Impact of Mitochondrial-Associated Proteins on Erectile Dysfunction: Insights from Mendelian Randomization Analysis

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Impact of Mitochondrial-Associated Proteins on Erectile Dysfunction: Insights from Mendelian Randomization Analysis

https://doi.org/10.21203/rs.3.rs-4406855/v1

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Mitochondrial dysfunction is implicated in the pathogenesis of erectile dysfunction (ED); however, establishing a causal relationship remains challenging. This study employed a two-sample Mendelian randomization (MR) approach to investigate the potential causal associations between mitochondria-associated proteins and ED. Association data on mitochondria-associated proteins from the IEU OpenGWAS database were used for exposure, whereas ED association data from the UK Biobank and FinnGen databases served as the outcome. Mendelian randomization analyses were conducted separately, primarily employing the inverse-variance weighted (IVW) method and supplemented by the MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses included Cochran’s Q test, MR-Egger test, and leave-one-out analysis with MR-PRESSO. A meta-analysis of both databases was conducted to enhance the credibility of the results.Meta-analysis revealed a significant causal relationship between five mitochondria-related proteins and ED: 39S ribosomal protein L33 (RPL33; P = 0.013; odds ratio [OR] = 0.94; 95% confidence interval [CI], 0.90–0.99), mitochondrial ubiquitin ligase activator of NFKB-1 (MULAN1; P = 0.039; OR = 1.08; 95% CI: 1.00–1.16), nucleoside diphosphate-linked moiety X motif -8 (NUDT8; P = 0.035; OR = 0.92; 95% CI: 0.84–0.99), pyruvate dehydrogenase (acetyl-transferring) kinase isozyme-1 (PDK1; P = 0.047; OR = 1.07; 95% CI: 1.00–1.14), and serine-tRNA ligase (SerRS; P = 0.005; OR = 1.18; 95% CI: 1.05–1.33). Sensitivity analyses revealed no abnormalities. RPL33 and NUDT8 exhibited potential protective effects against ED, whereas MULAN1, PDK1, and SerRS may increase the risk of developing ED. These findings offer new insights into the role of mitochondrial dysfunction in ED pathogenesis and may guide the development of future therapeutic strategies.

Health sciences/Diseases/Urogenital diseases/Erectile dysfunction

Health sciences/Diseases/Urogenital diseases/Sexual dysfunction

Erectile dysfunction

Mendelian randomization

Inverse-variance weighted method

Mitochondria- Associated proteins

Erectile dysfunction (ED) is characterized by an occasional or frequent inability to achieve and sustain satisfactory erections for sexual activity^[1]. An epidemiological study across eight countries involving 97,159 adult males found that the prevalence of ED among men aged ≥ 18 was 37.2–48.6%^[2].The high incidence and prevalence of ED can lead to various societal issues, including increased divorce rates and a heightened financial burden on families^[3–5]. Therefore, understanding the causes and mechanisms of ED is crucial to find effective solutions.

Mitochondria are often referred to as the "powerhouses" or "energy factories" of cells and are crucial for the synthesis of adenosine triphosphate (ATP), which is essential for cellular activities, regulating cell metabolism, and guiding cell apoptosis. Extensive research has elucidated the relationship between mitochondria and ED^[6–8]. Modulating the expression of specific mitochondrial proteins (such as phosphofurin acidic cluster sorting protein 2) significantly improves erectile function in rats with ED^[9]. Additionally, mitochondrial transplantation from adipose tissue mesenchymal stem cells effectively regulates the energy metabolism of corpus cavernosum smooth muscle cells in rats with ED induced by cavernous nerve injury, thereby reducing cell apoptosis and oxidative stress damage^[10]. Moreover, low-intensity pulsed ultrasound treatment protects endothelial cells and improves erectile function by activating mitochondrial autophagy in endothelial cells of the penile corpus cavernosum^[11]. Despite numerous studies indicating a close association between mitochondria and ED, clear causal evidence for this relationship remains elusive.

