bims-mignad 2025-05-11 papers

Issue of 2025–05–11
three papers selected by
Melisa Emel Ermert, Amsterdam UMC

Sheng Li Xue Bao. 2025 Apr 25. 77(2): 345-360

[NAD+ metabolism in cardiovascular diseases].

Zhao-Zhi Wen, Yi-Hang Yang, Dong Liu, Chong-Xu Shi.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Nicotinamide adenine dinucleotide (NAD+) is a central and pleiotropic metabolite involved in multiple cellular energy metabolism, such as cell signaling, DNA repair, protein modifications, and so on. Evidence suggests that NAD+ levels decline with age, obesity, and hypertension, which are all significant CVD risk factors. In addition, the therapeutic elevation of NAD+ levels reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances antioxidation and metabolism in vascular cells of humans with vascular disorders. In preclinical animal models, NAD+ boosting also extends the health span, prevents metabolic syndrome, and decreases blood pressure. Moreover, NAD+ storage by genetic, pharmacological, or natural dietary NAD+-increasing strategies has recently been shown to be effective in improving the pathophysiology of cardiac and vascular health in different animal models and humans. Here, we discuss NAD+-related mechanisms pivotal for vascular health and summarize recent research on NAD+ and its association with vascular health and disease, including hypertension, atherosclerosis, and coronary artery disease. This review also assesses various NAD+ precursors for their clinical efficacy and the efficiency of NAD+ elevation in the prevention or treatment of major CVDs, potentially guiding new therapeutic strategies.

DOI: https://doi.org/10.13294/j.aps.2025.0034

Med Oncol. 2025 May 06. 42(6): 201

Iron overload enhances the susceptibility to cysteine deprivation-induced ferroptosis in non-small cell lung cancer cells.

Selim Kim, Hyeon-Ok Jin, Se-Kyeong Jang, Se Hee Ahn, Gyeongmi Kim, Hyunggee Kim, Tae-Gul Lee, Cheol Hyeon Kim, In-Chul Park.

Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation accumulation. Due to the high iron demand of cancer cells, targeting ferroptosis is considered a promising approach for cancer therapy. This study aimed to elucidate the mechanisms underlying the differences in ferroptosis sensitivity in non-small cell lung cancer (NSCLC) cells and identify strategies to overcome ferroptosis resistance. H1299 cells were more sensitive to cysteine deprivation-induced ferroptosis and exhibited higher transferrin receptor (TfR) expression than H460 cells. Transferrin enhanced ferroptosis in cysteine-deprived H1299 cells, while TfR knockdown reduced ferroptosis, suggesting the involvement of TfR/transferrin system in this process. In H460 cells with low TfR expression, transferrin treatment did not induce ferroptosis under cysteine deprivation, indicating that the TfR/transferrin system was not involved. However, treatment with cell-permeable ferric ammonium citrate increased the sensitivity of ferroptosis to cysteine deprivation or RSL3 treatment. In conclusion, iron overload could be a potential strategy to overcome ferroptosis resistance in NSCLC.

Keywords: Cysteine deprivation; Ferroptosis; Iron; Transferrin; Transferrin receptor

DOI: https://doi.org/10.1007/s12032-025-02757-7

Aging Cell. 2025 May 02. e70085

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.

Hiroaki Tamashiro, Kaori Ishikawa, Koichi Sadotomo, Emi Ogasawara, Kazuto Nakada.

mtDNA mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear. Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced. To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal. These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.

Keywords: aging; mitochondria; mitochondrial DNA

DOI: https://doi.org/10.1111/acel.70085