bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–01–25
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. The Antiseizure Medication Stiripentol Inhibits Mitochondrial Complex I by Blocking Early-Stage Electron Transfer.
  2. C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
  3. Therapeutic potential of liposome@azoramide in cancer by suppressing oxidative phosphorylation.
  4. Prokaryotic organelle mitochondria drive tumorigenesis: "the original sin".
  5. SLC25A45: a gatekeeper for methylated amino acid metabolism.
  6. Dordaviprone/ONC201 Activation of the ClpP Mitochondrial Protease Inhibits the Growth of KRAS-Mutant Pancreatic Cancer and Overcomes RAS Inhibitor Resistance.
  7. Acetyl-CoA as a metabolic switch for selective mitophagy.
  8. NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.
  9. Selectively and efficiently eliciting a ROS-dependent energy crisis within cancer cells through a mitochondria-targeted catechol-based diphenylhextriene.
  10. BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia.
  11. NF-κB activation as a pro-survival signal from pharmacological inhibition of pyruvate dehydrogenase kinase 1 in non-small-cell lung carcinoma cell models.
  12. Single-cell proteogenomic analysis of clonal evolution in PDX models of AML treated with IDH inhibitors.
  13. Glucose-6-phosphate dehydrogenase deficiency is associated with improved survival in patients with acute myeloid leukemia treated with venetoclax and azacitidine.
  14. The 2025 Sir David Cuthbertson Lecture: Energy metabolism: Beyond calories, feeding the mitochondria.
  15. NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
  1. J Biol Chem. 2026 Jan 20. pii: S0021-9258(26)00049-9. [Epub ahead of print] 111179
    The Antiseizure Medication Stiripentol Inhibits Mitochondrial Complex I by Blocking Early-Stage Electron Transfer.
    Cyrielle L Bouchez, Thibaut Molinié, Guillaume Duranthon, Sebastian Lillo, Corinne Pellon, Nadia El Mammeri, Benjamin Dartigues, Philippe Pasdois, Benoit Pinson, Macha Nikolski, Anne Devin, Arnaud Mourier, Roland T Ullrich, Thomas Daubon.
      The oxidation of NADH is essential for maintaining cellular redox balance and supporting cell metabolism. Mitochondrial complex I (NADH:ubiquinone oxidoreductase) plays a central role in this process by coupling NADH oxidation to electron transfer and proton translocation across the inner mitochondrial membrane. We previously reported that the antiseizure medication stiripentol decreases lactate production and mitochondrial respiration, suggesting an impact on NADH turnover beyond its known inhibition of lactate dehydrogenase. In this study, we identify complex I as a target of stiripentol across multiple species and cell types. Biochemical and spectroscopic analyses demonstrate that stiripentol inhibits NADH oxidation and electron transfer through a mechanism distinct from that of classical ubiquinone pocket inhibitors such as rotenone or piericidin A. Remarkably, stiripentol acts upstream of the ubiquinone reduction site, representing the first example of a complex I inhibitor with a binding site within the N-module. These findings uncover a previously unrecognized mode of complex I inhibition and link stiripentol's metabolic effects to direct modulation of mitochondrial NADH oxidation. This work broadens the understanding of stiripentol's mechanism of action and highlights its potential to modulate redox metabolism in cancer cells.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111179
  2. Autophagy. 2026 Jan 22.
    C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
    Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.
      Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.
    Keywords:  Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2621110
  3. Int J Surg. 2026 Jan 23.
    Therapeutic potential of liposome@azoramide in cancer by suppressing oxidative phosphorylation.
    Xin Wang, Zihan Xu, Yiyao Zeng, Xiangyue Meng, Haitong Xie, Xin Zhao, Jie Chen.
       OBJECTIVE: Targeting cancer cell metabolism represents a promising therapeutic strategy; however, metabolic reprogramming in tumor cells complicates the effectiveness of therapies aimed at disrupting these pathways.
    METHODS: This study explored the potential of Azoramide, a compound previously associated with enhanced insulin sensitivity, to modulate cancer metabolism. Azoramide-loaded nano-liposomes (Lip@Azo) were prepared via the thin-film hydration method, chosen for its simplicity and efficiency. We evaluated the anti-tumor efficacy of Lip@Azo and investigated the underlying mechanisms.