We investigated the potential impact of mitochondria-related proteins on ED using the Mendelian randomization (MR) method. Mendelian randomization is a causal inference method that employs genetic variations (single nucleotide polymorphisms [SNPs]) as instrumental variables to identify causal links between exposures and outcomes^{[12, 13]}. This approach provides more reliable data by minimizing the influence of confounding factors and potential biases from reverse causation. We aimed to uncover the potential causal relationship between mitochondria-associated proteins and the onset of ED as well as explore the underlying biological mechanisms.

Study design

We employed a two-sample MR approach to establish causal links between 66 mitochondria-associated proteins and ED. To enhance statistical power and ensure result reliability, data from two independent ED databases were integrated, and a meta-analysis was conducted (Fig. 1). Three criteria were used to select instrumental variables for MR analysis: (i) significant association between the selected SNPs and the expression of the mitochondria-associated protein, (ii) no correlation between the selected SNPs and the confounding factors, and (iii) SNPs affecting ED outcomes solely through their relationship with mitochondria-associated proteins^{[14, 15]}. Approval from the relevant ethics review committees was obtained, and the participants provided informed consent.

Data Source

Data for 66 mitochondria-associated proteins were obtained from a genome-wide association study (GWAS) encompassing 3,301 participants (Supplementary 1). Erectile dysfunction statistics were sourced from the UK Biobank and FinnGen databases. The UK Biobank dataset comprised 223,805 individuals, including 6,175 patients with ED and 217,630 controls. The FinnGen database included 95,178 individuals, comprising 1,154 patients with ED and 94,024 controls. The GWAS ID numbers were “ebi-a-GCST006956” and “finn-b-ERECTILE_DYSFUNCTION,” respectively. The detailed information regarding the GWAS data used in this study can be found in Supplementary Table 1. No overlap was observed among the study populations.

Instrumental Variable Selection

Single nucleotide polymorphisms that were significantly associated with each mitochondria-associated protein (P < 5 × 10^− 6) were chosen as instrumental variables. Initially, linkage disequilibrium pruning was conducted to exclude SNPs with r² < 0.001 and a distance of 10,000 kb, retaining only the SNPs with the lowest P-value. Weak instrumental variables (F-statistics < 10) were eliminated to minimize their impact. The following formula was used to calculate the F-statistic: F = R² × (N − 1−K) / ([1 − R²] × K), where R² represents the proportion of exposure variance explained by genetic variation, N is the sample size, and K is the number of instrumental variables^[16].

Data analysis

The inverse-variance weighted (IVW) method was primarily used for statistical analysis owing to its statistical efficiency when all SNPs are valid instrumental variables. Additional methods included MR-Egger regression, weighted median, simple mode, and weighted mode. MR-Egger corrects for pleiotropy but has lower statistical power and stricter assumptions. The weighted median tolerates over 50% of the invalid instrumental variables, whereas the weighted model provides stable estimates but requires careful weight allocation. The simple mode offers intuitive computation but is sensitive to outliers. The Cochrane Q method was used to assess heterogeneity. MR-Egger regression detects pleiotropy, whereas MR-PRESSO identifies and corrects potential outliers and assesses pleiotropy caused by heterogeneity through its global test. A meta-analysis of the IVW results across the two datasets was conducted to evaluate their robustness and reliability. Statistical analyses were performed using R 4.3 software.

The IVW method demonstrated significant associations between ED and the four proteins using the UK Biobank database. Similarly, six proteins were significantly associated with ED using the FinnGen database. Details of the five MR analysis methods are provided in Supplement 2–3. A meta-analysis of the IVW results identified statistically significant associations between the five proteins and ED (Table 1 and Fig. 3). The detailed data after meta-analysis can be found in Supplement 4.

