bims-mignad 2025-04-06 papers

Issue of 2025–04–06
five papers selected by
Melisa Emel Ermert, Amsterdam UMC

Commun Biol. 2025 Apr 02. 8(1): 545

De novo NAD+ synthesis is ineffective for NAD+ supply in axenically cultured Caenorhabditis elegans.

Shihao Zhu, Runshuai Zhang, Luxia Yao, Zhirong Lin, Yanjie Li, Siyuan Li, Lianfeng Wu.

To secure an adequate nicotinamide adenine dinucleotide (NAD+) supply for survival, organisms typically rely on two complementary mechanisms: the de novo synthesis pathway and the salvage pathway. Notably, the classic quinolinic acid phosphoribosyltransferase (QPRTase) for de novo NAD+ synthesis is absent in Caenorhabditis elegans (C. elegans), despite the reported alternative mechanism involving uridine monophosphate phosphoribosyltransferase (UMPS). However, the effectiveness of this proposed mechanism for NAD+ production of C. elegans remains unclear. Here, using a chemically defined medium, we observed that removing NAD+ salvage precursors from the medium results in a significant decrease in NAD+ levels, causing severe developmental delay and fecundity loss in C. elegans. Strikingly, these defects cannot be restored by any metabolites from the de novo synthesis pathway, including the direct QPRTase substrate quinolinic acid (QA). Furthermore, the deficiency of umps-1 does not cause any significant changes in the NAD+ levels of C. elegans. Moreover, the growth defects of the umps-1 mutant could be rescued by uridine, but not the salvage NAD+ supply. Additionally, we discovered that commercially available QA products contain substantial amounts of nicotinic acid, potentially producing misleading information. Collectively, our results demonstrate that C. elegans lacks the necessary mechanisms for de novo synthesis of NAD+.

DOI: https://doi.org/10.1038/s42003-025-07984-2

Front Pharmacol. 2024 ;15 1505867

Mitochondria and oxidative stress in epilepsy: advances in antioxidant therapy.

Delphine Ji, Shanthini Mylvaganam, Prathyusha Ravi Chander, Mark Tarnopolsky, Keiran Murphy, Peter Carlen.

Epilepsy, affecting approximately 50 million individuals worldwide, is a neurological disorder characterized by recurrent seizures. Mitochondrial dysfunction and oxidative stress are critical factors in its pathophysiology, leading to neuronal hyperexcitability and cell death. Because of the multiple mitochondrial pathways that can be involved in epilepsy and mitochondrial dysfunction, it is optimal to treat epilepsy with multiple antioxidants in combination. Recent advancements highlight the potential of antioxidant therapy as a novel treatment strategy. This approach involves tailoring antioxidant interventions-such as melatonin, idebenone, and plant-derived compounds-based on individual mitochondrial health, including mitochondrial DNA mutations and haplogroups that influence oxidative stress susceptibility and treatment response. By combining antioxidants that target multiple pathways, reducing oxidative stress, modulating neurotransmitter systems, and attenuating neuroinflammation, synergistic effects can be achieved, enhancing therapeutic efficacy beyond that of a single antioxidant on its own. Future directions include conducting clinical trials to evaluate these combination therapies, and to translate preclinical successes into effective clinical interventions. Targeting oxidative stress and mitochondrial dysfunction through combination antioxidant therapy represents a promising adjunctive strategy to modify disease progression and improve outcomes for individuals living with epilepsy.

Keywords: antioxidant therapy; epilepsy; mitochondrial dysfunction; oxidative stress; reactive oxygen species

DOI: https://doi.org/10.3389/fphar.2024.1505867

J Transl Genet Genom. 2025 ;9(1): 1-10

What can ATP content tell us about Barth syndrome muscle phenotypes?

Jeffrey J Brault, Simon J Conway.

