Excel · study · 2026
NAD+ deficiency enhances mitochondria-endoplasmic reticulum contacts to promote stress urinary incontinence via the Sirt1-MFN2 axis
Listed in NCBI GEO
NAD+ is crucial for energy metabolism and biosynthesis.
Description
Muscle tissues, including the levator ani muscle (LAM), are particularly rich in mitochondria and have high energy demands, making them highly dependent on NAD+. Mechanical stress from pregnancy, childbirth, and elevated abdominal pressure can damage the LAM, increasing the risk of stress urinary incontinence (SUI).
However, the impact of NAD+ changes in the LAM during SUI development has not been thoroughly investigated, and the underlying mechanisms remain unclear. In this study, employing methodologies including Transmission electron microscope (TEM), proximity ligation assay (PLA), and RNA-seq, we demonstrated that decreased NAD+ due to increased DNA damage and CD38 protein levels induced by mechanical stress were associated with SUI onset in mouse models.
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Urinary incontinence in SUI mice and viability of myoblasts in SUI mice could be improved by restoring NAD+. Additionally, NAD+ depletion resulted in reduced Sirt1 deacetylation activity and increased acetylation of the downstream target MFN2. The increased MFN2 acetylation mediated the tethering of the endoplasmic reticulum (ER) to mitochondria, which enhanced the formation of mitochondrial-ER contacts (MERCs) and led to mitochondrial Ca2+ overload and dysfunction.
Supplementing NAD+ or enhancing Sirt1 activity significantly reduced MERCs formation, mitigated mitochondrial Ca2+ overload, and protected mitochondrial function. Finally, mutation of MFN2 lysine (K243) to glutamine, which mimicked protein acetylation, further clarified that acetylation of MFN2 promoted MERCs formation. Our findings suggest that NAD+ loss in the LAM plays a vital role in the development of SUI.
These insights provide valuable preclinical information for potential SUI treatments.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE331nnn/GSE331168 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331168 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1467434 ncbi.nlm.nih.gov/bioproject/PRJNA1467434 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- RNA sequencing 65%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE331168 | 15 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |