bims-mignad 2024-10-13 papers

Issue of 2024‒10‒13
six papers selected by
Melisa Emel Ermert, Amsterdam UMC

Front Cell Dev Biol. 2024 ;12 1464815

Mechanisms of the NAD+ salvage pathway in enhancing skeletal muscle function.

Mengzhu Su, Fanghui Qiu, Yansong Li, Tongtong Che, Ningning Li, Shuangshuang Zhang.

Nicotinamide adenine dinucleotide (NAD+) is crucial for cellular energy production, serving as a coenzyme in oxidation-reduction reactions. It also supports enzymes involved in processes such as DNA repair, aging, and immune responses. Lower NAD+ levels have been associated with various diseases, highlighting the importance of replenishing NAD+. Nicotinamide phosphoribosyltransferase (NAMPT) plays a critical role in the NAD+ salvage pathway, which helps sustain NAD+ levels, particularly in high-energy tissues like skeletal muscle.This review explores how the NAMPT-driven NAD+ salvage pathway influences skeletal muscle health and functionality in aging, type 2 diabetes mellitus (T2DM), and skeletal muscle injury. The review offers insights into enhancing the salvage pathway through exercise and NAD+ boosters as strategies to improve muscle performance. The findings suggest significant potential for using this pathway in the diagnosis, monitoring, and treatment of skeletal muscle conditions.

Keywords: NAD+; NAMPT; T2DM; aging; skelelal muscle

DOI: https://doi.org/10.3389/fcell.2024.1464815

Neurobiol Dis. 2024 Oct 05. pii: S0969-9961(24)00294-8. [Epub ahead of print] 106694

Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease.

Michiko Sekiya, Yasufumi Sakakibara, Yu Hirota, Naoki Ito, Sachie Chikamatsu, Kimi Takei, Risa Nishijima, Koichi M Iijima.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Amyloid-β (Aβ) accumulation triggers chronic neuroinflammation, initiating AD pathogenesis. Recent clinical trials for anti-Aβ immunotherapy underscore that blood-based biomarkers have significant advantages and applicability over conventional diagnostics and are an unmet clinical need. To further advance ongoing clinical trials and identify novel therapeutic targets for AD, developing additional plasma biomarkers closely associated with pathogenic mechanisms downstream of Aβ accumulation is critically important. To identify plasma metabolites reflective of neuroinflammation caused by Aβ pathology, we performed untargeted metabolomic analyses of the plasma by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) and analyzed the potential roles of the identified metabolic changes in the brain neuroinflammatory response using the female App knock-in (AppNLGF) mouse model of Aβ amyloidosis. The CE-TOFMS analysis of plasma samples from female wild-type (WT) and AppNLGF mice revealed that plasma levels of nicotinamide, a nicotinamide adenine dinucleotide (NAD+) precursor, were decreased in AppNLGF mice, and altered metabolite profiles were enriched for nicotinate/nicotinamide metabolism. In AppNLGF mouse brains, NAD+ levels were unaltered, but mRNA levels of NAD+-synthesizing nicotinate phosphoribosyltransferase (Naprt) and NAD+-degrading Cd38 genes were increased. These enzymes were induced in reactive astrocytes and microglia surrounding Aβ plaques in the cortex and hippocampus of female AppNLGF mouse brains, suggesting neuroinflammation increases NAD+ metabolism. This study suggests plasma nicotinamide could be indicative of the neuroinflammatory response and that nicotinate and nicotinamide metabolism are potential therapeutic targets for AD, by targeting both neuroinflammation and neuroprotection.

Keywords: Alzheimer's disease (AD); Amyloid-β (Aβ); App knock-in mouse; Metabolomic analysis; NAD(+); Neuroinflammation; Nicotinamide

DOI: https://doi.org/10.1016/j.nbd.2024.106694

Cell Death Dis. 2024 Oct 11. 15(10): 744

NAD+-boosting agent nicotinamide mononucleotide potently improves mitochondria stress response in Alzheimer's disease via ATF4-dependent mitochondrial UPR.

Xi Xiong, Jialong Hou, Yi Zheng, Tao Jiang, Xuemiao Zhao, Jinlai Cai, Jiani Huang, Haijun He, Jiaxue Xu, Shuangjie Qian, Yao Lu, XinShi Wang, Wenwen Wang, Qianqian Ye, Shuoting Zhou, Mengjia Lian, Jian Xiao, Weihong Song, Chenglong Xie.

