bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–08–31
fourteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis.
  2. The homoplasmic MT-TK m.8357T > C mtDNA variant as a cause of multiorgan mitochondrial disease.
  3. Mitochondria transfer.
  4. Dysfunctional Electron Transport Chain Assembly in COXPD8.
  5. Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
  6. Systemic Lonp1 Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Lonp1 Haploinsufficiency via Potential Inter-Organ Crosstalk.
  7. Mitochondrial Extracellular Vesicles: A Novel Approach to Mitochondrial Quality Control.
  8. Mitochondrial quality control in diabetes mellitus and complications: molecular mechanisms and therapeutic strategies.
  9. Early lineage segregation of primary myotubes from secondary myotubes and adult muscle stem cells.
  10. Investigating metabolic changes in single embryos during early development in Drosophila.
  11. A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism.
  12. Isoform-specific roles of AMP-activated protein kinase in cardiac physiology and pathophysiology.
  13. Programmable epigenome editing by transient delivery of CRISPR epigenome editor ribonucleoproteins.
  14. Structural basis for the dynamic regulation of mTORC1 by amino acids.
  1. EMBO J. 2025 Aug 26.
    RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis.
    Monika Oláhová, Rachel M Guerra, Jack J Collier, Juliana Heidler, Kyle Thompson, Chelsea R White, Paulina Castañeda-Tamez, Alfredo Cabrera-Orefice, Robert N Lightowlers, Zofia M A Chrzanowska-Lightowlers, Alexander Galkin, Ilka Wittig, David J Pagliarini, Robert W Taylor.
      A biochemical deficiency of mitochondrial complex I (CI) underlies approximately 30% of cases of primary mitochondrial disease, yet the inventory of molecular machinery required for CI assembly remains incomplete. We previously characterised patients with isolated CI deficiency caused by segregating variants in RTN4IP1, a gene that encodes a mitochondrial NAD(P)H oxidoreductase. Here, we demonstrate that RTN4IP1 deficiency causes a CI assembly defect in both patient fibroblasts and knockout cells, and report that RTN4IP1 is a bona fide CI assembly factor. Complexome profiling revealed accumulation of unincorporated ND5-module and impaired N-module production. RTN4IP1 patient fibroblasts also exhibited defective coenzyme Q biosynthesis, substantiating a second function of RTN4IP1. Thus, our data reveal RTN4IP1 plays necessary and independent roles in both the terminal stages of CI assembly and in coenzyme Q metabolism, and that pathogenic RTN4IP1 variants impair both functions in patients with mitochondrial disease.
    Keywords:  Coenzyme Q; Complex I Assembly; Complexome Profiling; Mitochondria; RTN4IP1
    DOI:  https://doi.org/10.1038/s44318-025-00533-x
  2. Mitochondrion. 2025 Aug 18. pii: S1567-7249(25)00077-7. [Epub ahead of print]85 102080
    The homoplasmic MT-TK m.8357T > C mtDNA variant as a cause of multiorgan mitochondrial disease.
    Luisa Zupin, Valeria Capaci, Maria Teresa Bonati, Eleonora Lamantea, Muhammad Suleman, Andrea Marsala, Fulvio Celsi, Beatrice Spedicati, Sergio Crovella, Giulia Gortani, Giorgia Girotto, Irene Bruno, Massimo Zeviani.
      The diagnosis of disorders associated with mitochondrial DNA (mtDNA) variants presents substantial complexity due to their genetic and clinical heterogeneity, which is largely influenced by mtDNA heteroplasmy. However, the level of heteroplasmy alone is often not sufficient to predict the clinical phenotype including its severity and progression. This study concerns the characterization of the m.8357T > C variant in the MT-TK gene, encoding for mt-tRNA-Lys found in two pediatric siblings. Both had symptoms suggestive of a mitochondrial disease, including severe hearing loss, easy fatigability, decreased activity of mitochondrial complex I in muscle samples, epilepsy, metabolic acidosis with hyperkalemia, and mild kidney impairment. The m.8357T > C mtDNA variant was homoplasmic in muscle, blood, urine and fibroblasts. Immortalized fibroblasts from the patients showed reduced activity of mitochondrial complexes I, III and IV, decreased mitochondrial respiration, and abnormal depolarization of the mitochondrial membrane potential. The mt-tRNA-Lys levels were reduced as compared to the mt-tRNA-Leu (UUR) or the snRNA encoded by RNU6B nuclear gene; the level of three mitochondrial DNA encoded proteins was decreased, altogether suggesting a defective translation machinery in cells carrying the variant. Consistently, fibroblasts from the mother, who had only mild hearing loss, despite high level of heteroplasmy, showed some biochemical abnormalities, however milder than in her daughter and son. Contrariwise, their maternal aunt, who showed intellectual disability, mild hearing loss, easy fatigability and weakness was also virtually homoplasmic for the m.8357T > C in blood and urinary sediment cells. These findings suggest the pathogenicity of the m.8357T > C variant but only in condition of homoplasmy.
