bims-mignad Biomed News
on Mitochondria galactose NAD
Issue of 2025–05–04
eight papers selected by
Melisa Emel Ermert, Amsterdam UMC
  1. Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
  2. Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
  3. NAD augmentation as a disease-modifying strategy for neurodegeneration.
  4. Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
  5. Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
  6. NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
  7. Mitochondria - the CEO of the cell.
  8. Mitochondrial complex I deficiency occurs in skeletal muscle of a subgroup of individuals with Parkinson's disease.
  1. Nat Metab. 2025 May 02.
    Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
    Kyle M Flickinger, Carlos A Mellado Fritz, Kimberly S Huggler, Gina M Wade, Gavin R Chang, Kathryn C Fox, Judith A Simcox, Jason R Cantor.
      Nicotinamide adenine dinucleotide kinase (NADK) catalyses the phosphorylation of NAD+ to produce NAD phosphate, the oxidized form of NADPH, a cofactor that serves a critical role in driving reductive metabolism. Cancer cells co-express two distinct NAD kinases that differ by localization (NADK, cytosol; NADK2, mitochondria). CRISPR screens performed across hundreds of cancer cell lines indicate that both are dispensable for growth in conventional culture media. By contrast, NADK deletion impaired cell growth in human plasma-like medium. Here we trace this conditional NADK dependence to the availability of folic acid. NADPH is the preferred cofactor of dihydrofolate reductase (DHFR), the enzyme that mediates metabolic activation of folic acid. We find that NADK is required for enabling cytosolic NADPH-driven DHFR activity sufficient to maintain folate-dependent nucleotide synthesis under low folic acid conditions. Our results reveal a basis for conditional NADK essentiality and suggest that folate availability determines whether DHFR activity can be sustained by alternative electron donors such as NADH.
    DOI:  https://doi.org/10.1038/s42255-025-01272-3
  2. Nat Metab. 2025 Apr 28.
    Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
    Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.
      During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.
    DOI:  https://doi.org/10.1038/s42255-025-01289-8
  3. Trends Endocrinol Metab. 2025 Apr 25. pii: S1043-2760(25)00070-0. [Epub ahead of print]
    NAD augmentation as a disease-modifying strategy for neurodegeneration.
    Christian Dölle, Charalampos Tzoulis.
      Neurodegenerative diseases (NDDs) pose a significant and rapidly growing global health challenge, but there are no effective therapies to delay or halt progression. In recent years augmentation of nicotinamide adenine dinucleotide (NAD) has emerged as a promising disease-modifying strategy that targets multiple key disease pathways across multiple NDDs, such as mitochondrial dysfunction, energy deficits, proteostasis, and neuroinflammation. Several early clinical trials of NAD augmentation have been completed, and many more are currently underway, reflecting the growing optimism and urgency within the field. We discuss the rationale and evolving therapeutic landscape of NAD augmentation. We argue that, to fully realize its therapeutic potential, it is essential to determine the specific contexts in which NAD supplementation is most effective and to address crucial knowledge gaps.
    Keywords:  Parkinson's disease; neurodegenerative disease; therapeutic
    DOI:  https://doi.org/10.1016/j.tem.2025.03.013
  4. Cell Metab. 2025 Apr 25. pii: S1550-4131(25)00217-7. [Epub ahead of print]
    Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
    Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Jeffrey Milbrandt, David K Imagawa, Dorota Skowronska-Krawczyk, Danica Chen, Gina Lee, Cholsoon Jang, Qin Yang.
      Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD+) catabolism primarily feeds systemic organs for NAD+ synthesis. We surprisingly found that, despite blunted hepatic NAD+ and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs' NAD+ are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5'-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD+ through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD+, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD+ homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD+ decline and kidney dysfunction.
    Keywords:  NAD(+); aging; kidney; liver; nicotinic acid riboside
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.007
  5. EMBO Rep. 2025 Apr 29.
    Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
    Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa.
      Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.
    Keywords:  CRISPR Screening; ECHS1; Mitochondria; OXPHOS; RTN4IP1
    DOI:  https://doi.org/10.1038/s44319-025-00459-9
  6. Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]
    NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
    Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.
      Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.
    Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.002
  7. J Cell Sci. 2025 May 01. pii: jcs263403. [Epub ahead of print]138(9):
    Mitochondria - the CEO of the cell.
    Laurie P Lee-Glover, Martin Picard, Timothy E Shutt.
      As we have learned more about mitochondria over the past decades, including about their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at the whim of the cell. Rather, mitochondria are dynamic information and energy processors that play crucial roles in directing dozens of cellular processes and behaviors. They provide instructions to enact programs that regulate various cellular operations, such as complex metabolic networks, signaling and innate immunity, and even control cell fate, dictating when cells should divide, differentiate or die. To help current and future generations of cell biologists incorporate the dynamic, multifaceted nature of mitochondria and assimilate modern discoveries into their scientific framework, mitochondria need a 21st century 'rebranding'. In this Opinion article, we argue that mitochondria should be considered as the 'Chief Executive Organelle' - the CEO - of the cell.
    Keywords:  Mitochondria; Organelle; mtDNA
    DOI:  https://doi.org/10.1242/jcs.263403
  8. Commun Med (Lond). 2025 Apr 27. 5(1): 141
    Mitochondrial complex I deficiency occurs in skeletal muscle of a subgroup of individuals with Parkinson's disease.
    Simon Ulvenes Kverneng, Kjersti Eline Stige, Haakon Berven, Sepideh Mostafavi, Katarina Lundervold, Michele Brischigliaro, Brage Brakedal, Geir Olve Skeie, Irene Hana Flønes, Lilah Toker, Erika Fernandez-Vizarra, Ragnhild Eide Skogseth, Kristoffer Haugarvoll, Yamila N Torres Cleuren, Christian Dölle, Gonzalo S Nido, Charalampos Tzoulis.
       BACKGROUND: Widespread neuronal mitochondrial complex I (CI) deficiency was recently reported to be a characteristic in a subgroup of individuals with idiopathic Parkinson's disease (PD). Here, we sought to determine whether a CI-deficient subgroup could be discerned using clinically accessible muscle biopsies. We further hypothesized that the inconsistency of previous findings of mitochondrial respiratory impairment in PD muscle may be due to interindividual variation, with respiratory deficiency only occurring in a subgroup of cases.
    METHODS: Using a cross-sectional design, vastus lateralis needle biopsies were collected from 83 individuals with PD and 29 neurologically healthy controls and analyzed by immunohistochemistry for CI and complex IV (CIV), cytochrome c oxidase/succinate dehydrogenase (COX/SDH) histochemistry, and spectrophotometric activity assays of complexes I-IV. Mitochondrial DNA (mtDNA) copy number, deletions, and point variation were analyzed in single muscle fibers and bulk biopsy samples.
    RESULTS: We show that PD muscle exhibits reduced CI activity at the group level, with 9% of cases falling below two standard deviations of the control group. In contrast, the activities of CII-CIV are not significantly different between the PD and control groups. No quantitative change of CI or CIV is detected, and the observed functional CI deficiency is not associated with mtDNA abnormalities.
    CONCLUSIONS: Our findings support the existence of a PD subpopulation characterized by CI pathology in skeletal muscle and suggest that stratification by extra-neural mitochondrial dysfunction may be informative for selecting individuals for clinical trials.
    DOI:  https://doi.org/10.1038/s43856-025-00817-7
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