bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–03–23
thirteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Developmental mitochondrial complex I activity determines lifespan.
  2. Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8.
  3. Fibroblasts and hiPS-Derived Astrocytes From CoPAN Patients Showed Different Levels of Iron Overload Correlated With Senescent Phenotype.
  4. Small-molecule hypoxia therapy in mitochondrial disease.
  5. Mitochondrial fission - changing perspectives for future progress.
  6. Clinical and molecular spectrum of TK2-deficiency: a large Brazilian cohort.
  7. Telomere length in offspring is determined by mitochondrial-nuclear communication at fertilization.
  8. Nicotinamide riboside supplementation protects against maternally diabetes-associated decline in oocyte quality.
  9. SIRT5 slows skeletal muscle ageing by alleviating inflammation.
  10. Patients with Allan-Herndon-Dudley Syndrome (MCT8 Deficiency) Display Symptoms of Parkinsonism in Childhood and Respond to Levodopa/Carbidopa Treatment.
  11. Generation of the human iPSC line UNIPDi006-A from a patient with arrhythmogenic cardiomyopathy carrying the DSG2 c.1672C > T pathogenic variant.
  12. How extreme lethargy can promote healthy ageing.
  13. Mitochondrial FIS1 level in cumulus cells correlates with morphological grades of human cleavage-stage embryos.
  1. EMBO Rep. 2025 Mar 17.
    Developmental mitochondrial complex I activity determines lifespan.
    Rhoda Stefanatos, Fiona Robertson, Beatriz Castejon-Vega, Yizhou Yu, Alejandro Huerta Uribe, Kevin Myers, Tetsushi Kataura, Viktor I Korolchuk, Oliver D K Maddocks, L Miguel Martins, Alberto Sanz.
      Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance.
    Keywords:  Ageing; Complex I; Drosophila; Mitochondria; Mitochondrial Disease
    DOI:  https://doi.org/10.1038/s44319-025-00416-6
  2. Neurology. 2025 Apr;104(7): e213462
    Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8.
    Sara Carli, Anna Levarlet, Daria Diodato, Enrico Silvio Bertini, Diego Martinelli, Alessandro Malandrini, Diego Lopergolo, Gian Nicola Gallus, Rebecca D Ganetzky, Chiara La Morgia, Valerio Carelli, Guido Primiano, Cristina Domínguez-González, Pablo Serrano-Lorenzo, Miguel A Martín, Anna Ardissone, Costanza Lamperti, Valeria Nicoletta, Thomas Klopstock, Felix Distelmaier, Leopold Zeng, Boriana Büchner, Michelangelo Mancuso, Markus Schuelke, Alessandro Prigione, Caterina Garone.
       BACKGROUND AND OBJECTIVES: The mitochondrial DNA (mtDNA) genes MT-ATP6 and MT-ATP8 encode for subunits α and 8 (A6L) of the adenosine triphosphate synthase complex. Pathogenetic variants in MT-ATP6/8 cause incurable mitochondrial syndromes encompassing a wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI. Typically, higher levels of mtDNA variants lead to more severe symptomatology although even individuals with similar mtDNA mutational loads exhibit high clinical variability. Hence, the establishment of potential therapeutics is currently challenging. In this article, we present an international multicenter study designed to provide a retrospective natural history of patients with MT-ATP6/8 deficiency and to identify primary and secondary end points for future clinical trials.
    METHODS: Clinical, biochemical, and molecular genetics data of patients with genetically confirmed MT-ATP6/8 defects were collected and analyzed from Italian, German, US, and Spain national reference centers through ethical committee-approved mitochondrial patients' national registries or local programs.
    RESULTS: A cohort of 111 patients, 98 unreported, were analyzed (55 male, 56 female). Patients had infantile-onset disease (<1 year) in 44% of cases, pediatric-onset (≥1 year and ≤12 years) in 36%, and late-onset (>12 years) in 20%. Kaplan-Meier analysis showed a significant difference (p value = 0.0349) in the survival of infantile and pediatric patients compared with adult patients, although only 8% of patients were not alive at the last follow-up. The CNS was the most frequently affected tissue (93%), followed by the muscle (75%), eye (46%), and heart (18%). Brain MRI showed isolated Leigh-like lesions (58%), Leigh-like lesions and cortical and/or cerebellar atrophy (15%), isolated cerebellar atrophy (10%), and other lesions (21%). At the last follow-up, 11% of patients were wheelchair-bound. Metabolic acidosis or acute deterioration complicated the clinical course in ≅55% of early-onset patients. Molecular genetics studies identified 26 pathogenic variants (6 of them novel). Reduced citrulline levels and increased alanine and lactate levels were reported in 56%, 49%, and 71% of patients, respectively, suggesting their role as potential biomarkers.
