bims-mignad 2025-03-30 papers

Issue of 2025–03–30
four papers selected by
Melisa Emel Ermert, Amsterdam UMC

Enzyme Microb Technol. 2025 Mar 21. pii: S0141-0229(25)00053-5. [Epub ahead of print] 110633

Establishing a novel pathway for the biosynthesis of nicotinamide mononucleotide.

Rongchen Feng, Ziting Yan, Guoguang Wei, Chaoqiang Wu, Feifei Chen, Alei Zhang, Sheng Xu, Xin Wang, Kequan Chen.

Nicotinamide mononucleotide (NMN) is a pivotal molecule within the realm of metabolic health, serving as a precursor to nicotinamide adenine dinucleotide (NAD+), a critical coenzyme in cellular energy metabolism. In recent years, the biological production of NMN has garnered significant interest. In this study, we developed the novel NRK-dependent synthesis routes for NMN production. Two strategies were designed to supply D-ribose-1-phosphate (R-1-P): (1) phosphorylation of exogenous D-ribose to ribose-5-phosphate (R-5-P) using engineered ribokinase (RK), followed by isomerization to R-1-P; (2) R-5-P synthesis from glucose through the pentose phosphate pathway. An optimized in vitro multi-enzyme cascade (XapA/PNP/NRK, PPM, NRK) identified NRK as the most efficient catalyst for NMN biosynthesis from D-ribose and niacinamide. In Escherichia coli, overexpression of this cascade, knockout of competing pathways, and secretion enhancement via a pelB signal peptide-fused PnuC transporter achieved an NMN titer of 62.0 mg L-¹ .This work provides a viable alternative for the biosynthesis of NMN.

Keywords: CRISPR-Cas9 gene editing; Nicotinamide mononucleotide; Nicotinamide ribose; Phosphoribomutase; Signal peptide; Transporter protein

DOI: https://doi.org/10.1016/j.enzmictec.2025.110633

Semin Cancer Biol. 2025 Mar 25. pii: S1044-579X(25)00053-7. [Epub ahead of print]

The Warburg effect: the hacked mitochondrial-nuclear communication in cancer.

Haowen Jiang, Jiangbin Ye.

Mitochondrial-nuclear communication is vital for maintaining cellular homeostasis. This communication begins with mitochondria sensing environmental cues and transmitting signals to the nucleus through the retrograde cascade, involving metabolic signals such as substrates for epigenetic modifications, ATP and AMP levels, calcium flux, etc. These signals inform the nucleus about the cell's metabolic state, remodel epigenome and regulate gene expression, and modulate mitochondrial function and dynamics through the anterograde feedback cascade to control cell fate and physiology. Disruption of this communication can lead to cellular dysfunction and disease progression, particularly in cancer. The Warburg effect is the metabolic hallmark of cancer, characterized by disruption of mitochondrial respiration and increased lactate generation from glycolysis. This metabolic reprogramming rewires retrograde signaling, leading to epigenetic changes and dedifferentiation, further reprogramming mitochondrial function and promoting carcinogenesis. Understanding these processes and their link to tumorigenesis is crucial for uncovering tumorigenesis mechanisms. Therapeutic strategies targeting these disrupted pathways, including metabolic and epigenetic components, provide promising avenues for cancer treatment.

Keywords: Warburg effect; cell dedifferentiation; epigenetic remodeling; metabolic reprogramming; metabolic therapy; mitochondrial dynamics; mitochondrial dysfunction

DOI: https://doi.org/10.1016/j.semcancer.2025.03.006

Neurotox Res. 2025 Mar 28. 43(2): 18

Kynurenine Pathway in Epilepsy: Unraveling Its Role in Glutamate Excitotoxicity, GABAergic Dysregulation, Neuroinflammation, and Mitochondrial Dysfunction.

Manpreet Kaur, Pratyush Porel, Royal Patel, Khadga Raj Aran.

Epilepsy is a chronic noncommunicable neurological disorder characterized by recurrent seizures and ranks as the seventh most prevalent neurological disease globally. According to the Global Burden of Disease report, 3.40 billion people were affected by epilepsy in 2021. The pathophysiology of epilepsy states that a disturbed balance between excitatory and inhibitory signaling at the synaptic level, which can cause seizure activity, is similar across epilepsies and includes mitochondrial dysfunction, neuroinflammation, and kynurenine metabolites such as kynurenic acid and quinolinic acid. The kynurenine pathway (KP) is the major metabolic pathway in which tryptophan (TRP) is the key precursor which is further converted into a variety of neuroactive substances that can have both neurotoxic metabolites (Quinolinic acid) and neuroprotective metabolites such as kynurenic acid, and picolinic acid. KP plays a significant role in the brain such as the metabolism of TRP, the production of metabolites, and its impact on aging. However, higher concentrations of kynurenine and its metabolites, such as quinolinic acid may increase the frequency and intensity of seizures, and dysregulation of the KP has been linked to the pathophysiology of epilepsy. Concurrently, glutamate and GABA signaling is altered by neuroinflammatory processes linked to epilepsy, which results in excitotoxic neuronal damage. This review aims to provide novel therapeutic strategies that might improve the prognosis of individuals with epilepsy and related disorders by elucidating the mechanisms underlying KP dysregulation in these circumstances. To develop targeted therapies for CNS disorders characterized by inflammation and seizures, it is essential to understand how kynurenine metabolites both promote and prevent excitotoxicity.

Keywords: Epilepsy; Glutamate excitotoxicity; Kynurenine pathway; Mitochondrial dysfunction; Neuroinflammation

DOI: https://doi.org/10.1007/s12640-025-00738-2

Free Radic Biol Med. 2025 Mar 22. pii: S0891-5849(25)00179-0. [Epub ahead of print]

Reductive Stress and Mitochondrial Dysfunction: The Hidden Link in Chronic Disease.

Joseph Mercola.

Conventional theories of oxidative stress have long focused on the deleterious consequences of excessive reactive oxygen species (ROS) formation. However, growing evidence reveals that an overload of reducing equivalents-termed reductive stress-may be equally pivotal in driving mitochondrial dysfunction and chronic disease. In this paradigm, abnormally high concentrations of NADH and NADPH create an electron "traffic jam" in the mitochondrial electron transport chain (ETC), leading to partial inhibition or reverse electron flow at upstream complexes. Paradoxically, this hyper-reduced environment promotes ROS generation by increasing electron leakage to molecular oxygen, thereby intensifying oxidative damage to lipids, proteins, and mitochondrial DNA. This review explores the intertwined nature of reductive and oxidative stress, showing how a surplus of reducing equivalents can potentiate metabolic derangements in conditions such as type 2 diabetes, nonalcoholic fatty liver disease, and neurodegenerative disorders. We discuss common drivers of reductive overload, including chronic hyperglycemia, high-fat diets, and specific dietary patterns-particularly those enriched in polyunsaturated omega-6 fatty acids-that inundate mitochondria with electron donors. We also highlight emerging evidence that targeted assessment of redox biomarkers (e.g., lactate:pyruvate, β-hydroxybutyrate:acetoacetate ratios) can provide clinically relevant indicators of reductive stress. Finally, we examine how novel therapeutic strategies can address the underlying reductive imbalance, from rational nutrient modulation to pharmacologic interventions that restore NAD+ levels or optimize ETC flux. Recognizing reductive stress as a critical inflection point in mitochondrial pathophysiology underscores the need for a refined redox framework, one that moves beyond conventional oxidative paradigms to embrace the full spectrum of redox dysregulation in chronic degenerative disease.

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.03.029