bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–04–20
eighteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
  2. The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.
  3. Coupling of ribosome biogenesis and translation initiation in human mitochondria.
  4. In vivo composition of the mitochondrial nucleoid in mice.
  5. Engineering mitochondrial DNA deletions in human cells improves disease modeling.
  6. Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
  7. NDUFS8-Related Leigh Syndrome Mimicking a Leukodystrophy.
  8. Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
  9. Optimization of mtDNA-targeted platinum TALENs for bi-directionally modifying heteroplasmy levels in patient-derived m.3243A>G-iPSCs.
  10. Role of Comprehensive Renal Genetic Testing in Diagnosing a RMND-1 Mitochondrial Disease in Two Adult Cases Exhibiting Variable Disease Phenotypes.
  11. Active control of mitochondrial network morphology by metabolism-driven redox state.
  12. Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging?
  13. Spatial analysis of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress.
  14. SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19.
  15. Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions.
  16. Gene-edited pig liver successfully transplanted into human.
  17. MITOCHONDRIAL METABOLISM AND HYPOXIC SIGNALLING IN DIFFERENTIATED HUMAN CARDIOMYOCYTE AC16 CELL LINE.
  18. Mitochondrial Dysfunction: The Nexus of Aging, Dyslipidemia, and CKD.
  1. Sci Adv. 2025 Apr 18. 11(16): eads1842
    Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
    Kristina Bubb, Julia Etich, Kristina Probst, Tanvi Parashar, Maximilian Schuetter, Frederik Dethloff, Susanna Reincke, Janica L Nolte, Marcus Krüger, Ursula Schlötzer-Schrehard, Julian Nüchel, Constantinos Demetriades, Patrick Giavalisco, Jan Riemer, Bent Brachvogel.
      Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.
    DOI:  https://doi.org/10.1126/sciadv.ads1842
  2. Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2417477122
    The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.
    Josefin M E Forslund, Tran V H Nguyen, Vimal Parkash, Andreas Berner, Steffi Goffart, Jaakko L O Pohjoismäki, Paulina H Wanrooij, Erik Johansson, Sjoerd Wanrooij.
      Mitochondrial DNA (mtDNA) stability, essential for cellular energy production, relies on DNA polymerase gamma (POLγ). Here, we show that the POLγ Y951N disease-causing mutation induces replication stalling and severe mtDNA depletion. However, unlike other POLγ disease-causing mutations, Y951N does not directly impair exonuclease activity and only mildly affects polymerase activity. Instead, we found that Y951N compromises the enzyme's ability to efficiently toggle between DNA synthesis and degradation, and is thus a patient-derived mutation with impaired polymerase-exonuclease switching. These findings provide insights into the intramolecular switch when POLγ proofreads the newly synthesized DNA strand and reveal a new mechanism for causing mitochondrial DNA instability.
    Keywords:  DNA polymerases; mitochondria; mitochondrial disease; mtDNA; mtDNA replication
    DOI:  https://doi.org/10.1073/pnas.2417477122
  3. Nat Commun. 2025 Apr 17. 16(1): 3641
    Coupling of ribosome biogenesis and translation initiation in human mitochondria.
    Marleen Heinrichs, Anna Franziska Finke, Shintaro Aibara, Angelique Krempler, Angela Boshnakovska, Peter Rehling, Hauke S Hillen, Ricarda Richter-Dennerlein.
      Biogenesis of mitoribosomes requires dedicated chaperones, RNA-modifying enzymes, and GTPases, and defects in mitoribosome assembly lead to severe mitochondriopathies in humans. Here, we characterize late-step assembly states of the small mitoribosomal subunit (mtSSU) by combining genetic perturbation and mutagenesis analysis with biochemical and structural approaches. Isolation of native mtSSU biogenesis intermediates via a FLAG-tagged variant of the GTPase MTG3 reveals three distinct assembly states, which show how factors cooperate to mature the 12S rRNA. In addition, we observe four distinct primed initiation mtSSU states with an incompletely matured rRNA, suggesting that biogenesis and translation initiation are not mutually exclusive processes but can occur simultaneously. Together, these results provide insights into mtSSU biogenesis and suggest a functional coupling between ribosome biogenesis and translation initiation in human mitochondria.