Adenosine triphosphate (ATP) is the energy currency within all living cells and is involved in many vital biochemical reactions, including cell viability, metabolic status, cell death, intracellular signaling, DNA and RNA synthesis, purinergic signaling, synaptic signaling, active transport, and muscle contraction. Consequently, altered ATP production is frequently viewed as a contributor to both disease pathogenesis and subsequent progression of organ failure. Barth syndrome (BTHS) is an X-linked mitochondrial disease characterized by fatigue, skeletal muscle weakness, cardiomyopathy, neutropenia, and growth delay due to inherited TAFAZZIN enzyme mutations. BTHS is widely hypothesized in the literature to be a model of defective mitochondrial ATP production leading to energy deficits. Prior patient data have linked both impaired ATP production and reduced phosphocreatine to ATP ratios (PCr/ATP) in BTHS children and adult hearts and muscles, suggesting a primary role for perturbed energetics. Moreover, although only limited direct measurements of ATP content and ADP/ATP ratio (an indicator of the energy available from ATP hydrolysis) have so far been carried out, analysis of divergent BTHS animal models, cultured cell types, and diverse organs has failed to uncover a unifying understanding of the molecular mechanisms linking TAFAZZIN deficiency to perturbed muscle energetics. This review mainly focuses on the energetics of striated muscle in BTHS mitochondriopathy.

Keywords: Barth syndrome; TAFAZZIN; adenosine triphosphate; cardiolipin; energetics; mitochondria; striated muscle

DOI: https://doi.org/10.20517/jtgg.2024.83

Methods Mol Biol. 2025 ;2905 1-16

A Systemic View of Target Identification: Modeling the Warburg Effect.

Jean-Yves Trosset, Gilles Bernot.

The dynamics of the cell signaling network is highly regulated to adapt to temporal fluctuations and spatial heterogeneity of the microenvironment. Formal modeling of biological regulatory networks is an approach to identify which key components of this biological network, sometimes individual therapeutic targets, have a long-term influence on a disease-related phenotype of interest. We present an in silico formal screening strategy in the context of cancer metabolism to identify key hot spots in the metabolic network that could induce a systemic change of pathological cell phenotype such as the reversal of the Warburg effect.

Keywords: Formal modeling; Formal screening; Metabolism; Polypharmacology; Renée Thomas modeling; Systemic target identification; TotemBioNet; Warburg effect

DOI: https://doi.org/10.1007/978-1-0716-4418-8_1

ACS Nano. 2025 Apr 03.

Synchronously Evoking Disulfidptosis and Ferroptosis via Systematical Glucose Deprivation Targeting SLC7A11/GSH/GPX4 Antioxidant Axis.

Mengsi Zhang, Hao Zheng, Xuanqi Zhu, Shuwei Liu, Hao Jin, Yang Chen, Lanlan Wan, Songling Zhang, Hao Zhang.

Disulfidptosis and ferroptosis are recently identified programmed cell deaths for tumor therapy, both of which highly depend on the intracellular cystine/cysteine transformation on the cystine transporter solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 (SLC7A11/GSH/GPX4) antioxidant axis. However, disulfidptosis and ferroptosis are usually asynchronous due to the opposite effect of cystine transport on them. Herein, systematic glucose deprivation, by both inhibiting upstream glucose uptake and promoting downstream glucose consumption, is proposed to synchronously evoke disulfidptosis and ferroptosis. As an example, Au nanodots and Fe-apigenin (Ap) complexes coloaded FeOOH nanoshuttles (FeOOH@Fe-Ap@Au NSs) are employed to regulate the SLC7A11/GSH/GPX4 axis for performing disulfidptosis- and ferroptosis-mediated tumor therapy synchronously. In this scenario, Au nanodots exhibit glucose oxidase-like activity when consuming massive glucose. Meanwhile, Ap can inhibit glucose uptake by downregulating glucose transporter 1, depriving glucose fundamentally. The systematical glucose deprivation limits the supplement of NADPH and suppresses cystine/cysteine transformation on the SLC7A11/GSH/GPX4 axis, thus solving the contradiction of cystine transport on disulfidptosis and ferroptosis. In addition, the efficient delivery of exogenous iron ions by FeOOH@Fe-Ap@Au NSs and self-supplied H2O2 through Au nanodots-catalytic glucose oxidation facilitate intracellular Fenton reaction and therewith help to amplify ferroptosis. As a result of synchronous occurrence of disulfidptosis and ferroptosis, FeOOH@Fe-Ap@Au NSs exhibit good efficacy in an ovarian cancer therapeutic model.

Keywords: SLC7A11/GSH/GPX4 axis; cystine transport; disulfidptosis; ferroptosis; glucose deprivation; ovarian cancer

DOI: https://doi.org/10.1021/acsnano.5c00730