    Keywords:  Heteroplasmy; Mitochondrial disease; mt-tRNA-Lys
    DOI:  https://doi.org/10.1016/j.mito.2025.102080
  3. Nat Metab. 2025 Aug 27.
    Mitochondria transfer.
    Navdeep S Chandel, Marni J Falk, Janine H Santos, Jonathan R Brestoff, Ana V Lechuga-Vieco, Yasemin S Sancak, Quan Chen, Alvaro A Elorza, Rubén Quintana-Cabrera.
      
    DOI:  https://doi.org/10.1038/s42255-025-01364-0
  4. J Cardiovasc Dev Dis. 2025 Aug 20. pii: 318. [Epub ahead of print]12(8):
    Dysfunctional Electron Transport Chain Assembly in COXPD8.
    Gisela Beutner, Heidie L Huyck, Gail Deutsch, Gloria S Pryhuber, George A Porter.
      Combined oxidative phosphorylation deficiency type 8 (COXPD8) is an autosomal recessive mitochondrial disorder caused by a mutation of the nuclear encoded mitochondrial alanyl-tRNA synthetase gene (AARS2). Clinical manifestations of COXPD8 include lethal infantile hypertrophic cardiomyopathy, pulmonary hypoplasia, generalized muscle weakness, and neurological involvement. We report a patient with COXPD8 caused by two mutations in the AARS2 gene. The c.1738 C>G mutation has not been previously reported, while the c.2872 C>T mutation has been associated with pulmonary hypoplasia and hypertrophic cardiomyopathy. Cardiac tissue, obtained through the LungMAP program, showed that, compared to other patients of similar ages, these two mutations affect not only the assembly of functional monomeric complexes (Cx) I and IV of the electron transport chain (ETC) but also limit the formation of respiratory supercomplexes. This patient had altered expression of some ETC proteins but normal expression of several enzymes of the tricarboxylic acid cycle. We also show that one of the control/comparison patients had an undiagnosed ETC Cx IV deficiency. In conclusion, our data demonstrate that the two mutations of the AARS2 gene are associated with failed assembly of Cx I and Cx IV and reduced formation of respiratory supercomplexes of the ETC, likely leading to acute bioenergetic stress.
    Keywords:  COXPD8; electron transport chain; hypertrophic cardiomyopathy; mitochondrial disease; mitochondrial supercomplexes
    DOI:  https://doi.org/10.3390/jcdd12080318
  5. Sci Adv. 2025 Aug 29. 11(35): eady0240
    Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
    William M Rosencrans, Ryan W Lee, Logan McGraw, Ian Horsburgh, Ting-Yu Wang, Baiyi Quan, Diana Huynh, Jennifer A Johnston, David C Chan, Tsui-Fen Chou.
      The PINK1/Parkin pathway targets damaged mitochondria for degradation via mitophagy. Genetic evidence implicates impaired mitophagy in Parkinson's disease, making its pharmacological enhancement a promising therapeutic strategy. Here, we characterize two mitophagy activators: a novel Parkin activator, FB231, and the reported PINK1 activator MTK458. Both compounds lower the threshold for mitochondrial toxins to induce PINK1/Parkin-mediated mitophagy. However, global proteomics revealed that FB231 and MTK458 independently induce mild mitochondrial stress, resulting in impaired mitochondrial function and activation of the integrated stress response, effects that result from PINK1/Parkin-independent off-target activities. We find that these compounds impair mitochondria by distinct mechanisms and synergistically decrease mitochondrial function and cell viability in combination with classical mitochondrial toxins. Our findings support a model whereby weak or "silent" mitochondrial toxins potentiate other mitochondrial stressors, enhancing PINK1/Parkin-mediated mitophagy. These insights highlight important considerations for therapeutic strategies targeting mitophagy activation in Parkinson's disease.
