bims-mignad Biomed News
on Mitochondria galactose NAD
Issue of 2025–04–13
six papers selected by
Melisa Emel Ermert, Amsterdam UMC
  1. Nampt as a new therapeutic target for modulating NAD+ levels in metabolic, cardiovascular and neurodegenerative diseases.
  2. The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.
  3. Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.
  4. Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
  5. Mitochondrial complex I deficiency in a 4-year-old boy due to compound heterozygous NDUFV1 mutation: a case report of a new pathogenic variant.
  6. Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.
  1. Can J Physiol Pharmacol. 2025 Apr 09.
    Nampt as a new therapeutic target for modulating NAD+ levels in metabolic, cardiovascular and neurodegenerative diseases.
    Ravikumar Manickam, Sandhya Santhana, Wanling Xuan, Kirpal S Bisht, Srinivas M Tipparaju.
      NAD+ is an important cofactor involved in regulating many biochemical processes in cells. An imbalance in NAD+/NADH ratio is linked to many diseases. NAD+ is depleted in diabetes, cardiovascular and neurodegenerative diseases, and in aging, and is increased in tumor cells. NAD+ is generated in cells via the de novo, Preiss-Handler, and salvage pathways. Most of the cellular NAD+ is generated through Nampt activation, a key rate-limiting enzyme that is involved in the salvage pathway. Restoration of NAD+/NADH balance offers therapeutic advantages for improving tissue homeostasis and function. NAD+ is known to benefit and restore the body's physiological mechanisms, including DNA replication, chromatin and epigenetic modifications, and gene expression. Recent studies elucidate the role of NAD+ in cells utilizing transgenic mouse models. Translational new therapeutics are positioned to utilize the NAD+ restoration strategies for overcoming the drawbacks that exist in the pharmacological toolkit. The present review highlights the significance of Nampt-NAD+ axis as a major player in energy metabolism and provides an overview with insights into future strategies, providing pharmacological advantages to address current and future medical needs.
    DOI:  https://doi.org/10.1139/cjpp-2024-0400
  2. J Bioenerg Biomembr. 2025 Apr 08.
    The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.
    Thomas N Seyfried, Derek C Lee, Tomas Duraj, Nathan L Ta, Purna Mukherjee, Michael Kiebish, Gabriel Arismendi-Morillo, Christos Chinopoulos.
      Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.
    Keywords:  Cardiolipin; Lactate; Lipid droplets; Oxidative phosphorylation; Oxygen consumption; Somatic mutations; Substrate level phosphorylation; Succinate
    DOI:  https://doi.org/10.1007/s10863-025-10059-w
  3. Nat Commun. 2025 Apr 04. 16(1): 3230
    Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.
    Huanhuan Cai, Xueyuan Chen, Yan Liu, Yingbo Chen, Gechang Zhong, Xiaoyu Chen, Shuo Rong, Hao Zeng, Lin Zhang, Zelong Li, Aihua Liao, Xiangtai Zeng, Wei Xiong, Cihang Guo, Yanfang Zhu, Ke-Qiong Deng, Hong Ren, Huan Yan, Zeng Cai, Ke Xu, Li Zhou, Zhibing Lu, Fubing Wang, Shi Liu.
      Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.
    DOI:  https://doi.org/10.1038/s41467-025-58563-2
  4. Cell Death Dis. 2025 Apr 05. 16(1): 254
    Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
    Ru Deng, Lingyi Fu, Haoyu Liang, Xixiong Ai, Fangyi Liu, Nai Li, Liyan Wu, Shuo Li, Xia Yang, Yansong Lin, Yuhua Huang, Jingping Yun.
      Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-025-07510-6
  5. Oxf Med Case Reports. 2025 Apr;2025(4): omae166
    Mitochondrial complex I deficiency in a 4-year-old boy due to compound heterozygous NDUFV1 mutation: a case report of a new pathogenic variant.
    Salim Haddad, Elie Salloum, Abdullah Silan, Gazel Kalecioğlu, Maria Abdulnour, Sultaneh Haddad, Diana Alasmar, Mahmoud Alayash, Ahmed Noman Ghaleb.
      Mutations in the NDUFV1 gene are associated with mitochondrial complex I deficiency and have been linked to various clinical conditions such as Leigh syndrome, severe infantile lactic acidosis, newborn cardiomyopathy, progressive leukoencephalopathy, and other encephalomyopathies. Genetic alterations revealed mitochondrial complex 1 deficiency, nuclear type 4 |AR: two compound heterozygous missense mutations in the NDUFV1 gene, c.640G < A (p.E214K) chr11:67377981 (Exon 1) and c.248C < T (p.S83L) chr11:67376115 (Exon 3) gene. Our case identifies a previously unknown pathogenic effect of the variant 'c.248C > T' in the NDUFV1 gene, observed in a 4-year-old boy with left-sided facial paralysis and balance impairment. While this discovery is significant, further exploration of NDUFV1 gene variants is essential for a comprehensive understanding and effective treatment strategies.
    Keywords:  NDUFV1 mutation; mitochondrial complex I deficiency; mitochondrial diseases; white matter
    DOI:  https://doi.org/10.1093/omcr/omae166
  6. Hum Mol Genet. 2025 Apr 11. pii: ddaf047. [Epub ahead of print]
    Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.
    Benjamin Munro, Declan Hines, Juliane S Mueller, Rita Horvath.
      Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are rare, clinically heterogeneous mitochondrial disorders resulting from nuclear variants in genes of the mitochondrial DNA replication or maintenance machinery. Supplementation with pyrimidine deoxynucleosides have been beneficial in patients and mice with TK2-related MDDS, however, it has not been systematically explored in other forms of MDDS. To investigate the effect of deoxynucleoside supplementation in mitigating the disease in mitochondrial DNA depletion due to pathogenic RRM2B variants, we generated a novel zebrafish knock-out model of this disease and studied the effect of different combinations of deoxynucleosides. Zebrafish larvae carrying a homozygous nonsense mutation in rrm2b present with impaired movement, reduced mtDNA copy number and elevated lactate. Supplementation with different combination of deoxynucleosides was performed, resulting in increased mtDNA copy numbers when supplemented with the two purine deoxynucleosides (dGuo and dAdo), while other combinations had no effect or even further compromised mtDNA copy number in zebrafish. In parallel with increased mtDNA copy number, we detected improved movement and reduction of lactate in the rrm2b-/- fish, confirming the beneficial effect of deoxynucleosides on the whole organism. This treatment did not result in any deleterious effect in wild type and heterozygous fish. Our data suggest that supplementation with deoxynucleosides may be beneficial and should be further investigated in RRM2B-related disease, adding to the growing evidence that it is a valid therapeutic approach which can be trialled for treating a wider range of genetic forms of MDDS.
    Keywords:  Deoxynucleoside supplementation; MDDS; Mitochondrial DNA depletion syndromes; RRM2B; zebrafish
    DOI:  https://doi.org/10.1093/hmg/ddaf047
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