bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–01–26
thirteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Precise modelling of mitochondrial diseases using optimized mitoBEs.
  2. Mitochondrial protein import stress.
  3. Derivation and Characterization of Isogenic OPA1 Mutant and Control Human Pluripotent Stem Cell Lines.
  4. Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.
  5. Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction.
  6. mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
  7. Mitochondrial quality control: a pathophysiological mechanism and potential therapeutic target for chronic obstructive pulmonary disease.
  8. Mitochondrial NAD+ transporter SLC25A51 linked to human aortic disease.
  9. Mitochondrial swap from cancer to immune cells thwarts anti-tumour defences.
  10. Mitochondrial DNA variants and their impact on epigenetic and biological aging in young adulthood.
  11. Mitochondrial regulation of obesity by POMC neurons.
  12. Immune evasion through mitochondrial transfer in the tumour microenvironment.
  13. Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.
  1. Nature. 2025 Jan 22.
    Precise modelling of mitochondrial diseases using optimized mitoBEs.
    Xiaoxue Zhang, Xue Zhang, Jiwu Ren, Jiayi Li, Xiaoxu Wei, Ying Yu, Zongyi Yi, Wensheng Wei.
      The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.
    DOI:  https://doi.org/10.1038/s41586-024-08469-8
  2. Nat Cell Biol. 2025 Jan 22.
    Mitochondrial protein import stress.
    Nikolaus Pfanner, Fabian den Brave, Thomas Becker.
      Mitochondria have to import a large number of precursor proteins from the cytosol. Chaperones keep these proteins in a largely unfolded state and guide them to the mitochondrial import sites. Premature folding, mitochondrial stress and import defects can cause clogging of import sites and accumulation of non-imported precursors, representing a critical burden for cellular proteostasis. Here we discuss how cells respond to mitochondrial protein import stress by regenerating clogged import sites and inducing stress responses. The mitochondrial protein import machinery has a dual role by serving as sensor for detecting mitochondrial dysfunction and inducing stress-response pathways. The production of chaperones that fold or sequester precursor proteins in deposits is induced and the proteasomal activity is increased to remove the excess precursor proteins. Together, these pathways reveal how mitochondria are tightly integrated into a cellular proteostasis and stress response network to maintain cell viability.
    DOI:  https://doi.org/10.1038/s41556-024-01590-w
  3. Cells. 2025 Jan 17. pii: 137. [Epub ahead of print]14(2):
    Derivation and Characterization of Isogenic OPA1 Mutant and Control Human Pluripotent Stem Cell Lines.
    Katherine A Pohl, Xiangmei Zhang, Johnny Jeonghyun Ji, Linsey Stiles, Alfredo A Sadun, Xian-Jie Yang.
      Dominant optic atrophy (DOA) is the most commonly inherited optic neuropathy. The majority of DOA is caused by mutations in the OPA1 gene, which encodes a dynamin-related GTPase located to the mitochondrion. OPA1 has been shown to regulate mitochondrial dynamics and promote fusion. Within the mitochondrion, proteolytically processed OPA1 proteins form complexes to maintain membrane integrity and the respiratory chain complexity. Although OPA1 is broadly expressed, human OPA1 mutations predominantly affect retinal ganglion cells (RGCs) that are responsible for transmitting visual information from the retina to the brain. Due to the scarcity of human RGCs, DOA has not been studied in depth using the disease affected neurons. To enable studies of DOA using stem-cell-derived human RGCs, we performed CRISPR-Cas9 gene editing to generate OPA1 mutant pluripotent stem cell (PSC) lines with corresponding isogenic controls. CRISPR-Cas9 gene editing yielded both OPA1 homozygous and heterozygous mutant ESC lines from a parental control ESC line. In addition, CRISPR-mediated homology-directed repair (HDR) successfully corrected the OPA1 mutation in a DOA patient's iPSCs. In comparison to the isogenic controls, the heterozygous mutant PSCs expressed the same OPA1 protein isoforms but at reduced levels; whereas the homozygous mutant PSCs showed a loss of OPA1 protein and altered mitochondrial morphology. Furthermore, OPA1 mutant PSCs exhibited reduced rates of oxygen consumption and ATP production associated with mitochondria. These isogenic PSC lines will be valuable tools for establishing OPA1-DOA disease models in vitro and developing treatments for mitochondrial deficiency associated neurodegeneration.
