bims-mignad 2025-10-19 papers

Issue of 2025–10–19
three papers selected by
Melisa Emel Ermert, Amsterdam UMC

Front Cell Dev Biol. 2025 ;13 1650462

Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.

Karis B D'Alessandro, Enrico Zampese, Jenna L E Blum, Britta Kuusik, Alec Palmiotti, Shawn M Davidson, Colleen R Reczek, D James Surmeier, Navdeep S Chandel.

Dysfunction of mitochondrial complex I (MCI) has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Here, we report the effect of expressing MitoLbNOX, a mitochondrial-targeted version of the bacterial enzyme LbNOX, which increases regeneration of NAD+ in the mitochondria to maintain the NAD+/NADH ratio, in dopaminergic neurons with impaired MCI (MCI-Park mice). MitoLbNOX expression did not ameliorate the cellular or behavioral deficits observed in MCI-Park mice, suggesting that alteration of the mitochondrial NAD+/NADH ratio alone is not sufficient to compensate for loss of MCI function in dopaminergic neurons.

Keywords: NAD+; Parkinson’s disease; dopaminergic neurons; mitochondrial complex I; neurodegeneration; neurometabolism

DOI: https://doi.org/10.3389/fcell.2025.1650462

Nat Metab. 2025 Oct 13.

NAD+ precursor supplementation in human ageing: clinical evidence and challenges.

Kasper T Vinten, Maria M Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E Janssens, Riekelt H Houtkooper.

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism.

DOI: https://doi.org/10.1038/s42255-025-01387-7

J Transl Med. 2025 Oct 16. 23(1): 1111

Targeting mitochondrial transporters and metabolic reprogramming for disease treatment.

Mboneye Anselme, Huafeng He, Chengyang Lai, Wenwei Luo, Shilong Zhong.

In the realm of cellular biochemistry, mitochondria have been increasingly recognized for their critical role in both cellular metabolism and the etiology of various diseases. Mitochondrial transporters (MTs) are essential for maintaining cellular energy dynamics and metabolic fluxes by facilitating the bidirectional transfer of metabolites across mitochondrial membranes. Dysregulation of these transporters, such as the mitochondrial pyruvate carrier (MPC), citrate carrier (SLC25A1), and voltage-dependent anion channel (VDAC), disrupts energy metabolism, redox balance, and cellular signaling, contributing to the pathogenesis of neurodegenerative diseases (NDDs), cardiovascular diseases (CVDs), type 2 diabetes (T2D), and cancer. In NDDs, impaired transporters exacerbate oxidative stress and neuronal death, while in CVDs, they lead to energy deficits and heart failure. In T2D, dysfunctional transporters like MPC and carnitine palmitoyltransferase (CPT) systems drive insulin resistance and metabolic dysregulation. In cancer, upregulated transporters such as citrate carrier (SLC25A1), and dicarboxylate carrier (SLC25A10) as well as metabolic shifts like the Warburg effect support tumor growth and survival. Targeting MTs and metabolic reprogramming (MR) offers significant therapeutic potential. Preclinical studies have demonstrated the efficacy of mitochondrial-targeted therapies (MTT), such as adenosine monophosphate-activated protein kinase (AMPK) activators and antioxidants, in restoring metabolic homeostasis and reducing disease pathology. In cancer, inhibitors of glutamine transporters and VDAC1 are being explored to disrupt tumor metabolism. Several therapies are advancing to clinical trials, including mitochondrial-targeted drugs for NDDs and metabolic modulators for T2D and cancer, highlighting their translational potential. Despite notable individual achievements and isolated reviews in this field, there remains a lack of comprehensive syntheses that integrate these advancements. This review seeks to combine the prevailing scientific evidence and outline prospective research trajectories. The gathered data robustly support the significant potential of targeting MTs as a groundbreaking approach in the treatment of complex diseases, with the potential to significantly improve health outcomes and mitigate disease progression.

Keywords: Cellular metabolism; Disease treatment; Metabolic reprogramming; Mitochondria; Mitochondrial transporters

DOI: https://doi.org/10.1186/s12967-025-06976-4