    RESULTS: We showed that azoramide effectively inhibits tumor growth by suppressing oxidative phosphorylation (OXPHOS) both in vitro and in vivo. Azoramide downregulated OXPHOS proteins, reduced mitochondrial respiration, and induced reactive oxygen species (ROS), leading to decreased mitochondrial ATP generation. Additionally, azoramide downregulated PGC-1α, a key regulator of mitochondrial function, disrupting mitochondrial homeostasis and further impairing tumor cell metabolism, which induced apoptosis and ferroptosis in cancer cells. To enhance the solubility and delivery of azoramide, we encapsulated the compound in liposomes (Lip@Azo), which significantly improved its therapeutic efficacy in vivo.
    CONCLUSION: Overall, our findings suggest that Lip@Azo is a promising strategy for targeting mitochondrial metabolism in cancer, offering a new avenue for therapeutic development in oncology.
    Keywords:  apoptosis; azoramide; cancer; ferroptosis; oxidative phosphorylation
    DOI:  https://doi.org/10.1097/JS9.0000000000004845
  4. Front Oncol. 2025 ;15 1632702
    Prokaryotic organelle mitochondria drive tumorigenesis: "the original sin".
    Chaoyi Wang, Ming Luo, Jinhui Zhou, Qihao Zhang, Xiawei Ji, Jiayao He, Lingfei Wang, Yingpeng Huang, Xiangyang Xue, Fangyan Wang.
      Mitochondria preserve bacterial traits because of their endosymbiotic origin, and their alterations in cancer cells reflect these prokaryotic-like traits. One such trait is the Warburg effect, wherein tumor cells rely primarily on aerobic glycolysis instead of oxidative phosphorylation. Cancer cells also exhibit metabolic abnormalities, such as an uncoupled electron transport chain and a truncated tricarboxylic acid (TCA) cycle, potentially generating additional energy. Intermediates from the disrupted TCA cycle can regulate key genes involved in cell differentiation, apoptosis, and tumor suppression while promoting aerobic glycolysis, angiogenesis, and resistance to cell death. Mitochondria-related gene mutations, particularly in D-loop and TCA-related enzymes, have been identified as key drivers of prokaryotic transformation in diverse cancers. Furthermore, the metabolic activity of cancer mitochondria results in the production of essential biosynthetic precursors for nucleotide synthesis and lipid synthesis, supporting tumor growth. Mitochondria also contribute to tumorigenesis by promoting inflammation and iron metabolism disorders. Mitochondrial dysfunctions have raised interest in the use of mitochondria-targeted anticancer strategies as possible cancer treatments, although their clinical application requires further investigation.
    Keywords:  TCA cycle; Warburg effect; cancer; endosymbiosis theory; mitochondria
    DOI:  https://doi.org/10.3389/fonc.2025.1632702
  5. Trends Endocrinol Metab. 2026 Jan 22. pii: S1043-2760(25)00283-8. [Epub ahead of print]
    SLC25A45: a gatekeeper for methylated amino acid metabolism.
    Yue Zhang, Yan Tian, Xianghui Fu.
      The metabolite substrates of numerous transporters remain largely elusive. Two recent studies by Khan et al. and Dias et al. identify SLC25A45 as a mitochondrial transporter of methylated amino acids that supports de novo carnitine synthesis, providing a valuable strategy for deorphanizing transporters and novel insights into cytoplasm-mitochondria communication and metabolic coordination.
    Keywords:  carnitine biosynthesis; fasting; machine learning; mitochondria; trimethyllysine
    DOI:  https://doi.org/10.1016/j.tem.2025.12.005
  6. bioRxiv. 2025 Dec 03. pii: 2025.12.01.691471. [Epub ahead of print]
    Dordaviprone/ONC201 Activation of the ClpP Mitochondrial Protease Inhibits the Growth of KRAS-Mutant Pancreatic Cancer and Overcomes RAS Inhibitor Resistance.
    Kristina Drizyte-Miller, Seamus E Degan, Ryan D Mouery, Amber M Amparo, Brandon L Mouery, Wen-Hsuan Chang, Runying Yang, Sheila R Nicewarner Peña, Elisa Baldelli, Jeffrey A Klomp, Edwin J Iwanowicz, Lee M Graves, Emanuel F Petricoin, Adrienne D Cox, Clint A Stalnecker, Kirsten L Bryant, Channing J Der.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS-driven oncogenic signaling and tumor growth. Blockade of the KRAS ERK-MAPK pathway via small molecule direct RAS inhibitors has shown clinical promise, but intrinsic and acquired resistance limit the efficacy of these inhibitors as single agents. To identify potential combination strategies, we first assessed the ability of dordaviprone/ONC201, an FDA-approved agent, to inhibit PDAC cell and organoid growth. We observed that ONC201 reduced the growth of a broad panel of KRAS-mutant PDAC cell lines, and that the expression of mitochondrial protease ClpP was required for this efficacy. Mechanistically, we observed that treatment with ONC201 led to inhibition of mitochondrial respiration, causing a compensatory increase in glycolysis. Furthermore, ONC201 caused ClpP-dependent activation of PI3K-AKT-mTOR signaling and concurrent PI3K and mTOR inhibition further enhanced ONC201 growth suppression. ONC201 demonstrated an additive effect when combined with a RAS(ON) multi-selective inhibitor RMC-7977 in PDAC cells and organoids. Finally, PDAC cell lines with acquired resistance to RMC-7977 or KEAP1 loss-driven resistance retained sensitivity to ONC201. We propose that concurrent treatment with ONC201 may delay onset of resistance to RAS inhibitor therapy.