    DOI:  https://doi.org/10.1038/s41467-025-58827-x
  4. Biochim Biophys Acta Mol Cell Res. 2025 Apr 15. pii: S0167-4889(25)00060-6. [Epub ahead of print] 119955
    In vivo composition of the mitochondrial nucleoid in mice.
    Rodolfo García-Villegas, Franka Odenthal, Yvonne Giannoula, Nina A Bonekamp, Inge Kühl, Chan Bae Park, Henrik Spåhr, Elisa Motori, Fredrik Levander, Nils-Göran Larsson.
      Mitochondrial DNA (mtDNA) is compacted into dynamic structures called mitochondrial nucleoids (mt-nucleoids), with the mitochondrial transcription factor A (TFAM) as the core packaging protein. We generated bacterial artificial chromosome (BAC) transgenic mice expressing FLAG-tagged TFAM protein (Tfam-FLAGBAC mice) to investigate the mt-nucleoid composition in vivo. Importantly, we show that the TFAM-FLAG protein is functional and complements the absence of the wild-type TFAM protein in homozygous Tfam knockout mice. We performed immunoprecipitation experiments from different mouse tissues and identified 12 proteins as core mt-nucleoid components by proteomics analysis. Among these, eight proteins correspond to mtDNA replication and transcription factors, while the other four are involved in the mitoribosome assembly. In addition, we used the Tfam-FLAGBAC mice to identify ten proteins that may stabilize TFAM-FLAG upon depletion of the mitochondrial RNA polymerase despite the absence of mtDNA and induction of the LONP1 protease. Finally, we evaluated the changes in mt-nucleoids caused by very high levels of TFAM unraveling nine interactors that could counteract the high TFAM levels to maintain active mtDNA transcription. Altogether, we demonstrate that the Tfam-FLAGBAC mice are a valuable tool for investigating the mt-nucleoid composition in vivo.
    Keywords:  Mitochondrial nucleoid; Mitochondrial translation; TFAM; Transgenic mice; mtDNA expression
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119955
  5. Nat Biotechnol. 2025 Apr;43(4): 501
    Engineering mitochondrial DNA deletions in human cells improves disease modeling.
    Iris Marchal.
      
    DOI:  https://doi.org/10.1038/s41587-025-02652-6
  6. Sci Adv. 2025 Apr 18. 11(16): eadw1489
    Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
    Maximilian Sichrovsky, Denis Lacabanne, Jonathan J Ruprecht, Jessica J Rana, Klaudia Stanik, Mariangela Dionysopoulou, Alice P Sowton, Martin S King, Scott A Jones, Lee Cooper, Steven W Hardwick, Giulia Paris, Dimitri Y Chirgadze, Shujing Ding, Ian M Fearnley, Shane M Palmer, Els Pardon, Jan Steyaert, Vanessa Leone, Lucy R Forrest, Sotiria Tavoulari, Edmund R S Kunji.
      The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.
    DOI:  https://doi.org/10.1126/sciadv.adw1489
  7. J Child Neurol. 2025 Apr 16. 8830738251328199
    NDUFS8-Related Leigh Syndrome Mimicking a Leukodystrophy.
    Bailyn Hogue, Mekka R Garcia, Connolly G Steigerwald, Maria J Borja, Nicolas J Abreu.
      Leigh syndrome is a progressive infantile neurodegenerative disorder of mitochondrial metabolism that often leads to decompensation in the setting of metabolic stress. It is genetically heterogenous with varied inheritance patterns. One subtype includes NDUFS8-related autosomal recessive Leigh syndrome. This nuclear gene encodes a complex I subunit of the mitochondrial complex chain. Although Leigh syndrome is typically associated with basal ganglia and brainstem involvement, cases of confluent white matter disease have been described with NDUFS8-related disorders. We present the case of a 6-month-old girl with initial imaging suggestive of a leukodystrophy, later found to have a novel homozygous variant in NDUFS8. In conjunction with the clinical course, a diagnosis of Leigh syndrome was made. This case highlights that mitochondrial disorders should be considered on the differential for confluent cerebral white matter disease in early childhood.
    Keywords:  Leigh syndrome; NDUFS8; leukodystrophy; leukoencephalopathy; white matter
    DOI:  https://doi.org/10.1177/08830738251328199
  8. Cell Rep Methods. 2025 Apr 08. pii: S2667-2375(25)00063-3. [Epub ahead of print] 101027
    Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
    Liam P Kelley, Song-Hua Hu, Sarah A Boswell, Peter K Sorger, Alison E Ringel, Marcia C Haigis.
      Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.
    Keywords:  CP: Metabolism; CP: Systems biology; cancer metabolism; integrated multi-omics; integrated stress response; metabolomics; mitochondria; mitochondrial stress response; mitochondrial unfolded protein response; stress signatures
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101027
  9. Mol Ther Nucleic Acids. 2025 Jun 10. 36(2): 102521
    Optimization of mtDNA-targeted platinum TALENs for bi-directionally modifying heteroplasmy levels in patient-derived m.3243A>G-iPSCs.
    Naoki Yahata, Yu-Ichi Goto, Ryuji Hata.
      Patient-derived induced pluripotent stem cells (iPSCs) are a useful pathological model for debilitating diseases caused by mitochondrial DNA (mtDNA) mutations. We established iPSCs derived from mitochondrial disease patients, heteroplasmic for the m.3243A>G mutation. The proportion of a selected mtDNA can be reduced by delivering a programmable nuclease into the mitochondria, and we developed various mtDNA-targeted Platinum TALENs (mpTALENs) to modify m.3243A>G-iPSC heteroplasmy levels in either wild-type or mutant direction. For TALEN optimization, the use of non-conventional repeat-variable di-residues (ncRVD)-LK/WK or NM-enhanced cleavage activity and specificity, and the replacement of conventional with obligate heterodimeric FokI nuclease domains increased target specificity and protected mtDNA from copy number depletion. In vitro, depending on whether wild-type or mutant mtDNA was targeted, we could obtain m.3243A>G-iPSCs with a higher or lower mutation load, while the cells retained their ability to differentiate into three germ layers. These results demonstrate that our mpTALEN optimization created a useful tool for altering heteroplasmy levels in m.3243A>G-iPSCs, improving the potential for studying mutation pathology. The enhanced efficiency also holds promise for using m.3243G(MUT)-mpTALEN as a therapeutic strategy for treating patients suffering from m.3243A>G mitochondrial diseases.
    Keywords:  MELAS; MT: RNA/DNA Editing; diabetes mellitus; induced pluripotent stem cells, iPSCs; mitochondria; mitochondrial DNA, mtDNA; transcription activator-like effector nuclease, TALEN
    DOI:  https://doi.org/10.1016/j.omtn.2025.102521
  10. Clin Case Rep. 2025 Apr;13(4): e70421
    Role of Comprehensive Renal Genetic Testing in Diagnosing a RMND-1 Mitochondrial Disease in Two Adult Cases Exhibiting Variable Disease Phenotypes.
    Quinn Stein, Ryan Mascarenhas, Sumit Punj, Maggie Westemeyer, Emily Hendricks, Tessa Pitman, Meg Hager, Nour Al Haj Baddar, Kristen Connors, Alexa Bacher, Robin Larson, Lauren Zec, Jennifer Stoddard.
      RMND1-related mitochondrial disease is a rare genetic condition that affects multiple organs, including the kidneys. We describe two adult patients whose diagnosis, initiated in childhood, was established through renal gene panel testing, emphasizing the value of genetic testing in uncovering kidney-related conditions that have a high degree of clinical heterogeneity.
    Keywords:  RMND1; RMND1‐related mitochondrial disease; genetic testing; kidney gene panel
    DOI:  https://doi.org/10.1002/ccr3.70421
  11. Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2421953122
    Active control of mitochondrial network morphology by metabolism-driven redox state.
    Gaurav Singh, Vineeth Vengayil, Aayushee Khanna, Swagata Adhikary, Sunil Laxman.
      Mitochondria are dynamic organelles that constantly change morphology. What controls mitochondrial morphology however remains unresolved. Using actively respiring yeast cells growing in distinct carbon sources, we find that mitochondrial morphology and activity are unrelated. Cells can exhibit fragmented or networked mitochondrial morphology in different nutrient environments independent of mitochondrial activity. Instead, mitochondrial morphology is controlled by the intracellular redox state, which itself depends on the nature of electron entry into the electron transport chain (ETC)-through complex I/II or directly to coenzyme Q/cytochrome c. In metabolic conditions where direct electron entry is high, reactive oxygen species (ROS) increase, resulting in an oxidized cytosolic environment and rapid mitochondrial fragmentation. Decreasing direct electron entry into the ETC by genetic or chemical means, or reducing the cytosolic environment rapidly restores networked morphologies. Using controlled disruptions of electron flow to alter ROS and redox state, we demonstrate minute-scale, reversible control between networked and fragmented forms in an activity-independent manner. Mechanistically, the fission machinery through Dnm1 responds in minute-scale to redox state changes, preceding the change in mitochondrial form. Thus, the metabolic state of the cell and its consequent cellular redox state actively control mitochondrial form.
