ATP5O Human

What is ATP5O and what is its primary function in human cells?

ATP5O, also known as OSCP or ATPO, is a nuclear-encoded subunit of complex V (ATP synthase) of the mitochondrial respiratory chain . It plays a crucial role in cellular energy production by connecting the catalytic core (F1 subunit) and the membrane proton channel (F0 subunit) of the ATP synthase complex . This strategic position allows ATP5O to influence the transmission of conformational changes and proton conductance, which are essential for efficient ATP production . The gene encoding ATP5O is located on chromosome 21q22.11 and is involved in multiple biological processes including ATP biosynthesis, proton transport, and mitochondrial ATP synthesis coupled proton transport .

How is ATP5O expression measured in research settings?

Researchers quantify ATP5O expression primarily through:

• mRNA quantification: Using TaqMan Real-Time PCR with specific probe/primer pairs covering exon boundaries (e.g., exon boundary 4-5) . This approach requires:

  • Total RNA extraction from tissue samples using reagents like Tri Reagent

  • cDNA synthesis using reverse transcriptase and random hexamer primers

  • Amplification using specific probes (e.g., Assays-on-demands, Hs00426889_m1)

  • Normalization to housekeeping genes such as cyclophilin A

  • Running samples in duplicates to ensure reliability

• Protein quantification: Using immunocytochemistry (IHC) to detect and quantify protein levels in tissue samples . For plasma samples, researchers may need to deplete highly abundant proteins (like IgG, albumin, and fibrinogen) before analysis .

For either approach, standardization with proper controls is essential for accurate interpretation of results.

What is the relationship between ATP5O and mitochondrial function?

ATP5O is integral to mitochondrial oxidative phosphorylation (OXPHOS), particularly as a component of ATP synthase (Complex V) . Research shows that:

• ATP5O connects the F1 (catalytic) and F0 (membrane channel) components of ATP synthase

• It facilitates the mechanical rotation that couples proton movement with ATP synthesis

• Alterations in ATP5O function directly impact ATP production efficiency

• Decreased ATP5O levels, particularly due to post-translational modifications like hypo-crotonylation, can reduce cytoplasmic energy levels

• This energy deficit can trigger broader metabolic dysregulation, including abnormalities in phospholipid metabolism

How is ATP5O implicated in prostate cancer progression?

Recent proteomic analyses have identified ATP5O as significantly upregulated in aggressive prostate cancer . Key findings include:

• ATP5O expression is significantly higher in intra-epithelial neoplasia and prostate cancer compared to benign prostate glands

• High expression of ATP5O (observed in 86.8% of samples in one study) was significantly associated with earlier biochemical recurrence

• ATP5O upregulation occurs concertedly with NDUFS1 (a Complex I component), suggesting coordinated enhancement of OXPHOS in aggressive prostate cancer

• Hormone refractory prostate cancer shows significantly higher ATP5O mRNA levels compared to hormone naïve samples

• These findings suggest ATP5O could serve as a potential biomarker for identifying high-risk prostate cancer patients

What is the relationship between ATP5O and glucose metabolism?

ATP5O expression in skeletal muscle has been directly linked to glucose metabolism and insulin sensitivity . Research indicates:

• ATP5O mRNA levels in skeletal muscle positively correlate with insulin-stimulated glucose uptake (regression coefficient = 6.6; p = 0.02)

• Expression of ATP5O is reduced in skeletal muscle from patients with type 2 diabetes compared to healthy controls (p = 0.0027)

• Specific SNPs (rs12482697 and rs11088262) are associated with both ATP5O mRNA expression and glucose uptake in young individuals

• The relationship suggests that ATP5O, in cooperation with other OXPHOS genes, plays an important role in regulating in vivo glucose metabolism

How does aging affect ATP5O expression in human tissues?

Research comparing young and elderly non-diabetic individuals reveals age-related changes in ATP5O expression :

• ATP5O mRNA levels in skeletal muscle are significantly reduced in elderly compared to young individuals, both during basal and insulin-stimulated conditions (p<0.0005)

• The heritability pattern of ATP5O expression differs between age groups:

  Age Group	Best Fitting Model	Additive Genetic Variance	Common Environment	Unique Environment
  Young	AE	0.77 (0.55-0.88)	-	0.23 (0.12-0.45)
  Elderly	CE	-	0.41 (0.09-0.065)	0.59 (0.35-0.91)

This table demonstrates that genetic factors strongly influence ATP5O expression in young individuals (77% of variance), while in elderly individuals, environmental factors become more dominant .

How do post-translational modifications (PTMs) affect ATP5O function?

Recent research has revealed that ATP5O undergoes important post-translational modifications, particularly crotonylation, which significantly impact its function :

• ATP5O-K51 crotonylation is significantly downregulated in chronic stress conditions

• This hypo-crotonylation causes gross ATP5O protein level reduction

• The mechanism involves HDAC2 (histone deacetylase 2), specifically HDAC2-S424 phosphorylation, which determines its decrotonylation activity on ATP5O-K51

• The functional consequence of ATP5O hypo-crotonylation includes:

  • Decreased ATP synthase function

  • Reduced cytoplasmic energy levels

  • Abnormal phospholipid metabolism, particularly downregulation of beneficial phospholipids (PC, PE) and upregulation of detrimental phospholipids (LPC, LPE)

What role does ATP5O play in aging processes across species?