    DISCUSSION: Our results define a more accurate classification based on the age at onset for MT-ATPase deficiency and provide fundamental clinical and biochemical data for disease management.
    DOI:  https://doi.org/10.1212/WNL.0000000000213462
  3. Glia. 2025 Mar 19.
    Fibroblasts and hiPS-Derived Astrocytes From CoPAN Patients Showed Different Levels of Iron Overload Correlated With Senescent Phenotype.
    Anna Cozzi, Paolo Santambrogio, Andrea Stefano Moro, Alessio Pelagatti, Alicia Rubio, Chiara Balestrucci, Ivano Di Meo, Valeria Tiranti, Sonia Levi.
      COASY protein-associated neurodegeneration (CoPAN) is a rare autosomal recessive disorder within the Neurodegeneration with Brain Iron Accumulation spectrum, resulting from mutations in COASY. This gene encodes the bifunctional enzyme essential for the final steps of coenzyme A biosynthesis. To elucidate the pathophysiology and iron dyshomeostasis underlying CoPAN, we analyzed fibroblasts and human induced pluripotent stem (hiPS)-derived astrocytes from two patients carrying distinct COASY mutations. Our findings reveal that CoPAN fibroblasts display altered iron homeostasis, characterized by iron aggregates, elevated cytosolic labile iron pool, and impaired tubulin acetylation. Patients hiPS-derived astrocytes showed mitochondrial morphological abnormalities and compromised vesicular trafficking. Notably, both cell types demonstrated evidence of ferroptosis, but the astrocytes exhibited more pronounced iron accumulation and lipid peroxidation. These results demonstrate that astrocytes may more accurately recapitulate the pathological phenotype of CoPAN compared to fibroblasts. Interestingly, astrocytes exhibited different levels of iron accumulation concomitant with cellular senescence, indicating a possible role of iron-induced cellular senescence. This finding suggests that the accumulation of cytosolic iron, possibly caused by mitochondrial dysfunction, actively promotes senescence. Our data emphasize the potential therapeutic efficacy of drugs that enhance mitochondrial functionality to attenuate the effects of CoPAN.
    Keywords:  CoPAN disease; NBIA disorders; iron metabolism; mitochondrial dysfunction; neurodegenerative diseases
    DOI:  https://doi.org/10.1002/glia.70017
  4. Cell. 2025 Mar 20. pii: S0092-8674(25)00207-7. [Epub ahead of print]188(6): 1462-1465
    Small-molecule hypoxia therapy in mitochondrial disease.
    Marni J Falk.
      In this issue of Cell, Blume et al. provide compelling rationale for pursuing pharmacologic optimization of a small-molecule "HypoxyStat," which left-shifts the oxyhemoglobin dissociation curve in red blood cells in an attempt to induce an effective and sustained reduction of chronic tissue hyperoxia in primary mitochondrial disease (PMD) and was well-tolerated and effective for both pre-symptomatic and advanced disease treatment to extend survival and improve neurologic outcomes in a mouse model of Leigh syndrome spectrum.
    DOI:  https://doi.org/10.1016/j.cell.2025.02.019
  5. J Cell Sci. 2025 May 01. pii: jcs263640. [Epub ahead of print]138(9):
    Mitochondrial fission - changing perspectives for future progress.
    Sukrut C Kamerkar, Ao Liu, Henry N Higgs.