    Statement of Significance: ClpP activation by dordaviprone/ONC201 suppressed PDAC cell growth and overcame resistance to the RAS(ON) multi-selective inhibitor RMC-7977, providing support for investigating this combination as a potential combination treatment for KRAS-mutant pancreatic cancer.
    DOI:  https://doi.org/10.64898/2025.12.01.691471
  7. Autophagy. 2026 Feb;22(2): 235-237
    Acetyl-CoA as a metabolic switch for selective mitophagy.
    Daolin Tang, Rui Kang, Daniel J Klionsky.
      A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.
    Keywords:  Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2593032
  8. Front Immunol. 2025 ;16 1734203
    NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.
    Oded Shamriz, Zahala Bar-On, Omri Yosef, Leonor Cohen-Daniel, Ayelet Sheer, Or Reuven, Wajeeh Salaymeh, Amijai Saragovi, Raz Somech, Atar Lev, Hagar Mor-Shaked, Yuval Tal, Aviva Fattal-Valevski, Simon Edvardson, Michael Berger.
       Introduction: Mitochondrial metabolism is essential for T-cell function, but the roles of individual electron transport chain (ETC) components are unclear. Here, we aimed to explore the role of mitochondrial complex I (CI) subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (NDUFS4) in T-cell metabolic fitness and immunity.
    Methods: We used a T cell-specific Ndufs4 knockout mouse model to find that NDUFS4 deficiency disrupts CI function, leading to metabolic and redox imbalances. Additionally, T cells from a patient with Leigh syndrome induced by NDUFS4 loss-of-function were analyzed.
    Results: Ndufs4-deficient T cells exhibit impaired OXPHOS, reduced respiratory capacity, and increased glycolysis, accompanied by reactive oxygen species (ROS) accumulation and defective TCR-driven activation, including reduced proliferation and cytokine production. In vivo, Ndufs4(-/-) mice show T-cell lymphopenia and impaired humoral and cytotoxic immunity. Importantly, T cells from a single Leigh syndrome patient with an NDUFS4 loss-of-function variant showed similar defects, including impaired activation and proliferation.
    Discussion: These findings highlight the importance of NDUFS4 for human immunity and establish a mechanistic link between complex I dysfunction and T-cell immunodeficiency. Our results identify NDUFS4 as a key regulator connecting mitochondrial integrity to adaptive immune function.
    Keywords:  NDUFS4; NDUFS4 knockout mice; T cells; leigh syndrome (LS); mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2025.1734203
  9. Bioorg Chem. 2026 Jan 13. pii: S0045-2068(26)00041-6. [Epub ahead of print]170 109505
    Selectively and efficiently eliciting a ROS-dependent energy crisis within cancer cells through a mitochondria-targeted catechol-based diphenylhextriene.
    Xia-Zhen Bao, Xiao-Rong Ren, Wei Tang, Yu Zhang, Zheng-Kai Deng, Fang Dai, Bo Zhou.
      To effectively trigger an energy crisis within cancer cells, we devised and synthesized mitochondria-targeted catechol-based diphenylpolyenes by coupling them with a triphenylphosphonium unit via a modular synthetic approach. The exploration of structure-activity relationships in terms of cytotoxicity discloses that Mito-DHH, a catechol-type diphenylhextriene that specifically targets mitochondria, is the most potent molecule among those tested, manifesting its preferential elimination of A549 cells (IC50 = 0.25 μM) as opposed to normal L02 cells (IC50 = 2.8 μM). In this regard, it outperforms doxorubicin and 5-fluorouracil, the commonly employed chemotherapy drugs. Mechanistic investigation affirms that the rapid accumulation of Mito-DHH within mitochondria of A549 cells enables its efficient auto-oxidation by leveraging the alkaline mitochondrial matrix to effectively and selectively generate reactive oxygen species (ROS). Through the generation of ROS, Mito-DHH initiates a ROS-dependent reduction of ATP levels within A549 cells in a dual-effect inhibitory pattern against both mitochondrial and glycolytic metabolisms, and the ultimate and selective apoptosis of A549 cells. This study takes Mito-DHH as an example to emphasize the universality of a ROS-generating strategy by targeting mitochondria in effectively inducing an energy crisis within cancer cells.
