Cho, Y. M. | bioRxiv Science

bioRxiv2025

The mitochondrial NAD transporter SLC25A51 is a modulator of beta cell senescence and type 2 diabetes

AbstractNicotinamide adenine dinucleotide (NAD+) is an essential redox cofactor and signaling molecule linked to age-dependent metabolic decline, with its compartmentalization regulated by the mitochondrial carrier SLC25A51. The mechanisms contributing to declining NAD+ levels during aging and the consequences of altered NAD+ homeostasis across tissues are poorly understood. Here, we show that SLC25A51 is upregulated in aging and aging-associated conditions, particularly in senescent cells. In a mouse model of beta-cell senescence, upregulated SLC25A51 was associated with beta-cell identity loss, senescence progression, and a reduced NAD+/NADH ratio. SLC25A51 was elevated following p16INK4a-, replicative-, irradiation-, and H2O2-induced senescence, with NRF2 implicated as a potential transcriptional regulator. Overexpression of SLC25A51, but not a transport-dead mutant, induced senescence factors, while its deletion prevented this effect. Beta-cell-specific deletion of SLC25A51 lowered p16INK4a levels in pancreatic islets, circulating insulin, and glucose levels, improving insulin sensitivity and indicating its role in cellular senescence and the metabolic control of beta-cell function.

cell biology↗

bioRxiv2017

Functional Difference of Mitochondrial Genome and Its Association with Traits of Common Complex Diseases in Humans

Recent evidence suggests that mitochondrial genomes harboring common mitochondrial DNA polymorphisms might have functional difference and could be associated with common complex human diseases such as metabolic syndrome and cancer that are related to mitochondrial dysfunction. However, there has been no report examining the functional difference of mitochondrial genome in the pathogenesis of such diseases at the cellular or molecular level. In order to examine the effect of mitochondrial genome on metabolic syndrome or cancer without interference from nuclear genes, we analyzed trans-mitochondrial cytoplasmic hybrid cells (cybrids) with common Asian mtDNA haplogroups A, B, D, and F from healthy volunteers. The mitochondrial oxygen consumption rates of cybrids were associated with multiple components of metabolic syndrome such as body mass index, waist circumference, serum triglyceride levels and high-density lipoprotein cholesterol levels. In addition, the cybrids showed varying degree of tumorigenicity both in vitro and in vivo. Especially, the cybrids harboring mtDNA haplogroup D had a significantly slower growth rate. These findings suggest that the phenotypes of common complex diseases in humans can be determined by their mitochondrial genomes. Therefore, not only nuclear genome but also mitochondrial genome should be considered in explaining the genetic pathogenesis of common complex human diseases.

genetics↗