      Mitochondrial fission is important for many aspects of cellular homeostasis, including mitochondrial distribution, stress response, mitophagy, mitochondrially derived vesicle production and metabolic regulation. Several decades of research has revealed much about fission, including identification of a key division protein - the dynamin Drp1 (also known as DNM1L) - receptors for Drp1 on the outer mitochondrial membrane (OMM), including Mff, MiD49 and MiD51 (also known as MIEF2 and MIEF1, respectively) and Fis1, and important Drp1 regulators, including post-translational modifications, actin filaments and the phospholipid cardiolipin. In addition, it is now appreciated that other organelles, including the endoplasmic reticulum, lysosomes and Golgi-derived vesicles, can participate in mitochondrial fission. However, a more holistic understanding of the process is lacking. In this Review, we address three questions that highlight knowledge gaps. First, how do we quantify mitochondrial fission? Second, how does the inner mitochondrial membrane (IMM) divide? Third, how many 'types' of fission exist? We also introduce a model that integrates multiple regulatory factors in mammalian mitochondrial fission. In this model, three possible pathways (cellular stimulation, metabolic switching or mitochondrial dysfunction) independently initiate Drp1 recruitment at the fission site, followed by a shared second step in which Mff mediates subsequent assembly of a contractile Drp1 ring. We conclude by discussing some perplexing issues in fission regulation, including the effects of Drp1 phosphorylation and the multiple Drp1 isoforms.
    Keywords:  Drp1 receptors; Dynamin related protein-1; Inner mitochondrial membrane division; Mitochondrial fission
    DOI:  https://doi.org/10.1242/jcs.263640
  6. Sci Rep. 2025 Mar 15. 15(1): 9013
    Clinical and molecular spectrum of TK2-deficiency: a large Brazilian cohort.
    Cristiane Araujo Martins Moreno, Mariana Cunha Artilheiro, Alulin Tacio Quadros Santos Monteiro Fonseca, André Macedo Serafim da Silva, Tatiana Ribeiro Fernandes, Clara Gontijo Camelo, Michelle Abdo Paiva, Filipe Tupinamba di Pace, Andre Luiz Santos Pessoa, Vitor Lucas Lopes Braga, Tamiris Carneiro Mariano, Eduardo de Paula Estephan, Maria da Penha Morita, Anna Paula Paranhos Miranda Covaleski, Vanessa Van der Linden, Pedro José Tomaselli, Giuliano Roberto Scarpellini, Juliana Gurgel-Giannetti, Lívia Maria Ferreira Sobrinho, Thais Martins de Oliveira, Rodrigo Holanda Mendonça, Elizabeth Lemos Silveira Lucas, Marcelo Maroco Cruzeiro, Carlos Wagner Pereira Junior, Wilson Marques Júnior, Claudia Ferreira da Rosa Sobreira, Acary Sousa Bulle Oliveira, Fernando Kok, Michio Hirano, Andres Nascimento-Osorio, David Schlesinger, Edmar Zanoteli.
      Biallelic pathogenic variants at TK2 lead to a severe and progressive myopathy (TK2d). For a disease with unspecific clinical findings, and the possibility of a supplementation therapy that changes the natural history of the disease, highlighting clinical features that increase suspicion and accelerate diagnosis is essential. Clinical and genetic findings of 36 Brazilian patients with TK2d were identified and presented in this work. Genotype-phenotype correlation was performed for recurrent and novel variants. Motor and respiratory assessments were systematically performed in 13 patients, three of them were receiving the nucleosides replacement therapy. Natural history data was gathered from the follow up of five adult patients. Eight patients with the infantile form, 19 with childhood-onset and five with late-onset form were described. Extramuscular features were present in 30% of the cohort. Neuropathy and encephalopathy were the clinically predominant features for some patients. Four variants were recurrent (p.Thr108M, p.His121Asn, p.Arg183Trp and c.536_538 + 8del) allowing genotype-phenotype correlations, and one was novel (G91D). P.Thr108Met patients presented a milder presentation when compared to the p.His121Asn group. P.Arg183Trp was associated with peripheral nerve involvement and c.536_538 + 8del with encephalomyopathy. Long-term follow-up of 5 patients harbouring p.Thr108Met showed decreased motor, bulbar, and respiratory function, compared to a dramatic improvement in the treated patients. TK2d is a very debilitating and progressive disease among all forms including the childhood-onset as we demonstrated. Early diagnosis is essential since a potential treatment can change the natural history of the disease. Extramuscular involvement plays an important role for diagnostic strategies.
