bims-mignad 2024-12-22 papers

Issue of 2024–12–22
three papers selected by
Melisa Emel Ermert, Amsterdam UMC

Subcell Biochem. 2024 ;107 63-90

Jared Rice, Sofie Lautrup, Evandro F Fang.

Nicotinamide adenine dinucleotide (oxidized form, NAD+) serves as a co-substrate and co-enzyme in cells to execute its key roles in cell signalling pathways and energetic metabolism, arbitrating cell survival and death. It was discovered in 1906 by Arthur Harden and William John Young in yeast extract which could accelerate alcohol fermentation. NAD acts as an electron acceptor and cofactor throughout the processes of glycolysis, Tricarboxylic Acid Cycle (TCA), β oxidation, and oxidative phosphorylation (OXPHOS). NAD has two forms: NAD+ and NADH. NAD+ is the oxidising coenzyme that is reduced when it picks up electrons. NAD+ levels steadily decline with age, resulting in an increase in vulnerability to chronic illness and perturbed cellular metabolism. Boosting NAD+ levels in various model organisms have resulted in improvements in healthspan and lifespan extension. These results have prompted a search for means by which NAD+ levels in the body can be augmented by both internal and external means. The aim of this chapter is to provide an overview of NAD+, appraise clinical evidence of its importance and success in potentially extending health- and lifespan, as well as to explore NAD+ boosting strategies.

Keywords: Ageing; Caloric restriction; NAD+; Neurodegeneration; Nicotinamide mononucleotide; Nicotinamide riboside; Oxidative stress; Supplementation

DOI: https://doi.org/10.1007/978-3-031-66768-8_4

Nat Metab. 2024 Dec;6(12): 2319-2337

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.

The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.

DOI: https://doi.org/10.1038/s42255-024-01174-w

BMB Rep. 2024 Dec 17. pii: 6336. [Epub ahead of print]

PGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death.

Byeong Geun Seok, Eunhee Park, Young-Jun Park, Young-Jun Park, Hyuk Nam Kwon, Su Wol Chung.

A type of programmed cell death called ferroptosis is defined by increased iron-dependent lipid peroxidation. Mitochondria play a central role in iron metabolism. Mitochondrial defects include decreased cristae density, membrane rupture, and decreased mitochondrial membrane density, which occur as a result of ferroptosis. One of the important regulator of mitochondrial biogenesis is PGC1α. While recent studies have begun to explore the association between PGC1α and ferroptosis, the specific role of PGC1α in erastin-induced mitochondrial dysfunction during ferroptotic cell death has not been fully elucidated. In this study, we demonstrate for the first time that PGC1α is a key regulator of erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis in HT1080 fibrosarcoma cells. In this study, we examined PGC1α function in ferroptosis. Erastin, an inducer of ferroptosis, boosted the expression of PGC1α. Moreover, PGC1α down-regulation reduced erastin-induced ferroptosis. The most important biochemical feature of ferroptosis is the increase in iron ion (Fe2+)-dependent lipid peroxide (LOOH) concentration. Mitochondrial-dependent lipid peroxidation was abolished by PGC1α downregulation. In addition, PGC1α was induced during mitochondrial dysfunction in erastin-induced ferroptosis. Mitochondrial membrane potential loss and mitochondrial ROS production associated with erastin-induced mitochondrial dysfunction were blocked by PGC1α inhibition. In addition, erastin-induced lipid peroxidation in HT1080 fibrosarcoma cells was regulated by PGC1α inhibitor. This phenomenon was also consistent in HT1080 cells transfected with PGC1α shRNA transfected cells. Taken together, these results suggest that PGC1α is a key factor in erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis cell death.