bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–01–12
eleven papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. COA5 has an essential role in the early stage of mitochondrial complex IV assembly.
  2. Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.
  3. Mitochondrial diseases: from molecular mechanisms to therapeutic advances.
  4. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  5. Diagnosis and Management of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome.
  6. Identification of a new COQ4 spliceogenic variant causing severe primary coenzyme Q deficiency.
  7. C19orf12 gene variants causing mitochondrial membrane protein-associated neurodegeneration (MPAN).
  8. Spermidine Enhances Mitochondrial Bioenergetics in Young and Aged Human-Induced Pluripotent Stem Cell-Derived Neurons.
  9. The role of mitochondria in aging, cell death, and tumor immunity.
  10. Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis.
  11. Mitochondrial phosphatase PPTC7 promotes EGFR recycling by facilitating VPS4A endosomal localization.
  1. Life Sci Alliance. 2025 Mar;pii: e202403013. [Epub ahead of print]8(3):
    COA5 has an essential role in the early stage of mitochondrial complex IV assembly.
    Jia Xin Tang, Alfredo Cabrera-Orefice, Jana Meisterknecht, Lucie S Taylor, Geoffray Monteuuis, Maria Ekman Stensland, Adam Szczepanek, Karen Stals, James Davison, Langping He, Sila Hopton, Tuula A Nyman, Christopher B Jackson, Angela Pyle, Monika Winter, Ilka Wittig, Robert W Taylor.
      Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.
    DOI:  https://doi.org/10.26508/lsa.202403013
  2. Commun Biol. 2025 Jan 09. 8(1): 24
    Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.
    Julie Faitg, Tracey Davey, Ross Laws, Conor Lawless, Helen Tuppen, Eric Fitton, Doug Turnbull, Amy E Vincent.
      Mitochondria play a crucial role in maintaining cellular health. It is interesting that the shape of mitochondria can vary depending on the type of cell, mitochondrial function, and other cellular conditions. However, there are limited studies that link functional assessment with mitochondrial morphology evaluation at high magnification, even fewer that do so in situ and none in human muscle biopsies. Therefore, we have developed a method which combines functional assessment of mitochondria through Cytochrome c Oxidase (COX) histochemistry, with a 3D electron microscopy (EM) technique, serial block-face scanning electron microscopy (SBFSEM). Here we apply COX-SBFSEM to muscle samples from patients with single, large-scale mtDNA deletions, a cause of mitochondrial disease. These deletions cause oxidative phosphorylation deficiency, which can be observed through changes in COX activity. One of the main advantages of combining 3D-EM with the COX reaction is the ability to look at how per-mitochondrion oxidative phosphorylation status is spatially distributed within muscle fibres. Here we show a robust spatial pattern in COX-positive and intermediate-fibres and that the spatial pattern is less clear in COX-deficient fibres.
    DOI:  https://doi.org/10.1038/s42003-024-07389-7
  3. Signal Transduct Target Ther. 2025 Jan 10. 10(1): 9
    Mitochondrial diseases: from molecular mechanisms to therapeutic advances.
    Haipeng Wen, Hui Deng, Bingyan Li, Junyu Chen, Junye Zhu, Xian Zhang, Shigeo Yoshida, Yedi Zhou.
      Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of oxidative phosphorylation, one of the mitochondria's most critical functions. Mitochondrial diseases, a common group of genetic disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However, recent advancements in research and technology have significantly improved our understanding and management of these conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications. Additionally, this review discusses future perspectives on mitochondrial genetic diseases.
    DOI:  https://doi.org/10.1038/s41392-024-02044-3
  4. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  5. Biomolecules. 2024 Nov 28. pii: 1524. [Epub ahead of print]14(12):
    Diagnosis and Management of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome.
    Ji-Hoon Na, Young-Mock Lee.
      Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a complex mitochondrial disorder characterized by a wide range of systemic manifestations. Key clinical features include recurrent stroke-like episodes, seizures, lactic acidosis, muscle weakness, exercise intolerance, sensorineural hearing loss, diabetes, and progressive neurological decline. MELAS is most commonly associated with mutations in mitochondrial DNA, particularly the m.3243A>G mutation in the MT-TL1 gene, which encodes tRNALeu (CUR). These mutations impair mitochondrial protein synthesis, leading to defective oxidative phosphorylation and energy failure at the cellular level. The clinical presentation and severity vary widely among patients, but the syndrome often results in significant morbidity and reduced life expectancy because of progressive neurological deterioration. Current management is largely focused on conservative care, including anti-seizure medications, arginine or citrulline supplementation, high-dose taurine, and dietary therapies. However, these therapies do not address the underlying genetic mutations, leaving many patients with substantial disease burden. Emerging experimental treatments, such as gene therapy and mitochondrial replacement techniques, aim to correct the underlying genetic defects and offer potential curative strategies. Further research is essential to understand the pathophysiology of MELAS, optimize current therapies, and develop novel treatments that may significantly improve patient outcomes and extend survival.
    Keywords:  MELAS; MT-TL1; mitochondrial disease; mitochondrial encephalopathy lactic acidosis and stroke-like episodes; stroke-like episode
    DOI:  https://doi.org/10.3390/biom14121524
  6. Mol Genet Metab Rep. 2025 Mar;42 101176
    Identification of a new COQ4 spliceogenic variant causing severe primary coenzyme Q deficiency.
    María Alcázar-Fabra, Elsebet Østergaard, Daniel J M Fernández-Ayala, María Andrea Desbats, Valeria Morbidoni, Laura Tomás-Gallado, Laura García-Corzo, María Del Mar Blanquer-Roselló, Abigail K Bartlett, Ana Sánchez-Cuesta, Lucía Sena, Ana Cortés-Rodríguez, María Victoria Cascajo-Almenara, David J Pagliarini, Eva Trevisson, Sabine W Gronborg, Gloria Brea-Calvo.
       Background and aims: Primary Coenzyme Q (CoQ) deficiency caused by COQ4 defects is a clinically heterogeneous mitochondrial condition characterized by reduced levels of CoQ10 in tissues. Next-generation sequencing has lately boosted the genetic diagnosis of an increasing number of patients. Still, functional validation of new variants of uncertain significance is essential for an adequate diagnosis, proper clinical management, treatment, and genetic counseling.
    Materials and methods: Both fibroblasts from a proband with COQ4 deficiency and a COQ4 knockout cell model have been characterized by a combination of biochemical and genetic analysis (HPLC lipid analysis, Oxygen consumption, minigene analysis, RNAseq, among others).
    Results: Here, we report the case of a subject harboring a new variant of the COQ4 gene in compound heterozygosis, which shows severe clinical manifestations. We present the molecular characterization of this new pathogenic variant affecting the splicing of COQ4.
    Conclusion: Our results highlight the importance of expanding the genetic analysis beyond the coding sequence to reduce the misdiagnosis of primary CoQ deficiency patients.
    Keywords:  COQ4; Coenzyme Q10 deficiency; Hybrid minigene; Mitochondrial disorder; Spliceogenic variant; WES
    DOI:  https://doi.org/10.1016/j.ymgmr.2024.101176
  7. Eur J Hum Genet. 2025 Jan 04.
    C19orf12 gene variants causing mitochondrial membrane protein-associated neurodegeneration (MPAN).
    Riyanka Kumari, Vikram V Holla, Neeharika Sriram, Nitish Kamble, Ajay Asranna, Jitender Saini, Gautham Arunachal, Ravi Yadav, Akhilesh Pandey, Pramod Kumar Pal, Babylakshmi Muthusamy.
      Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurodegenerative disorder characterized by spastic paraplegia, parkinsonism and psychiatric and/or behavioral symptoms caused by variants in gene encoding chromosome-19 open reading frame-12 (C19orf12). We present here seven patients from six unrelated families with detailed clinical, radiological, and genetic investigations. Childhood-onset patients predominantly had a spastic ataxic phenotype with optic atrophy, while adult-onset patients were presented with cognitive, behavioral, and parkinsonian symptoms. Levodopa induced choreiform dyskinesia was observed in one patient who showed a response to levodopa. Brain magnetic resonance imaging showed mineralization in all patients and cerebellar atrophy in one patient. The "pallidal splitting sign" was found in two patients and additional caudate and putamen mineralization was noted in two patients. Exome sequencing identified six variants in the C19orf12 gene, including two novel splice-site variants, four previously reported missense variants. Transcript analysis using RT-PCR followed by Sanger sequencing was performed on a splice site variant (c.194-2delA) to understand the splice defect and its consequences. This analysis confirmed the splice defect and use of an alternate cryptic splice site in the downstream exonic region. The variants identified in this study expand the spectrum of clinical and genetic knowledge on MPAN patients, highlighting the importance of genetic testing in the diagnosis and management of this disorder.