Table 1

Meta-analysis shows that five kinds of mitochondrial-related proteins are significantly associated with erectile dysfunction.
Exposure	Outcome	N.SNPs	Method	IVW-OR (95% CI)	P (IVW)	MA-OR (95% CI)	P (MA)
RPL33 (prot-a-1942)	ED (ebi-a-GCST006956)	11	IVW	0.945 (0.898–0.996)	0.036	0.942 (0.899–0.987)	0.013
RPL33 (prot-a-1942)	ED (finn-b-ERECTILE_DYSFUNCTION)	11	IVW	0.925 (0.899–0.987)	0.164	0.942 (0.899–0.987)	0.013
MULAN1 (prot-a-1970)	ED (ebi-a-GCST006956)	14	IVW	1.070 (0.988–1.158)	0.097	1.079 (1.004–1.160)	0.039
MULAN1 (prot-a-1970)	ED (finn-b-ERECTILE_DYSFUNCTION)	13	IVW	1.127 (0.945–1.344)	0.183	1.079 (1.004–1.160)	0.039
NUDT8 (prot-a-2128)	ED (ebi-a-GCST006956)	12	IVW	0.931 (0.850–1.020)	0.127	0.916 (0.845–0.994)	0.035
NUDT8 (prot-a-2128)	ED (finn-b-ERECTILE_DYSFUNCTION)	11	IVW	0.864 (0.724–1.031)	0.106	0.916 (0.845–0.994)	0.035
PDK1 (prot-a-2235)	ED (ebi-a-GCST006956)	9	IVW	1.069 (1.000–1.144)	0.052	1.067 (1.001–1.138)	0.047
PDK1 (prot-a-2235)	ED (finn-b-ERECTILE_DYSFUNCTION)	9	IVW	1.047 (0.846–1.298)	0.670	1.067 (1.001–1.138)	0.047
SerRS (prot-a-2627)	ED (ebi-a-GCST006956)	11	IVW	1.213 (1.066–1.380)	0.003	1.182 (1.051–1.328)	0.005
SerRS (prot-a-2627)	ED (finn-b-ERECTILE_DYSFUNCTION)	10	IVW	1.049 (0.795–1.383)	0.734	1.182 (1.051–1.328)	0.005
Comments: RPL33: 39S ribosomal protein L33, mitochondrial; MULAN1: Mitochondrial ubiquitin ligase activator of NFKB 1; NUDT8: Nucleoside diphosphate-linked moiety X motif 8, mitochondrial; PDK1: Pyruvate dehydrogenase (acetyl-transferring) kinase isozyme 1, mitochondrial; SerRS: Serine–tRNA ligase, mitochondrial. IVW: inverse variance weighted. MA: meta-analysis.

39S Ribosomal Protein L33 (RPL33) and ED. In the UK Biobank data, the IVW method revealed a significant association between RPL33 and ED (P = 0.036; OR = 0.95; 95% CI: 0.90–1.00) (Supplement 2). Conversely, the IVW method in the FinnGen data showed a non-significant association (P = 0.163) (Supplement 3). However, a meta-analysis of both datasets indicated a significant association (P = 0.013; OR = 0.94; 95% CI: 0.90–0.99), suggesting that RPL33 may decrease the risk of ED (Fig. 2–3).

Mitochondrial Ubiquitin Ligase Activator of NFKB-1 (MULAN1) and ED. In the UK Biobank data, the IVW method demonstrated a non-significant association between MULAN1 and ED (P = 0.097) (Supplement 2). Similarly, the IVW method also showed a non-significant association in the FinnGen data (P = 0.183) (Supplement 3). However, a meta-analysis of both datasets revealed a significant association (P = 0.039; OR = 1.08; 95% CI: 1.00–1.16), suggesting that MULAN1 may increase the risk of ED (Fig. 2–3).

Nucleoside Diphosphate-linked Moiety X Motif − 8 (NUDT8) and ED. In the UK Biobank data, the IVW method showed a non-significant association between NUDT8 and ED (P = 0.124) (Supplement 2). Similarly, the IVW method showed a non-significant association in the FinnGen data (P = 0.106) (Supplement 3). However, a meta-analysis indicated a significant association (P = 0.035; OR = 0.92; 95% CI: 0.84–0.99), suggesting that NUDT8 may decrease the risk of ED (Fig. 2–3).