    Keywords:  electron transport chain; mitochondrial network; reactive oxygen species; redox state
    DOI:  https://doi.org/10.1073/pnas.2421953122
  12. Aging Dis. 2025 Apr 08.
    Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging?
    Xinxin Zuo.
      Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), is a complex condition associated with neurodevelopmental impairments and accelerated brain aging, often culminating in early-onset Alzheimer's disease (AD). Central to this accelerated aging is mitochondrial imbalance, characterized by disrupted energy metabolism, increased oxidative stress, impaired dynamics, and defective quality control mechanisms like mitophagy. These abnormalities exacerbate neuronal vulnerability, driving cognitive decline and neurodegeneration. This review examines the genetic and biochemical underpinnings of mitochondrial dysfunction in DS, with a focus on the role of HSA21-encoded genes. We also highlight how mitochondrial dysfunction, amplified by oxidative stress and HSA21 gene dosage effects, converges with cellular senescence and neuroinflammation to accelerate Alzheimer-like pathology and brain aging in DS. Finally, we discuss emerging therapeutic strategies targeting mitochondrial pathways, which hold promise for mitigating neurodegenerative phenotypes and improving outcomes in DS.
    DOI:  https://doi.org/10.14336/AD.2025.0189
  13. Sci Adv. 2025 Apr 18. 11(16): eads6830
    Spatial analysis of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress.
    Adam Begeman, John A Smolka, Ahmad Shami, Tejashree Pradip Waingankar, Samantha C Lewis.
      Protein- and RNA-rich bodies contribute to the spatial organization of gene expression in the cell and are also sites of quality control critical to cell fitness. In most eukaryotes, mitochondria harbor their own genome, and all steps of mitochondrial gene expression co-occur within a single compartment-the matrix. Here, we report that processed mitochondrial RNAs are consolidated into micrometer-scale translation hubs distal to mitochondrial DNA transcription and RNA processing sites in human cells. We find that, during stress, mitochondrial messenger and ribosomal RNA are sequestered in mesoscale bodies containing mitoribosome components, concurrent with suppression of active translation. Stress bodies are triggered by proteotoxic stress downstream of double-stranded RNA accumulation in cells lacking unwinding activity of the highly conserved helicase SUPV3L1/SUV3. We propose that the spatial organization of nascent polypeptide synthesis into discrete domains serves to throttle the flow of genetic information to support recovery of mitochondrial quality control.
    DOI:  https://doi.org/10.1126/sciadv.ads6830
  14. Cell Rep. 2025 Apr 11. pii: S2211-1247(25)00333-X. [Epub ahead of print]44(4): 115562
    SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19.
    Marine Barthez, Biyun Xue, Jian Zheng, Yifei Wang, Zehan Song, Wei-Chieh Mu, Chih-Ling Wang, Jiayue Guo, Fanghan Yang, Yuze Ma, Xuetong Wei, Chengjin Ye, Nicholas Sims, Luis Martinez-Sobrido, Stanley Perlman, Danica Chen.
      Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD+-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD+ booster, 78c, protects aged mice from lethal infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of cyclic GMP-AMP synthase (cGAS), an immune sensor for cytosolic DNA, and suppresses aging-associated cGAS activation and inflammation. Furthermore, we show that SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release and cGAS activation. Collectively, our study reveals a molecular basis for aging-associated susceptibility to COVID-19 and suggests therapeutic approaches to protect aged populations from severe SARS-CoV-2 infection.
    Keywords:  COVID-19; CP: Immunology; CP: Microbiology; NAD; ORF3a; SARS-CoV-2; SIRT1; SIRT2; SIRT3; SIRT6; SIRT7; aging; cGAS; inflammation; mitochondria; sirtuin
    DOI:  https://doi.org/10.1016/j.celrep.2025.115562
  15. Sci Rep. 2025 Apr 14. 15(1): 12839
    Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions.