    DOI:  https://doi.org/10.1038/s41431-024-01778-6
  8. Antioxidants (Basel). 2024 Dec 04. pii: 1482. [Epub ahead of print]13(12):
    Spermidine Enhances Mitochondrial Bioenergetics in Young and Aged Human-Induced Pluripotent Stem Cell-Derived Neurons.
    Leonora Szabo, Imane Lejri, Amandine Grimm, Anne Eckert.
      The accumulation of damaged mitochondria has long been considered a hallmark of the aging process. Among various factors, age-related mitochondrial alterations comprise bioenergetic impairments and disturbances in reactive oxygen species (ROS) control, thereby negatively affecting mitochondrial performance and ultimately accelerating aging. Previous studies have revealed that polyamine spermidine appears to exert health-protective and lifespan-promoting effects. Notably, recent findings have also described a spermidine-induced improvement in age-associated mitochondrial dysfunction, but the beneficial effects of spermidine on aged mitochondria have not been entirely examined yet. Here, we show that spermidine positively regulates several parameters related to mitochondrial bioenergetics and mitochondrial redox homeostasis in young and aged human-induced pluripotent stem cell-derived neurons. We report that spermidine treatment increases adenosine triphosphate production and mitochondrial membrane potential, which is accompanied by an attenuation in mitochondrial ROS levels in both age groups. Furthermore, we demonstrate a spermidine-mediated amelioration in mitochondrial respiration in both young and aged neurons. Overall, our findings suggest that nutritional spermidine supplementation might represent an attractive therapeutic approach to enhance mitochondrial function, consequently decelerating aging.
    Keywords:  aging; bioenergetics; induced pluripotent stem cell-derived neurons; mitochondria; oxidative stress; spermidine
    DOI:  https://doi.org/10.3390/antiox13121482
  9. Front Immunol. 2024 ;15 1520072
    The role of mitochondria in aging, cell death, and tumor immunity.
    Qiang Wang, Yixiao Yuan, Jing Liu, Chunhong Li, Xiulin Jiang.
      Mitochondria are essential double-membrane organelles with intricate structures and diverse functions within cells. Under normal physiological conditions, mitochondria regulate cellular metabolism and maintain energy homeostasis via the electron transport chain, mediate stem cell fate, and modulate reactive oxygen species production, playing a pivotal role in energy supply and lifespan extension. However, mitochondrial dysfunction can lead to various pathological changes, including cellular aging, necrosis, dysregulated tumor immunity, and the initiation and progression of cancer. Moreover, abnormal mitochondrial metabolism is closely associated with numerous diseases, such as neurodegenerative disorders, metabolic syndromes, and cancers. In recent years, targeting mitochondria has emerged as a promising anticancer strategy, aiming to modulate mitochondrial functions and metabolism for therapeutic benefits. Nonetheless, such approaches face limitations, including low delivery efficiency and insufficient specificity. This review systematically explores mitochondrial structure and function, their physiological and pathological roles, and the potential and challenges of mitochondria-targeted strategies in cancer therapy, providing insights for future research directions.
    Keywords:  TME; aging; cancer; cell death; metabolism; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2024.1520072
  10. J Transl Med. 2025 Jan 07. 23(1): 26
    Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis.
    Ana Maria Vega-Letter, Cynthia García-Guerrero, Liliana Yantén-Fuentes, Carolina Pradenas, Yeimi Herrera-Luna, Eliana Lara-Barba, Felipe A Bustamante-Barrientos, Masyelly Rojas, María Jesús Araya, Nicole Jeraldo, Constanza Aros, Francisca Troncoso, Daniela Poblete, Angela Court, Alexander Ortloff, Jose Barraza, Francesca Velarde, Carlos Farkas, Claudio Carril, Noymar Luque-Campos, Gonzalo Almarza, Maximiliano Barahona, Jose Matas, Lucas Cereceda, Rocío Lorca, Jorge Toledo, Karina Oyarce, Rolando Vernal, Andrés Caicedo, Andrea Del Campo, Yessia Hidalgo, Roberto Elizondo-Vega, Farida Djouad, Maroun Khoury, Fernando E Figueroa, Patricia Luz-Crawford.