Pyruvate Dehydrogenase Kinase Isozyme-1 (PDK1) and ED. In the UK Biobank data, the IVW method showed a non-significant association between PDK1 and ED (P = 0.052) (Supplement 2). Similarly, the IVW method showed a non-significant association using the FinnGen data (P = 0.670) (Supplement 3). However, a meta-analysis indicated a significant association (P = 0.047; OR = 1.07; 95% CI: 1.00–1.14), suggesting that PDK1 may increase the risk of ED (Fig. 2–3).

Serine-tRNA Ligase (SerRS) and ED. In the UK Biobank data, the IVW method showed a significant association between SerRS and ED (P = 0.003; OR = 1.21; 95% CI: 1.07–1.38) (Supplement 2). In contrast, the IVW method showed no significant association in the FinnGen data (P = 0.737) (Supplement 3). Nevertheless, a meta-analysis of both datasets indicated a significant association (P = 0.005; OR = 1.18; 95% CI: 1.05–1.33), suggesting that SerRS may increase the risk of ED (Fig. 2–3).

For the remaining proteins, the results were not significant after meta-analysis, although statistical differences were observed when separately analyzing the UK Biobank or FinnGen databases through MR (Supplement 2–4).

This study utilized MR to explore the causal links between 66 mitochondria-associated proteins listed in the IEU OpenGWAS project and ED, leveraging data from the UK Biobank and FinnGen databases. A meta-analysis of the IVW results across diverse database sources indicated the potential protective effects of RPL33 and NUDT8 against ED, whereas MULAN1, PDK1, and SerRS were associated with an increased risk of ED.

RPL33 is a constituent of the large (39S) subunit of the mammalian mitochondrial ribosome, although its function remains largely unexplored^[17]. Mitochondrial protein synthesis, folding, and assembly rely on mitochondrial ribosomes. 39S rRNA is a component of the large subunit L33 that ensures ribosomal structural integrity and facilitates efficient protein synthesis, potentially preserving mitochondrial function and mitigating ED risk.

NUDT8 is a novel CoA diphosphatase located in the mitochondrial matrix with widespread tissue distribution^[18]. As a crucial coenzyme in cellular metabolism, CoA participates in various metabolic processes crucial for maintaining mitochondrial function and activity. For instance, a decrease in CoA levels may lead to reduced synthesis of long-chain fatty acids, thereby affecting the levels of lipids such as triglycerides in the body^[19]. Additionally, CoA is involved in the reduction of HMG-CoA, contributing to the biosynthesis of cholesterol^[20]. Abnormal lipid accumulation may contribute to ED^[21]. While direct evidence linking NUDT8 to ED is currently lacking, our research suggests a potential role for NUDT8 in reducing the risk of ED, possibly associated with its ability to hydrolyze CoA; further investigation is warranted to explore its mechanism in depth.

MULAN1 harbors an intermembrane mitochondrial domain and a mitochondrial membrane-intrinsic RING finger domain, enabling it to sense intramitochondrial changes and modulate specific cytoplasmic target proteins^[22]. This modulation often involves ubiquitination, marking proteins for degradation, or participation in signaling pathways. MULAN1 ubiquitination is crucial to maintain mitochondrial function and morphology. Dysregulated MULAN1 expression disrupts this process, leading to mitochondrial dysfunction and morphological alterations that affect cellular metabolism, energy production, and apoptosis^[23]. Additionally, MULAN1 activates NF-кB, inducing ubiquitination reactions that regulate various cellular processes, including those in penile corpus cavernosum endothelial and smooth muscle cells^[24–27]. Although direct evidence linking MULAN1 to ED is lacking, our findings suggest its potential involvement in ED etiology.

PDK1 has diverse biological functions and regulates cellular signal transduction and energy metabolism. It activates and phosphorylates PKC, which subsequently triggers the activation of proteins such as MAPK family members and p38, thereby contributing to endothelial dysfunction in penile corpus cavernosum tissue^[28]. Additionally, PDK1 activates AKT kinase through either phosphorylating AKT-Thr308 or mTORC2-mediated AKT-Ser473 phosphorylation, leading to elevated expression of the gap junction protein GJ CX43 in penile corpus cavernosum smooth muscle cells, enhancing smooth muscle contractility and relaxation^{[29, 30]}. Additionally, AKT phosphorylation can improve ED through various pathways^[31]. However, PDK1 also plays a role in promoting fibrosis, which is one of the challenging factors in the treatment of ED^[32]. This suggests that PDK1 plays multiple roles in ED, yet our MR study revealed an increased risk of ED associated with it, warranting further exploration into its detailed mechanisms.