ATP5O has been implicated in aging processes, particularly through comparative studies across species :

• In roundworms (C. elegans), reducing the activity of atp-3 (ATP5O homolog) during larval stages extends lifespan

• Importantly, this lifespan extension effect is stage-specific and does not occur when ATP5O activity is reduced during adulthood

• The gene has homologs across diverse model organisms including:

  • Caenorhabditis elegans (atp-3)

  • Danio rerio (atp5o)

  • Drosophila melanogaster (Oscp)

  • Mus musculus (Atp5o)

  • Rattus norvegicus (Atp5o)

  • Saccharomyces cerevisiae (ATP5)

  • Schizosaccharomyces pombe (atp5)

While the involvement of ATP5O in mammalian aging is not fully established, the conservation across species suggests potentially shared mechanisms .

How is ATP5O expression regulated at the genetic and epigenetic levels?

Research has investigated multiple regulatory mechanisms affecting ATP5O expression :

• Genetic regulation: Specific SNPs influence ATP5O mRNA expression in skeletal muscle:

  • rs12482697: T/T versus T/G; p = 0.02

  • rs11088262: A/A versus A/G; p = 0.004

• DNA methylation: Analysis of the ATP5O promoter shows minimal methylation (<1%) in both young and elderly individuals, with no significant association between methylation status and mRNA expression (p = 0.32)

• Heritability: ATP5O expression shows high heritability (0.77) in young individuals, suggesting strong genetic influence, while environmental factors play a larger role in elderly individuals

What are the optimal approaches for studying ATP5O in clinical samples?

When investigating ATP5O in clinical settings, researchers should consider multiple methodological approaches:

• For tissue samples:

  • Obtain biopsies from relevant tissues (e.g., vastus lateralis muscle for metabolism studies)

  • Process for both protein (IHC) and mRNA analysis (RT-PCR)

  • Include age-matched controls due to significant age-related expression differences

• For plasma samples:

  • Pre-deplete highly abundant proteins (IgG, albumin, fibrinogen) to improve detection of lower-abundance proteins

  • Consider analyzing both protein levels and PTM status, particularly crotonylation

  • Correlate with clinical parameters (e.g., stress scores, metabolic markers)

• For genetic association studies:

  • Include multiple SNPs across the ATP5O locus (studies have used 11+ SNPs)

  • Consider age as a significant covariate in analysis

  • Examine both genetic associations with ATP5O expression and relevant phenotypes (e.g., glucose metabolism)

How should researchers design experiments to investigate ATP5O's role in metabolic disorders?

When studying ATP5O in the context of metabolic disorders, optimal experimental design includes:

• Functional studies:

  • Measure ATP5O expression at both mRNA and protein levels

  • Assess ATP5O post-translational modifications, particularly crotonylation status

  • Correlate with functional outcomes (ATP production, glucose uptake)

• Clinical study design considerations:

  • Control for age, which significantly affects ATP5O expression

  • Include euglycemic hyperinsulinemic clamp to assess insulin sensitivity

  • Consider twin studies to separate genetic from environmental influences

• Integrative approach:

  • Combine proteomic, metabolomic, and genetic analyses for comprehensive understanding

  • Compare findings across tissues and plasma to identify systemic effects

  • Validate findings from model systems in human clinical samples

What are the appropriate controls when studying ATP5O post-translational modifications?

When investigating ATP5O post-translational modifications, particularly crotonylation, researchers should include:

• Tissue-specific controls:

  • Multiple tissue analysis is essential as PTM patterns vary significantly (e.g., crotonylation is downregulated in hypothalamus, liver, and ovaries but unchanged in kidney, heart, lung, and spleen)

• Technical controls:

  • Analysis of multiple PTM types to confirm specificity (research shows crotonylation changes while other PTMs remain stable)

  • Standardized methods for protein depletion when working with plasma samples

• Validation approaches:

  • Correlation of PTM status with total protein levels

  • Functional validation through modulation of regulatory enzymes (e.g., HDAC2)

  • Metabolomic analysis to confirm downstream effects of PTM changes

How might ATP5O serve as a therapeutic target in metabolic and age-related disorders?

Based on current research, several therapeutic approaches targeting ATP5O show promise:

• PTM modulation:

  • Correcting HDAC2 hyperphosphorylation has been shown to recover ATP5O levels and partially rescue downregulated phospholipid metabolism in chronic stress models

  • Targeting specific enzymes regulating ATP5O crotonylation could provide a novel therapeutic avenue

• Expression enhancement:

  • Given the positive correlation between ATP5O expression and insulin-stimulated glucose uptake, therapies enhancing ATP5O expression could potentially improve insulin sensitivity

  • Age-specific approaches may be necessary given the different regulatory mechanisms in young versus elderly individuals

• Biomarker development:

  • ATP5O levels in plasma correlate with stress scores and metabolic parameters, suggesting potential as a biomarker for stress-related metabolic dysfunction

  • In prostate cancer, ATP5O (along with NDUFS1) shows promise as a marker for identifying high-risk patients

What are the unresolved questions regarding ATP5O genetic variation across populations?

Despite significant advances, several questions remain regarding ATP5O genetics:

• Population differences:

  • Current studies have not fully explored population-specific genetic variations in ATP5O

  • The relationship between these variations and disease susceptibility across different ethnic groups remains unclear

• Disease associations:

  • While ATP5O SNPs associate with expression and glucose metabolism in healthy individuals, research has not detected genetic association with type 2 diabetes

  • This suggests complex interactions with other genetic or environmental factors

• Functional consequences:

  • The molecular mechanisms by which ATP5O SNPs affect gene expression and protein function require further investigation

  • How these genetic variations interact with age-related changes in ATP5O regulation remains an open question