ArticleCellular & molecular biology letters2025
Multi-omics integration reveals Vha68-3 as a testicular aging-specific factor that coordinates spermatid elongation through mitochondrial metabolic homeostasis.
Article in Cellular & molecular biology letters, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Testicular ageing as a central hallmark of male senescence: characteristics, molecular mechanisms and emerging therapeutic strategies.Annals of medicine · 2026Review
- Review
- Super-Multiplexed Label-Free Raman Imaging Uncovers Novel Testicular Metabolic Couplings for Residual Body and Spermatogonial Differentiation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Cap 2'-O-methyltransferase CMTR2 regulates male meiosis independent of its methyltransferase activity.Nucleic acids research · 2026Article
- Credit to the Fruit Fly: How the Tiny Insect Lights Up Our Understanding of Human Disease.Insects · 2026Review
- Research Progress on the Interaction Between SIRT1 and Mitochondrial Biochemistry in the Aging of the Reproductive System.Biology · 2025Review
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19 authors.
Funding
Abstract
backgroundTesticular aging has profound effects on spermatogenesis, sperm function, and the spermatogenic microenvironment, contributing to reduced male fertility. However, the precise molecular mechanisms by which mitochondria influence spermiogenesis during aging still remain largely unclear.
methodsVha68-3 KO flies were generated using the CRISPR/Cas9 technique. Testicular phenotypes and functions were mainly observed through immunofluorescence staining and transmission electron microscopy. Multi-omics study was mainly conducted through single-cell RNA sequencing and transcriptome-metabolomics association analysis. Vha68-3 binding proteins were identified via liquid chromatography-tandem mass spectrometry. The therapeutic potential of modulating mitochondrial metabolism for testicular aging mainly relied on the dietary intake of related compounds in fruit flies.
resultsIn this study, we identified Vha68-3, a testis-specific subunit of the V-type adenosine triphosphate (ATP) synthase, predominantly localized in the tails of elongated spermatids, as a key age-related regulator of male fertility and spermatid elongation in Drosophila testes. Crucially, Vha68-3 deficiency impaired mitochondrial homeostasis in elongated spermatids during testicular aging. Through a multi-omics approach, including single-cell transcriptomics, protein interaction mapping of Vha68-3, and transcriptome-metabolome integration, we identified pyruvate metabolism as a critical pathway disrupted by Vha68-3 deficiency. Moreover, dietary supplementation with pyruvate (PA), S-lactoylglutathione (SLG), and phosphoenolpyruvate (PEP) effectively alleviated mitochondrial dysfunction and testicular aging linked to Vha68-3 deficiency.
conclusionsOur findings uncover novel mechanisms by which mitochondrial metabolism regulates spermatid elongation and propose potential therapeutic strategies to combat mitochondrial metabolic disorders in aging testes.
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