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NAD+ deficiency enhances mitochondria-endoplasmic reticulum contacts to promote stress urinary incontinence via the Sirt1-MFN2 axis

ABSTRACT: NAD+ is crucial for energy metabolism and biosynthesis. 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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE331168 | GEO | 2026/05/20

REPOSITORIES: GEO

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Project description:BACKGROUND: Strategies to increase cellular NAD+ (oxidized nicotinamide adenine dinucleotide) level have prevented cardiac dysfunction in multiple models of heart failure, but molecular mechanisms remain unclear. Little is known about the benefits of NAD+-based therapies in failing hearts after the symptoms of heart failure have appeared. Most pretreatment regimens suggested mechanisms involving activation of sirtuin, especially Sirt3 (sirtuin 3), and mitochondrial protein acetylation. METHODS: We induced cardiac dysfunction by pressure overload in SIRT3-deficient (knockout) mice and compared their response with nicotinamide riboside chloride treatment with wild-type mice. To model a therapeutic approach, we initiated the treatment in mice with established cardiac dysfunction. RESULTS: We found nicotinamide riboside chloride improved mitochondrial function and blunted heart failure progression. Similar benefits were observed in wild-type and knockout mice. Boosting NAD+ level improved the function of NAD(H) redox sensitive SDR (short-chain dehydrogenase/reductase) family proteins. Upregulation of Mrpp2 (mitochondrial ribonuclease P protein 2), a multifunctional SDR protein and a subunit of mitochondrial ribonuclease P, improves mitochondrial DNA transcripts processing and electron transport chain function. Activation of SDRs in the retinol metabolism pathway stimulates RXRα (retinoid X receptor α)/PPARα (proliferator-activated receptor α) signaling and restores mitochondrial oxidative metabolism. Downregulation of Mrpp2 and impaired mitochondrial ribonuclease P were found in human failing hearts, suggesting a shared mechanism of defective mitochondrial biogenesis in mouse and human heart failure. CONCLUSIONS: These findings identify SDR proteins as important regulators of mitochondrial function and molecular targets of NAD+-based therapy. Furthermore, the benefit is observed regardless of Sirt3-mediated mitochondrial protein deacetylation, a widely held mechanism for NAD+-based therapy for heart failure. The data also show that NAD+-based therapy can be useful in pre-existing heart failure.

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NAD+ deficiency enhances mitochondria-endoplasmic reticulum contacts to promote stress urinary incontinence via the Sirt1-MFN2 axis

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