       OBJECTIVE: The inflammatory responses from synovial fibroblasts and macrophages and the mitochondrial dysfunction in chondrocytes lead to oxidative stress, disrupt extracellular matrix (ECM) homeostasis, and accelerate the deterioration process of articular cartilage in osteoarthritis (OA). In recent years, it has been proposed that mesenchymal stromal cells (MSC) transfer their functional mitochondria to damaged cells in response to cellular stress, becoming one of the mechanisms underpinning their therapeutic effects. Therefore, we hypothesize that a novel cell-free treatment for OA could involve direct mitochondria transplantation, restoring both cellular and mitochondrial homeostasis.
    METHODS: Mitochondria were isolated from Umbilical Cord (UC)-MSC (Mito-MSC) and characterized based on their morphology, phenotype, functions, and their ability to be internalized by different articular cells. Furthermore, the transcriptional changes following mitochondrial uptake by chondrocytes were evaluated using an Affymetrix analysis, Lastly, the dose dependence therapeutic efficacy, biodistribution and immunogenicity of Mito-MSC were assessed in vivo, through an intra-articular injection in male C57BL6 mice in a collagenase-induced OA (CIOA) model.
    RESULTS: Our findings demonstrate the functional integrity of Mito-MSC and their ability to be efficiently transferred into chondrocytes, synovial macrophages, and synovial fibroblasts. Moreover, the transcriptomic analysis showed the upregulation of genes involved in stress such as DNA reparative machinery and inflammatory antiviral responses. Finally, Mito-MSC transplantation yielded significant reductions in joint mineralization, a hallmark of OA progression, as well as improvements in OA-related histological signs, with the lower dose exhibiting better therapeutic efficacy. Furthermore, Mito-MSC was detected within the knee joint for up to 24 h post-injection without eliciting an inflammatory response in CIOA mice.
    CONCLUSION: Collectively, our results reveal that mitochondria derived from MSC are transferred to key articular cells and are retained in the joint without generating an inflammatory immune response mitigating articular cartilage degradation in OA, probably through a restorative effect triggered by the stress antiviral response within OA chondrocytes.
    Keywords:  Biodistribution; Immuno-safety; Mesenchymal stromal cells; Mitochondria transplantation; Murine OA model; Osteoarthritis
    DOI:  https://doi.org/10.1186/s12967-024-05945-7
  11. J Cell Sci. 2025 Jan 08. pii: jcs.263676. [Epub ahead of print]
    Mitochondrial phosphatase PPTC7 promotes EGFR recycling by facilitating VPS4A endosomal localization.
    Rahul Baroi, Hilal Ahmad Reshi, SubbaReddy Maddika.
      PPTC7 is a mitochondrial phosphatase that is essential for mitochondrial biogenesis, metabolism, protein content maintenance and transport. While the mitochondrial roles of PPTC7 are well-characterized, its roles outside the mitochondria are unclear. Here we identified a non-mitochondrial role for PPTC7 in regulating epidermal growth factor receptor (EGFR) trafficking. PPTC7 interacts with and dephosphorylates VPS4A, a critical ESCRT and multivesicular body-associated protein. PPTC7-mediated dephosphorylation of VPS4A at Serine 335 is required for VPS4A stability and its early endosomal localization. Either loss of PPTC7 or presence of constitutively phosphorylated VPS4A leads to defective recycling of EGFR, thus leading to EGFR re-routing to lysosomes for degradation. Further, we demonstrate that PPTC7-VPS4A-dependent EGFR recycling promotes the AKT signaling pathway thus enhancing cell proliferation and migration. Overall, our studies unveil an important mechanism where the PPTC7-VPS4A complex orchestrates an endosomal switch to promote EGFR recycling.
    Keywords:  EGFR; Endosome; Mitogen signaling; PPTC7; Receptor recycling; VPS4A
    DOI:  https://doi.org/10.1242/jcs.263676
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