    Keywords:  Apoptosis; Catechol; Energy crisis; Metabolic reprograming; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bioorg.2026.109505
  10. Ann Hematol. 2026 Jan 19. 105(1): 32
    BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia.
    Florian Robert, Cherif Badja, Soraya Boushaki, Andrea Degasperi, Yasin Memari, Sophie Momen, Theodoros I Roumeliotis, Zuza Kozik, Malgorzata Gozdecka, Jyoti Choudhary, George Vassiliou, Gene Cc Koh, Serena Nik-Zainal.
      Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co-repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH's role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.
    Keywords:  Acute myeloid leukemia; BCOR; DHODH; DHODH inhibition; Leukemia; Synthetic lethality; Targeted therapy 
    DOI:  https://doi.org/10.1007/s00277-026-06773-z
  11. Transl Oncol. 2026 Jan 21. pii: S1936-5233(26)00018-5. [Epub ahead of print]65 102681
    NF-κB activation as a pro-survival signal from pharmacological inhibition of pyruvate dehydrogenase kinase 1 in non-small-cell lung carcinoma cell models.
    Quan Liu, Maoxin Ran, Wenying Shan, Shao-Lin Zhang, Kin Yip Tam.
      Targeting Pyruvate dehydrogenase kinase (PDK) has emerged as one of the potential therapeutic strategies for non-small cell lung carcinoma (NSCLC). 64, a recently reported PDK1 inhibitor derived from 2,2-dichloroacetophenone (DAP), exhibited promising anticancer effects in NSCLC models. Herein, we sought to investigate the mechanism of action of 64 in two NSCLC cell lines, namely, NCI-H1975 and NCI-H1650. We found that 64 induced intrinsic cancer cell apoptosis by releasing cytochrome C (CytC) from mitochondria, leading to caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage, which was mediated by reactive oxygen species (ROS). Moreover, we have shown that 64 induced mitochondrial membrane potential (MMP) depolarization and AMPK/MAPK activations were also ROS driven. With the aid of sequencing studies and follow-up biochemical evaluations, we found that 64 activated the NF-κB pathway through P38 MAPK, while the combination of P38 MAPK inhibitor SB203580 with 64 diminished such activation. Interestingly, the combined use of 64 and NF-κB inhibitor (JSH-23) increased pro-apoptosis protein (Bax) expression and decreased pro-survival protein (Bcl-2) expression, resulting in enhanced cancer cell apoptosis via JNK pathway. Our results suggested that 64 induces cancer cell apoptosis in NSCLC models through ROS, while NF-κB activation serves as a survival mechanism upon PDK1 inhibition.
    Keywords:  Apoptosis; NF-κB; NSCLC; PDK1; ROS
    DOI:  https://doi.org/10.1016/j.tranon.2026.102681
  12. Blood Neoplasia. 2026 Feb;3(1): 100182
    Single-cell proteogenomic analysis of clonal evolution in PDX models of AML treated with IDH inhibitors.
    Alex C H Liu, Severine Cathelin, Dhanoop Manikoth Ayyathan, Yitong Yang, Farzaneh Aboualizadeh, Amina Abow, Gurbaksh Basi, Lance Li, David L Dai, Abdula Maher, Eric Grignano, Mohsen Hosseini, Vivian Wang, Troy Ketela, Brandon Nicolay, Dylan M Marchione, Adriana E Tron, Andrea Arruda, Mark D Minden, Steven M Chan.
      Clonal heterogeneity in acute myeloid leukemia (AML) can drive drug resistance because different clones may respond variably to treatments. Studying the evolution of these clones under the influence of therapeutic selective pressures is important for designing strategies to overcome drug resistance. Here, we used single-cell proteogenomic analysis to monitor the clonal evolution and differentiation of isocitrate dehydrogenase (IDH)-mutated AML in patient-derived xenografts (PDX) treated with IDH inhibitors alone or in combination with other antileukemic therapies. Furthermore, we generated mixed PDX models by coengrafting ≥2 leukemic samples into the same animal and used single-cell DNA sequencing to deconvolute their clonal composition. Using these models, we tracked clonal evolution under selective pressure from IDH inhibitors and combination therapies, identifying an association between WT1 mutations and ivosidenib (IDH1 inhibitor) monotherapy resistance, as well as an antagonism between ivosidenib and enasidenib (IDH2 inhibitor) when tested in IDH1-mutated cells. Our findings demonstrate how single-cell proteogenomic analysis of PDX models can illuminate drug resistance mechanisms and inform therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100182
  13. Cancer. 2026 Feb 01. 132(3): e70265
    Glucose-6-phosphate dehydrogenase deficiency is associated with improved survival in patients with acute myeloid leukemia treated with venetoclax and azacitidine.