    DOI:  https://doi.org/10.1126/sciadv.ady0240
  6. Biomolecules. 2025 Aug 13. pii: 1159. [Epub ahead of print]15(8):
    Systemic Lonp1 Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Lonp1 Haploinsufficiency via Potential Inter-Organ Crosstalk.
    Sakthijothi Muthu, Zinnia Tran, Ramasamy Saminathan, Pratikshya Shrestha, Sundararajan Venkatesh.
      Efficient mitochondrial matrix protein quality control (mPQC), regulated by the mitochondrial matrix protease LONP1, is essential for preserving cardiac bioenergetics, particularly in post-mitotic cardiomyocytes, which are highly susceptible to mitochondrial dysfunction. While cardiac mPQC defects could impair heart function, it remains unclear whether such defects can be mitigated through inter-organ crosstalk by modulating mPQC in extra-cardiac tissues, a potentially valuable strategy given the challenges of directly targeting the heart. To investigate this, we examined two mouse models of Lonp1 haploinsufficiency at young adulthood: a cardiomyocyte-specific heterozygous knockout (Lonp1CKO-HET) and a whole-body heterozygous knockout (Lonp1GKO-HET). Despite similar reductions in Lonp1 mRNA expression in the hearts, Lonp1GKO-HET mice exhibited no cardiac dysfunction, whereas Lonp1CKO-HET mice showed mild cardiac dysfunction accompanied by activation of the mitochondrial stress response, including induction of genes such as Clpx, Spg7, Hspa9, and Hspd1, increased mitochondrial dynamics (Pink1, Dnm1l), reduced mitochondrial biogenesis, and compensatory upregulation of the mtDNA transcriptional regulator Tfam, all occurring without overt structural remodeling. These alterations were absent in Lonp1GKO-HET hearts. Our findings reveal a novel adaptive mechanism in which systemic mPQC deficiency can buffer mitochondrial dysfunction in the heart through inter-organ communication that is lost with cardiomyocyte-specific mPQC disruption. This study identifies systemic modulation of Lonp1-mediated mitochondrial stress pathways as a promising strategy to promote cardiac resilience through protective inter-organ signaling.
    Keywords:  LONP1; cardiac dysfunction; heart; mitochondria; mitochondrial dysfunction; mitochondrial matrix; protein quality control
    DOI:  https://doi.org/10.3390/biom15081159
  7. Biomolecules. 2025 Aug 08. pii: 1145. [Epub ahead of print]15(8):
    Mitochondrial Extracellular Vesicles: A Novel Approach to Mitochondrial Quality Control.
    Jie Kong, Rui Sun, Chengying Du, Yiyang Tang, Chengzhi Xie, Qian Li, Li Lin, Hongyan Wang.
      Mitochondria are central to cellular energy metabolism and play a key role in regulating important physiological processes, including apoptosis and oxidative stress. Mitochondrial quality control has recently garnered significant attention, with the underlying mechanisms traditionally considered to be mitophagy and its dynamics. Various studies have demonstrated that extracellular vesicles are crucial for the transmission of mitochondria and their components. These vesicles effectively transport mitochondria to target cells, facilitating intercellular material exchange and signal transmission, thereby enhancing cellular function and viability. This review explores the mechanisms of mitochondrial transfer through mitochondrial extracellular vesicles (MitoEVs), analyzes the novel roles of MitoEVs in mitochondrial quality control, and discusses their applications in disease treatment. We aim to provide new perspectives for future research and support the development of relevant therapeutic strategies.
    Keywords:  MitoEVs; extracellular vesicle; intercellular material exchange; mitochondria; mitochondrial quality control; signal transmission
    DOI:  https://doi.org/10.3390/biom15081145
  8. Cell Death Dis. 2025 Aug 27. 16(1): 652
    Mitochondrial quality control in diabetes mellitus and complications: molecular mechanisms and therapeutic strategies.
    Yanling Chen, Xun Liu, Yixuan Liu, Yujia Li, Dingxiang Li, Zhigang Mei, Yihui Deng.