SerRS is located in the mitochondria and catalyzes the binding of serine to specific sites on Trna(Ser), forming acylated seryl-tRNA(Ser)^[33]. This ensures precise protein synthesis within the mitochondria, influencing mitochondrial function and potentially contributing to ED pathogenesis. Our findings revealed a plausible biological mechanism and therapeutic avenue for ED. Other proteins implicated in ED were not significant in the meta-analysis, possibly owing to sample heterogeneity or statistical biases.

We successfully employed MR to explore the causal relationship between mitochondria-associated proteins and ED. Leveraging MR minimizes confounding bias and enhances the credibility of the findings. This study sheds light on the biological mechanisms underlying ED pathogenesis and offers potential therapeutic targets for intervention. However, this study has several limitations to consider. First, we used two independent ED databases, which may have introduced a sample selection bias and limited the generalizability of the results to other populations. Second, there may still be genetic or environmental factors that were not considered, that could potentially affect the accuracy of the results, although MR can mitigate the influence of reverse causation and confounding factors. Finally, this study relied on observational data, which could not establish causality. Therefore, further experimental studies are required to validate these results.

In conclusion, this study provides valuable insights into the causal association between mitochondria-associated proteins and ED, advancing our understanding of ED pathophysiology. Specifically identified proteins such as RPL33, NUDT8, MULAN1, PDK1, and SerRS, present potential therapeutic targets for ED treatment. However, translating these findings into clinical practice requires future investigations focusing on elucidating the underlying mechanisms and validating their therapeutic potential. Subsequent research employing animal models or humanized systems, coupled with mechanistic studies, is crucial for confirming causality and developing effective interventions. Moreover, exploring the interplay between mitochondrial dysfunction and other ED risk factors, such as cardiovascular disease and diabetes, could provide a more comprehensive understanding of ED etiology and aid in the development of personalized treatment strategies. Ultimately, the integration of multidisciplinary approaches (including genetics, molecular biology, and clinical medicine) is essential to realize the full potential of mitochondria-targeted therapies in managing ED.

Our Mendelian randomization analysis has provided genetic evidence that the RPL33 and NUDT8 genes are associated with a reduced risk of ED, while also indicating that the MULAN1, PDK1, and SerRS genes may increase the risk of ED. These findings suggest that enhancing mitochondrial function might represent a potential strategy for the future treatment of ED.

Data availability statement

Publicly available data sets were analyzed in this study. These data sets can be found here: https://gwas.mrcieu.ac.uk/. Please refer to the supplementary materials for the original code of this

Study.

Ethical Statement

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The

current analyses are based on publicly available summary data and therefore do not require ethical approval. Original studies have been approved by ethic committees and written informed

consent was obtained from study participants or caregivers. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

AUTHOR CONTRIBUTIONS

The study's design was created by Bodong Lv. Xin Zhang and Jie Wang analyzed the data and wrote the manuscript. Data downloads were assisted by Yijia Fu. Jianxiong Ma revised the manuscript. The manuscript's published form was accepted by all authors after they had read it.

ACKNOWLEDGMENTS

The authors acknowledge the data contributions made by all participants and researchers in the included GWAS studies.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

FUNDING INFORMATION

Zhejiang Province Traditional Chinese Medicine Prevention and Control Major Disease Research Plan (No. 2018ZY007), National Natural Science Foundation of China (Nos: 82174376, 82074433), The Natural Science Foundation of Zhejiang Province, China (No. LGF20H270002).

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There is NO conflict of interest to disclose.

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Impact of Mitochondrial-Associated Proteins on Erectile Dysfunction: Insights from Mendelian Randomization Analysis

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