    Shira Buchrits, Alon Rozental, Noa Korngold, Ofer Algor, Shirly Partouche, Galit Granot, Pia Raanani, Ofir Wolach.
       BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency impairs cellular redox balance through reduced NADPH production and is the most common enzymatic disorder-causing anemia. Venetoclax combined with azacitidine (Ven-Aza) targets leukemic stem cells by disrupting oxidative phosphorylation and inducing mitochondrial stress. This study hypothesized that G6PD deficiency may enhance the efficacy of Ven-Aza in acute myeloid leukemia (AML) by reducing leukemic cell metabolic resilience.
    METHODS: The authors studied 73 consecutive patients with newly diagnosed (ND) AML treated with Ven-Aza. G6PD activity was systematically assessed at diagnosis in all patients and categorized as normal (n = 47), borderline (n = 11), or deficient (n = 15).
    RESULTS: Composite complete remission rates were 93% in the G6PD deficient group versus 69% in the normal/borderline group (p = .03). Patients with G6PD deficiency had a significantly longer median overall survival (23.8 months; 95% confidence interval [CI], 8.9-38.7), as compared to 8.96 months (95% CI, 2.9-15.0) in the normal/borderline group (p = .034). In multivariate analysis, G6PD-deficiency was associated with improved survival as compared to patients with normal G6PD activity (hazard ratio, 0.417; 95% CI, 0.181-0.965, p = .043). No significant differences were observed across groups in rates of febrile neutropenia, pneumonia, sepsis, or grade 3-4 cytopenia.
    CONCLUSION: G6PD deficiency is associated with higher response rates and improved survival in patients with ND-AML treated with Ven-Aza. These findings support G6PD deficiency as a potential biomarker of therapeutic sensitivity to Ven-AZA and may uncover metabolic vulnerabilities in AML with potential therapeutic implications.
    Keywords:  acute myeloid leukemia; azacitidine; biomarkers; glucose‐6‐phosphate dehydrogenase deficiency; survival analysis; venetoclax
    DOI:  https://doi.org/10.1002/cncr.70265
  14. Clin Nutr. 2026 Jan 09. pii: S0261-5614(26)00002-6. [Epub ahead of print]57 106575
    The 2025 Sir David Cuthbertson Lecture: Energy metabolism: Beyond calories, feeding the mitochondria.
    Eric Fontaine.
      In this article, I explore how energy metabolism depends on proper mitochondrial function. Adenosine triphosphate (ATP), the main source of energy for cells, is mainly produced in the mitochondria as a result of the fusion of hydrogen produced by the breakdown of nutrients with oxygen. This reaction allows protons to be pumped across the inner mitochondrial membrane, creating a gradient that powers ATP synthesis. However, ATP production is not perfectly efficient. Some oxygen is consumed without generating ATP due to proton leaks or other processes that utilize the gradient. Diet, hormones, and cellular signals can alter mitochondrial efficiency: for example, hyperthyroidism and polyunsaturated fatty acid deficiency cause uncoupling, while hypothyroidism and nitric oxide increase coupling but reduce maximum ATP production. I also point out that the use of ATP depends on its thermodynamic value, which is reflected in the Adenosine triphosphate/Adenosine diphosphate ratio ([ATP]/[ADP] ratio). A decrease in this ratio can selectively reduce certain ATP-consuming processes, as shown in studies on metformin and imeglimin. In cases of stress or nutritional deficiency, cells can consume ATP without performing useful work, leading to inefficiency or even cell death when the [ATP]/[ADP] ratio collapses. Knowing that these concepts are quite complex, I have simplified them to make clear that mitochondria are more than just passive "powerhouses of cells".
    Keywords:  Efficiency; Energy metabolism; Flux–force relationship; Kinetics; Mitochondria; Thermodynamics
    DOI:  https://doi.org/10.1016/j.clnu.2026.106575
  15. JCI Insight. 2026 Jan 23. pii: e181812. [Epub ahead of print]11(2):
    NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
    Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro Tm Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B Orger, Philipp Gut.
      Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2-/- zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2-/- zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.
    Keywords:  Cell biology; Genetic diseases; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.181812
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