Extensive studies indicate that mitochondria dysfunction is pivotal for Alzheimer's disease (AD) pathogenesis; while cumulative evidence suggests that increased mitochondrial stress response (MSR) may mitigate neurodegeneration in AD, explorations to develop a MSR-targeted therapeutic strategy against AD are scarce. We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which NAD+-boosting agent nicotinamide mononucleotide (NMN) regulates MSR in AD models. Here, we report dyshomeostasis plasma UPRmt-mitophagy-mediated MSR profiles in AD patient samples. NMN restores NAD+ metabolic profiles and improves MSR through the ATF4-dependent UPRmt pathway in AD-related cross-species models. At the organismal level, NAD+ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD. Remarkably, omics features of the hippocampus with NMN show that NMN leads to transcriptional changes of genes and proteins involved in MSR characteristics, principally within the astrocyte unit rather than microglia and oligodendrocytes. In brief, our work provides evidence that MSR has an active role in the pathogenesis of AD, as reducing mitochondrial homeostasis via atf4 depletion in AD mice aggravates the hallmarks of the disease; conversely, bolstering mitochondrial proteostasis by NMN decreases protein aggregation, restores memory performance, and delays disease progression, ultimately translating to increased healthspan.

DOI: https://doi.org/10.1038/s41419-024-07062-1

Cell Commun Signal. 2024 Oct 11. 22(1): 491

Disulfidptosis: a novel cell death modality induced by actin cytoskeleton collapse and a promising target for cancer therapeutics.

Tianyi Li, Ying Song, Lijuan Wei, Xiangyi Song, Ruifeng Duan.

Disulfidptosis is a novel discovered form of programmed cell death (PCD) that diverges from apoptosis, necroptosis, ferroptosis, and cuproptosis, stemming from disulfide stress-induced cytoskeletal collapse. In cancer cells exhibiting heightened expression of the solute carrier family 7 member 11 (SLC7A11), excessive cystine importation and reduction will deplete nicotinamide adenine dinucleotide phosphate (NADPH) under glucose deprivation, followed by an increase in intracellular disulfide stress and aberrant disulfide bond formation within actin networks, ultimately culminating in cytoskeletal collapse and disulfidptosis. Disulfidptosis involves crucial physiological processes in eukaryotic cells, such as cystine and glucose uptake, NADPH metabolism, and actin dynamics. The Rac1-WRC pathway-mediated actin polymerization is also implicated in this cell death due to its contribution to disulfide bond formation. However, the precise mechanisms underlying disulfidptosis and its role in tumors are not well understood. This is probably due to the multifaceted functionalities of SLC7A11 within cells and the complexities of the downstream pathways driving disulfidptosis. This review describes the critical roles of SLC7A11 in cells and summarizes recent research advancements in the potential pathways of disulfidptosis. Moreover, the less-studied aspects of this newly discovered cell death process are highlighted to stimulate further investigations in this field.

Keywords: Actin dynamics; Arp2/3 complex; Cancer treatment; Cystine; Disulfide stress; Disulfidptosis; Programmed cell death; Rac1; SLC7A11; WAVE regulatory complex

DOI: https://doi.org/10.1186/s12964-024-01871-9

Biochem Biophys Res Commun. 2024 Sep 29. pii: S0006-291X(24)01302-0. [Epub ahead of print]734 150766

LDHB-deficient brain exhibits resistance to ischemic neuronal cell death due to increased vasodilation.

Jin Soo Lee, Bok Seon Yoon, Yihyang Kim, Chan Bae Park.

Ischemic stroke triggers a cascade of metabolic and inflammatory events leading to neuronal death, particularly in the hippocampus. Here, we investigate the role of lactate metabolism in ischemic resistance using LDHB-deficient mice, which exhibit impaired lactate utilization. Contrary to expectations of severe neuronal damage due to metabolic defects, LDHB-deficient mice displayed significantly increased neuronal survival following ischemic insult. Magnetic resonance spectroscopy revealed elevated lactate levels in LDHB-deficient brains, which correlated with enhanced vasodilation of the posterior communicating artery (PComA) and increased extracellular PGE2 levels. These findings suggest that elevated lactate inhibits PGE2 reabsorption, promoting vasodilation and neuronal protection. Our results highlight lactate's potential role in neuroprotection and its therapeutic promise for ischemic stroke.

Keywords: Ischemic stroke; Lactate; Lactate dehydrogenase B; Vasodilation

DOI: https://doi.org/10.1016/j.bbrc.2024.150766

Nat Commun. 2024 Oct 07. 15(1): 8682

Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.

Lucia Del Prado, Myriam Jaraíz-Rodríguez, Mauro Agro, Marcos Zamora-Dorta, Natalia Azpiazu, Manuel Calleja, Mario Lopez-Manzaneda, Jaime de Juan-Sanz, Alba Fernández-Rodrigo, José A Esteban, Mònica Girona, Albert Quintana, Eduardo Balsa.

Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.

DOI: https://doi.org/10.1038/s41467-024-52968-1