      Diabetes mellitus (DM), a metabolic disease of globally health concern, is pathologically attributed to mitochondrial dysfunction, an essential component in disease progression. Mitochondrial quality control (MQC) acts as a critical defense mechanism for metabolic homeostasis, yet its implications in DM and its complications remain incompletely understood. This study thoroughly summarizes emerging evidence that delineates the molecular processes of MQC, with an emphasis on effector protein post-translational regulation, upstream signaling hubs, and interactions with other metabolic processes including ferroptosis and lipid metabolism. We highlight newly discovered processes involving mitochondrial-derived vesicles, licensed mitophagy, and mitocytosis that broaden the regulatory landscape of MQC, going beyond the traditionally recognized process including biogenesis, dynamics and mitophagy. MQC imbalance exacerbates insulin resistance, while impaired insulin signaling reciprocally compromises mitochondrial function, creating a vicious cycle of metabolic deterioration. Despite tissue-specific pathophysiology, diabetic complications exhibit identical MQC impairment including suppressed biogenesis, fission-fusion imbalance, and deficient mitophagy. Emerging therapies including clinical hypoglycemic agents and bioactive phytochemicals demonstrate therapeutic potential by restoring MQC. However, current strategies remain anchored to classical pathways, neglecting novel MQC mechanisms such as mitocytosis. Addressing this gap demands integration of cutting-edge MQC insights into drug discovery, particularly for compounds modulating upstream regulators. Future studies must prioritize mechanistic dissection of MQC novel targets and their translational relevance in halting metabolic collapse of diabetes progression. Since mitochondrial function is a cornerstone of metabolic restoration, synergizing precision MQC modulation with multi-target interventions, holds transformative potential for refine diabetic complications therapeutics.
    DOI:  https://doi.org/10.1038/s41419-025-07936-y
  9. Nat Commun. 2025 Aug 22. 16(1): 7858
    Early lineage segregation of primary myotubes from secondary myotubes and adult muscle stem cells.
    Gauthier Toulouse, William Jarassier, Sabrina Jagot, Valérie Morin, Fabien Le Grand, Christophe Marcelle.
      Myogenesis in amniotes occurs in two waves. Primary myotubes express slow myosin (often with fast myosin) and likely act as scaffolds for secondary myotubes, which express only fast myosin. The embryonic origins and relationships of these lineages, and their connection to satellite cells, remain unknown. Here, we combine a TCF-LEF/β-catenin signaling reporter with precise in vivo electroporation in avian embryos to trace limb muscle progenitors from early migration to fetal stages. We identify two distinct progenitor populations that coexist from the onset: reporter-positive cells give rise exclusively to primary myotubes, while reporter-negative cells generate secondary myotubes and satellite cells. We also reveal a previously unrecognized role for TCF-LEF/β-catenin signaling in spatially organizing the primary lineage via Cxcr4-mediated control of myoblast migration. These findings redefine the developmental origin of myogenic lineages, resolve a longstanding question in muscle biology, and provide a molecular framework for investigating how muscle fiber diversity emerges and how distinct lineages contribute to the functional specialization of skeletal muscle.
    DOI:  https://doi.org/10.1038/s41467-025-61767-1
  10. Nat Metab. 2025 Aug 22.
    Investigating metabolic changes in single embryos during early development in Drosophila.
      
    DOI:  https://doi.org/10.1038/s42255-025-01375-x
  11. Nat Commun. 2025 Aug 23. 16(1): 7863
    A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism.
    Abner Gonzalez, Alex Pon, Kelly Servage, Krzysztof Pawłowski, Yan Han, Anju Sreelatha.
      Protein AMPylation, the covalent addition of adenosine monophosphate (AMP) to protein substrates, has been known as a post translational modification for over 50 years. Research in this field is largely underdeveloped due to the lack of tools that enable the systematic identification of AMPylated substrates. Here, we address this gap by developing an enrichment technique to isolate and study AMPylated proteins using a nucleotide-binding protein, hinT. Cryo-EM reconstruction of an AMPylated protein bound to hinT provides a structural basis for AMP selectivity. Using structure guided mutagenesis, we optimize enrichment to identify novel substrates of the evolutionarily conserved AMPylase, Selenoprotein O. We show that mammalian Selenoprotein O regulates metabolic flux through AMPylation of key mitochondrial proteins including glutamate dehydrogenase and pyruvate dehydrogenase. Our findings highlight the broader significance of AMPylation, an emerging post translational modification with critical roles in signal transduction and disease pathology. Furthermore, we establish a powerful enrichment platform for the discovery of novel AMPylated proteins to study the mechanisms and significance of protein AMPylation in cellular function.
    DOI:  https://doi.org/10.1038/s41467-025-63014-z
  12. Front Cardiovasc Med. 2025 ;12 1638515
    Isoform-specific roles of AMP-activated protein kinase in cardiac physiology and pathophysiology.
