Work

Nicotinamide nucleotide transhydrogenase dysfunction transcriptionally impacts mitochondrial β-oxidation and neuromuscular junction in M. Gastrocnemius of 24-day-old mice

Year: 2025

Type: article

Abstract: Nicotinamide nucleotide transhydrogenase (NNT) is a key mitochondrial enzyme generating NADPH by utilizing the proton gradient produced by oxidative phosphorylation (OXPHOS), thereby linking redox homeostasis to mitochondrial energy metabolism. The commonly used C57BL/6 J mouse strain lacks functional NNT, yet its impact during early development remains unclear. This study aimed to characterize adaptive molecular responses in the gastrocnemius muscle of young mice with NNT deficiency. Congenic Nnt deficient ( Nnt Δ ; BL6JRcc.BL6J- Nnt C57BL/6J / Wuhap) and wild-type ( Nnt wt ; B6JRcc(B6J)- Nnt + /Wuhap) mouse lines were newly created. Transcriptome profiling was performed on gastrocnemius muscles of 24-day-old male mice, followed by validation of key findings. Energy metabolism emerged as the most affected process, and Nnt Δ mice exhibited significant reduced OXPHOS-related genes, particularly within complex I and complex V showing a downregulation of 42.2 % and 50 % of their subunits, respectively. Additionally, expression of Cpt1b , Cpt2 , and Slc25a20 , involved in fatty acid transport, was reduced by 33 %, 19 % and 23 %, respectively. These results may explain the trend toward decreased oxygen consumption rates using palmitoylcarnitine (29 %; P -value = 0.068) and octanoylcarnitine (18 %; P-value = 0.081). CHRNA1, a protein critical for neuromuscular junction (NMJ) function, was also downregulated by 31 %. These results suggest that functional loss of NNT impairs mitochondrial energy pathways and β-oxidation, potentially influencing NMJ in the gastrocnemius muscle during development.

Source: International Journal of Biological Macromolecules

DOI: 10.1016/j.ijbiomac.2025.148609

Authors: Jingyi Song, Jaap Keijer, Melissa Bekkenkamp-Grovenstein, Melanie Humphry, Claudia Carmone, Sander Grefte

Institution: Wageningen University & Research

Language: English

Topic: Mitochondrial Function and Pathology

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,390