    Keywords:  CRISPR-Cas9 editing; OPA1 gene; dominant optic atrophy; isogenic human pluripotent stem cell lines; mitochondria
    DOI:  https://doi.org/10.3390/cells14020137
  4. Sci Adv. 2025 Jan 24. 11(4): eadu4369
    Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.
    Joshua S Stoolman, Rogan A Grant, Leah K Billingham, Taylor A Poor, Samuel E Weinberg, Madeline C Harding, Ziyan Lu, Jason Miska, Marten Szibor, Gr Scott Budinger, Navdeep S Chandel.
      Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of macrophage immune responses are not fully understood. Here, we report that mutant mice with mitochondria ETC complex III (CIII)-deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow-derived macrophages (BMDMs) isolated from these mitochondria CIII-deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondria CIII-deficient BMDMs following LPS stimulation. In addition, mitochondria CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondria CIII-generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation.
    DOI:  https://doi.org/10.1126/sciadv.adu4369
  5. Commun Biol. 2025 Jan 21. 8(1): 105
    Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction.
    Shih-Cheng Wu, Yan-Jhen Chen, Shih-Han Su, Pai-Hsiang Fang, Rei-Wen Liu, Hui-Ying Tsai, Yen-Jui Chang, Hsing-Han Li, Jian-Chiuan Li, Chun-Hong Chen.
      Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.
    DOI:  https://doi.org/10.1038/s42003-025-07457-6
  6. FASEB J. 2025 Jan 31. 39(2): e70277
    mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
    Jingwen Li, Agnete B Madsen, Jonas R Knudsen, Carlos Henriquez-Olguin, Kaspar W Persson, Zhencheng Li, Steffen H Raun, Tianjiao Li, Bente Kiens, Jørgen F P Wojtaszewski, Erik A Richter, Leonardo Nogara, Bert Blaauw, Riki Ogasawara, Thomas E Jensen.
      The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity-dependent manner. Contraction-stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2-dependent phosphorylations were affected in muscle-specific kinase-dead AMPK mice with no detectable mTOR Ser1261 phosphorylation in skeletal muscle. Thus, mTOR Ser1261 is an exercise but not insulin-responsive AMPK-dependent phosphosite in human and murine skeletal muscle, playing an unclear role in mTORC1 regulation but clearly not required for mTORC2 activity.
    Keywords:  AMPK; exercise; mTORC1; mTORC2; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202402064R
  7. Front Pharmacol. 2024 ;15 1474310
    Mitochondrial quality control: a pathophysiological mechanism and potential therapeutic target for chronic obstructive pulmonary disease.
    Mengjiao Xu, Peng Feng, Jun Yan, Lei Li.
      Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease worldwide. Mitochondrial quality control mechanisms encompass processes such as mitochondrial biogenesis, fusion, fission, and autophagy, which collectively maintain the quantity, morphology, and function of mitochondria, ensuring cellular energy supply and the progression of normal physiological activities. However, in COPD, due to the persistent stimulation of harmful factors such as smoking and air pollution, mitochondrial quality control mechanisms often become deregulated, leading to mitochondrial dysfunction. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of COPD, contributing toinflammatory response, oxidative stress, cellular senescence. However, therapeutic strategies targeting mitochondria remain underexplored. This review highlights recent advances in mitochondrial dysfunction in COPD, focusing on the role of mitochondrial quality control mechanisms and their dysregulation in disease progression. We emphasize the significance of mitochondria in the pathophysiological processes of COPD and explore potential strategies to regulate mitochondrial quality and improve mitochondrial function through mitochondrial interventions, aiming to treat COPD effectively. Additionally, we analyze the limitations and challenges of existing therapeutic strategies, aiming to provide new insights and methods for COPD treatment.
    Keywords:  chronic obstructive pulmonary disease; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial quality control; mitophagy; therapeutic strategies
    DOI:  https://doi.org/10.3389/fphar.2024.1474310
  8. Nat Cardiovasc Res. 2025 Jan 22.
    Mitochondrial NAD+ transporter SLC25A51 linked to human aortic disease.
    Gabriel K Adzika, Ricardo A Velázquez Aponte, Joseph A Baur.
      
    DOI:  https://doi.org/10.1038/s44161-024-00599-6
  9. Nature. 2025 Jan 22.
    Mitochondrial swap from cancer to immune cells thwarts anti-tumour defences.