    Ani Rakoubian, Julia Khinchin, Johnathan Yarbro, Satoru Kobayashi, Qiangrong Liang.
      AMP-activated protein kinase (AMPK) is a central regulator of cellular energy homeostasis, integrating metabolic, mitochondrial, and oxidative stress responses. In the heart, an organ with high and dynamically fluctuating energy demands, AMPK is essential for maintaining metabolic balance, particularly during conditions such as exercise, ischemia, hypertrophy, and heart failure. The AMPK complex comprises a catalytic α subunit and regulatory β and γ subunits, each with multiple isoforms (α1, α2; β1, β2; γ1, γ2, γ3) that confer tissue-specific distribution and functional specialization. This review highlights the isoform-specific roles of AMPK in the heart, emphasizing their distinct contributions to myocardial energy metabolism, contractile function, and cardiac remodeling across diverse physiological and pathological conditions.
    Keywords:  AMPK; cardiac remodeling; energy metabolism; isoform-specific; mitochondria quality control
    DOI:  https://doi.org/10.3389/fcvm.2025.1638515
  13. Nat Commun. 2025 Aug 26. 16(1): 7948
    Programmable epigenome editing by transient delivery of CRISPR epigenome editor ribonucleoproteins.
    Da Xu, Swen Besselink, Gokul N Ramadoss, Philip H Dierks, Justin P Lubin, Rithu K Pattali, Jinna I Brim, Anna E Christenson, Peter J Colias, Izaiah J Ornelas, Carolyn D Nguyen, Sarah E Chasins, Bruce R Conklin, James K Nuñez.
      Programmable epigenome editors modify gene expression in mammalian cells by altering the local chromatin environment at target loci without inducing DNA breaks. However, the large size of CRISPR-based epigenome editors poses a challenge to their broad use in biomedical research and as future therapies. Here, we present Robust ENveloped Delivery of Epigenome-editor Ribonucleoproteins (RENDER) for transiently delivering programmable epigenetic repressors (CRISPRi, DNMT3A-3L-dCas9, CRISPRoff) and activator (TET1-dCas9) as ribonucleoprotein complexes into human cells to modulate gene expression. After rational engineering, we show that RENDER induces durable epigenetic silencing of endogenous genes across various human cell types, including primary T cells. Additionally, we apply RENDER to epigenetically repress endogenous genes in human stem cell-derived neurons, including the reduction of the neurodegenerative disease associated V337M-mutated Tau protein. Together, our RENDER platform advances the delivery of CRISPR-based epigenome editors into human cells, broadening the use of epigenome editing in fundamental research and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41467-025-63167-x
  14. Nature. 2025 Aug 20.
    Structural basis for the dynamic regulation of mTORC1 by amino acids.
    Max L Valenstein, Maximilian Wranik, Pranav V Lalgudi, Karen Y Linde-Garelli, Yuri Choi, Raghu R Chivukula, David M Sabatini, Kacper B Rogala.
      The mechanistic target of rapamycin complex 1 (mTORC1) anchors a conserved signalling pathway that regulates growth in response to nutrient availability1-5. Amino acids activate mTORC1 through the Rag GTPases, which are regulated by GATOR, a supercomplex consisting of GATOR1, KICSTOR and the nutrient-sensing hub GATOR2 (refs. 6-9). GATOR2 forms an octagonal cage, with its distinct WD40 domain β-propellers interacting with GATOR1 and the leucine sensors Sestrin1 and Sestrin2 (SESN1 and SESN2) and the arginine sensor CASTOR1 (ref. 10). The mechanisms through which these sensors regulate GATOR2 and how they detach from it upon binding their cognate amino acids remain unknown. Here, using cryo-electron microscopy, we determined the structures of a stabilized GATOR2 bound to either Sestrin2 or CASTOR1. The sensors occupy distinct and non-overlapping binding sites, disruption of which selectively impairs the ability of mTORC1 to sense individual amino acids. We also resolved the apo (leucine-free) structure of Sestrin2 and characterized the amino acid-induced structural rearrangements within Sestrin2 and CASTOR1 that trigger their dissociation from GATOR2. Binding of either sensor restricts the dynamic WDR24 β-propeller of GATOR2, a domain essential for nutrient-dependent mTORC1 activation. These findings reveal the allosteric mechanisms that convey amino acid sufficiency to GATOR2 and the ensuing structural changes that lead to mTORC1 activation.
    DOI:  https://doi.org/10.1038/s41586-025-09428-7
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