    Yuka Nozaki, Masaki Kobayashi, Tomoyoshi Fukuoh, Mamiko Ishimatsu, Takumi Narita, Kanari Taki, Yuto Hirao, Shota Ayabe, Miku Yokoyama, Yuina Otani, Yuhei Mizunoe, Mami Matsumoto, Nobuhiko Ohno, Tomonori Kaifu, Shogo Okazaki, Ryo Goitsuka, Yoshimi Nakagawa, Hitoshi Shimano, Yoichiro Iwakura, Yoshikazu Higami.
      Most mitochondrial proteins encoded in the nuclear genome are synthesized in the cytoplasm. These proteins subsequently undergo maturation through the cleavage of a signal sequence at the N-terminus by one or two mitochondrial signal peptidases, which is essential for their function within mitochondria. The present study demonstrates that adipocyte-specific knockout of one mitochondrial signal peptidase, mitochondrial intermediate peptidase (MIPEP), resulted in disordered mitochondrial proteostasis of MIPEP substrate proteins and their defective maturation. MIPEP deficiency in white and brown adipocytes suppressed the expression of adipocyte differentiation, lipid metabolism, and mitochondrial biogenesis genes. These alterations led to lipoatrophy in white adipose tissue and the whitening of brown adipose tissue. Additionally, it induced an atypical mitochondrial unfolded protein response and local inflammation in white and brown adipose tissue. Furthermore, it induced fatty liver and splenomegaly and caused systemic impairments in glucose metabolism and inflammation. These findings indicate that maturation defects of certain mitochondrial proteins and subsequent proteostasis disorders in white and brown adipocytes cause chronic and systemic inflammatory and metabolic dysfunctions.
    DOI:  https://doi.org/10.1038/s41598-025-97307-6
  16. Nat Med. 2025 Apr 14.
    Gene-edited pig liver successfully transplanted into human.
    Karen O'Leary.
      
    Keywords:  Liver diseases; Organ transplantation
    DOI:  https://doi.org/10.1038/d41591-025-00025-9
  17. Am J Physiol Cell Physiol. 2025 Apr 17.
    MITOCHONDRIAL METABOLISM AND HYPOXIC SIGNALLING IN DIFFERENTIATED HUMAN CARDIOMYOCYTE AC16 CELL LINE.
    Lukas Alan, Barbora Opletalova, Habiba Hayat, Aleksandra Markovic, Marketa Hlavackova, Marek Vrbacky, Tomas Mracek, Petra Alánová.
      Cardiovascular diseases are associated with an altered cardiomyocyte metabolism. Due to a shortage of human heart tissue, experimental studies mostly rely on alternative approaches including animal and cell culture models. Since the use of isolated primary cardiomyocytes is limited, immortalized cardiomyocyte cell lines may represent a useful tool as they closely mimic human cardiomyocytes. This study is focused on the AC16 cell line generated from adult human ventricular cardiomyocytes. Despite an increasing number of articles employing AC16 cells, the comprehensive proteomic, bioenergetic and oxygen-sensing characterization of proliferating versus differentiated cells is still lacking. Here, we provide a comparison of these two stages, particularly emphasizing cell metabolism, mitochondrial function, and hypoxic signalling. The label-free quantitative mass spectrometry revealed a decrease in autophagy and cytoplasmic translation in differentiated AC16, confirming their phenotype. Cell differentiation led to the global increase in mitochondrial proteins (e.g. OXPHOS proteins, TFAM, VWA8, etc.) reflected by elevated mitochondrial respiration. Fatty acid oxidation proteins were increased in differentiated cells, while the expression levels of proteins associated with fatty acid synthesis were unchanged, and glycolytic proteins were decreased. There was a profound difference between proliferating and differentiated cells in their response to hypoxia and anoxia/reoxygenation. We conclude that AC16 differentiation leads to proteomic and metabolic shifts and altered cell response to oxygen deprivation. This underscores the requirement for proper selection of particular differentiation state during experimental planning.
    Keywords:  AC16; differentiation; hypoxia; metabolism; mitochondria
    DOI:  https://doi.org/10.1152/ajpcell.00083.2025
  18. Kidney Int Rep. 2025 Mar;10(3): 973-974
    Mitochondrial Dysfunction: The Nexus of Aging, Dyslipidemia, and CKD.
    Yu-Hsiang Lin, Kuo-Jen Lin, Chih-Hsiang Chang.
      
    DOI:  https://doi.org/10.1016/j.ekir.2025.01.010
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