    Jonathan R Brestoff.
      
    Keywords:  Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-00077-4
  10. Transl Psychiatry. 2025 Jan 22. 15(1): 16
    Mitochondrial DNA variants and their impact on epigenetic and biological aging in young adulthood.
    Klara Mareckova, Ana Paula Mendes-Silva, Martin Jáni, Anna Pacinkova, Pavel Piler, Vanessa F Gonçalves, Yuliya S Nikolova.
      The pace of biological aging varies between people independently of chronological age and mitochondria dysfunction is a key hallmark of biological aging. We hypothesized that higher functional impact (FI) score of mitochondrial DNA (mtDNA) variants might contribute to premature aging and tested the relationships between a novel FI score of mtDNA variants and epigenetic and biological aging in young adulthood. A total of 81 participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort had good quality genetic data as well as blood-based markers to estimate biological aging in the late 20. A subset of these participants (n = 69) also had epigenetic data to estimate epigenetic aging in the early 20s using Horvath's epigenetic clock. The novel FI score was calculated based on 7 potentially pathogenic mtDNA variants. Greater FI score of mtDNA variants was associated with older epigenetic age in the early 20s and older biological age in the late 20s. These medium to large effects were independent of sex, current BMI, cigarette smoking, cannabis, and alcohol use. These findings suggest that elevated FI score of mtDNA variants might contribute to premature aging in young adulthood.
    DOI:  https://doi.org/10.1038/s41398-025-03235-4
  11. Biochim Biophys Acta Mol Basis Dis. 2025 Jan 19. pii: S0925-4439(25)00027-4. [Epub ahead of print] 167682
    Mitochondrial regulation of obesity by POMC neurons.
    Xing-Dan Luo, Si Tang, Xiang-Yun Luo, Luosang Quzhen, Ruo-Han Xia, Xian-Wang Wang.
      Pro-opiomelanocortin (POMC) neurons, nestled in the hypothalamus, play a pivotal role in the intricate coordination of energy homeostasis and metabolic pathways. These neurons' mitochondria, often hailed as the cell's powerhouses, are crucial for maintaining cellular energy equilibrium and metabolic functionality. Recent research has illuminated the complex interplay between mitochondrial dynamics and POMC neuronal activity, underscoring their critical involvement in the pathogenesis of a spectrum of metabolic disorders, notably obesity and diabetes. This comprehensive review delves into the molecular mechanisms that underlie how mitochondrial function within POMC neurons modulates metabolic regulation. We dissect the impact of mitochondrial dynamics, encompassing fusion, fission, mitophagy, and biogenesis, on the regulation of POMC neuronal activity. Furthermore, we scrutinize the role of mitochondrial dysfunction in POMC neurons in the etiology of obesity, identifying key therapeutic targets within these pathways. We offer an in-depth perspective on the indispensable role of POMC neuronal mitochondria in metabolic regulation and chart future research directions to bridge the existing knowledge gaps in this field.
    Keywords:  Metabolic regulation; Mitochondrion; Obesity; POMC
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167682
  12. Nature. 2025 Jan 22.
    Immune evasion through mitochondrial transfer in the tumour microenvironment.
    Hideki Ikeda, Katsushige Kawase, Tatsuya Nishi, Tomofumi Watanabe, Keizo Takenaga, Takashi Inozume, Takamasa Ishino, Sho Aki, Jason Lin, Shusuke Kawashima, Joji Nagasaki, Youki Ueda, Shinichiro Suzuki, Hideki Makinoshima, Makiko Itami, Yuki Nakamura, Yasutoshi Tatsumi, Yusuke Suenaga, Takao Morinaga, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Yukiko Kiniwa, Eiki Ichihara, Hidetoshi Hayashi, Jun-Ichiro Ikeda, Toyoyuki Hanazawa, Shinichi Toyooka, Hiroyuki Mano, Takuji Suzuki, Tsuyoshi Osawa, Masahito Kawazu, Yosuke Togashi.
      Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2-4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-024-08439-0
  13. Sci Adv. 2025 Jan 24. 11(4): eadq9301
    Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.
    Jing Wu, Komudi Singh, Vivian Shing, Anand Gupta, Brett C Arenberg, Rebecca D Huffstutler, Duck-Yeon Lee, Michael N Sack.
      Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1-/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.
    DOI:  https://doi.org/10.1126/sciadv.adq9301
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