](/details-pathway/R-HSA-1592230)' reinforces its role as a central player in cellular bioenergetics. These processes are not specific to any single cell type but are vital for nearly all cells in the human body. The clinical association of [ATP5MC3](/details-gene/518) mutations with variable neurological phenotypes, including dystonia and spastic paraplegia (PubMed: [34636445](https://pubmed.ncbi.nlm.nih.gov/34636445/), [34954817](https://pubmed.ncbi.nlm.nih.gov/34954817/)), suggests that while the gene is expressed broadly, certain neuronal populations are exquisitely vulnerable to even minor perturbations in its function. ## Research Directions The available data is limited to a single **Retina + Healthy** context, which precludes a direct comparative analysis of [ATP5MC3](/details-gene/518) expression in disease states. However, by integrating its fundamental biological role with known clinical associations, several testable hypotheses can be formulated. 1. **Hypothesis:** Disease-causing variants in [ATP5MC3](/details-gene/518) that lead to neurological symptoms may also cause subclinical or overt retinal degeneration due to the high metabolic demand of photoreceptors and retinal ganglion cells. * **Experimental Approach:** Conduct a longitudinal study on a cohort of patients with confirmed pathogenic [ATP5MC3](/details-gene/518) variants, performing detailed retinal imaging (e.g., Optical Coherence Tomography) and functional tests (e.g., electroretinography). Concurrently, use patient-derived induced pluripotent stem cells (iPSCs) to generate retinal organoids harboring these mutations to assess photoreceptor development, survival, and metabolic function *in vitro*. 2. **Hypothesis:** The tissue-specific vulnerability observed in [ATP5MC3](/details-gene/518)-related disorders stems from cell-type-specific metabolic thresholds, where neurons with the highest firing rates (e.g., motor neurons, certain interneurons) are unable to compensate for reduced ATP synthase efficiency. * **Experimental Approach:** Generate a knock-in mouse model with a clinically relevant [ATP5MC3](/details-gene/518) mutation. Perform single-cell RNA sequencing and electrophysiological recordings (patch-clamp) on distinct neuronal populations (e.g., cortical pyramidal neurons, Purkinje cells, spinal motor neurons) to correlate gene expression profiles with functional deficits under metabolic stress. 3. **Hypothesis:** The functional impact of pathogenic [ATP5MC3](/details-gene/518) variants is modulated by cell-type-specific differences in the expression of ATP synthase assembly factors or post-translational modifying enzymes. As reported by (PubMed: [30530489](https://pubmed.ncbi.nlm.nih.gov/30530489/)), post-translational modifications can optimize ATP synthase function. * **Experimental Approach:** Use targeted proteomics and mass spectrometry to quantify the interactome and post-translational modification landscape of mutant [ATP5MC3](/details-gene/518) protein in vulnerable (e.g., CNS) versus resilient (e.g., liver) tissues from a relevant animal model. This could identify key interacting proteins like [TMEM70](/details-gene/54968) or modifying enzymes whose expression levels dictate the phenotypic outcome. **Therapeutic Potential:** Given its essential and ubiquitous nature, [ATP5MC3](/details-gene/518) presents a challenging therapeutic target. Direct modulation is likely to have widespread systemic effects. However, for monogenic disorders caused by loss-of-function mutations, AAV-mediated gene replacement therapy delivered directly to the most affected tissues, such as the central nervous system or the retina, could be a viable strategy. Additionally, developing small molecule chaperones or stabilizers that enhance the function or assembly of the partially compromised ATP synthase complex could offer a pathway to ameliorate disease symptoms in patients with specific missense mutations.

Genular Protein ID: 2195643636

Symbol: AT5G3_HUMAN

Name: ATP synthase lipid-binding protein

UniProtKB Accession Codes:

P48201 B2R4Z0 D3DPF0 Q4ZFX7

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 3 GO 7 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HAMAP 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PIR 1 PRINTS 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 2 RefSeq 2 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TopDownProteomics 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7698763

Title: Sequence analysis and mapping of a novel human mitochondrial ATP synthase subunit 9 cDNA (ATP5G3).

PubMed ID: 7698763

DOI: 10.1006/geno.1994.1631

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 30530489

Title: Lysine methylation by the mitochondrial methyltransferase FAM173B optimizes the function of mitochondrial ATP synthase.

PubMed ID: 30530489

DOI: 10.1074/jbc.ra118.005473

PubMed ID: 33753518

Title: TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase and interact with assembly factors for complex I.

PubMed ID: 33753518

DOI: 10.1073/pnas.2100558118

PubMed ID: 34636445

Title: A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia.

PubMed ID: 34636445

DOI: 10.1002/mds.28821

PubMed ID: 34954817

Title: Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes.

PubMed ID: 34954817

DOI: 10.1002/ana.26293

Sequence Information:

  • Length: 142
  • Mass: 14693
  • Checksum: 19EC0D1710A0AA3F
  • Sequence:
    • MFACAKLACT PSLIRAGSRV AYRPISASVL SRPEASRTGE GSTVFNGAQN GVSQLIQREF 
QTSAISRDID TAAKFIGAGA ATVGVAGSGA GIGTVFGSLI IGYARNPSLK QQLFSYAILG 
FALSEAMGLF CLMVAFLILF AM