    Keywords:  Mitochondrial myopathy; MtDNA depletion syndrome; Nucleosides supplementation; TK2-deficiency
    DOI:  https://doi.org/10.1038/s41598-024-84373-5
  7. Nat Commun. 2025 Mar 14. 16(1): 2527
    Telomere length in offspring is determined by mitochondrial-nuclear communication at fertilization.
    Yasmyn E Winstanley, Ryan D Rose, Alexander P Sobinoff, Linda L Wu, Deepak Adhikari, Qing-Hua Zhang, Jadon K Wells, Lee H Wong, Hazel H Szeto, Sandra G Piltz, Paul Q Thomas, Mark A Febbraio, John Carroll, Hilda A Pickett, Darryl L Russell, Rebecca L Robker.
      The initial setting of telomere length during early life in each individual has a major influence on lifetime risk of aging-associated diseases; however there is limited knowledge of biological signals that regulate inheritance of telomere length, and whether it is modifiable is not known. We now show that when mitochondrial activity is disrupted in mouse zygotes, via exposure to 20% O2 or rotenone, telomere elongation between the 8-cell and blastocyst stage is impaired, with shorter telomeres apparent in the pluripotent Inner Cell Mass (ICM) and persisting after organogenesis. Identical defects of elevated mtROS in zygotes followed by impaired telomere elongation, occurred with maternal obesity or advanced age. We further demonstrate that telomere elongation during ICM formation is controlled by mitochondrial-nuclear communication at fertilization. Using mitochondrially-targeted therapeutics (BGP-15, MitoQ, SS-31, metformin) we demonstrate that it is possible to modulate the preimplantation telomere resetting process and restore deficiencies in neonatal telomere length.
    DOI:  https://doi.org/10.1038/s41467-025-57794-7
  8. Reproduction. 2025 Mar 01. pii: REP-24-0350. [Epub ahead of print]
    Nicotinamide riboside supplementation protects against maternally diabetes-associated decline in oocyte quality.
    Chenlu Wei, Xinxin Zeng, Keer Wang, Mengchen Wang, Min Lei, Zhenye Zhu, Yining Xu, Yanqing Zhao, Qingling Yang, Ying-Pu Sun.
      Diabetes mellitus is strongly correlated with a decline in oocyte quality, however, non-invasive and effective methods to improve this issue have yet to be fully development. Here, we demonstrate that in vivo supplementation with nicotinamide riboside (NR) 400 mg/kg/day for 14 days effectively enhances the quality of oocytes from diabetic mice induced by streptozocin 190 mg/kg by restoring nicotinamide adenine dinucleotide (NAD+) levels. NR supplementation not only improved superovulation function of diabetic mice but also improved their oocyte quality and embryonic development potential after fertilization by maintaining normal spindle structure and alleviating mitochondrial dysfunction. In addition, NR supplementation reduced ROS levels in oocytes rom diabetic mice. Overall, our findings suggest that dietary NR supplementation is a viable strategy to protect oocytes from diabetes-related deterioration, thereby enhancing reproductive outcomes in maternal diabetes and improving the efficacy of assisted reproductive technology.
    DOI:  https://doi.org/10.1530/REP-24-0350
  9. Nat Metab. 2025 Mar 14.
    SIRT5 slows skeletal muscle ageing by alleviating inflammation.
    Vera Gorbunova, Andrei Seluanov.
      
    DOI:  https://doi.org/10.1038/s42255-025-01228-7
  10. Mov Disord. 2025 Mar 15.
    Patients with Allan-Herndon-Dudley Syndrome (MCT8 Deficiency) Display Symptoms of Parkinsonism in Childhood and Respond to Levodopa/Carbidopa Treatment.
    Nina-Maria Wilpert, Angela L Hewitt, Roser Pons, Marie-Thérèse Henke, Andrea Dell'Orco, Martin Bauer, Christiane Grolik, Stephan Menz, Monika Wahle, Annika Zink, Alessandro Prigione, Christina Reinauer, Catharina Lange, Christian Furth, Knut Brockmann, Sabine Jung-Klawitter, Stine Christ, Angela M Kaindl, Anna Tietze, Heiko Krude, Thomas Opladen, Markus Schuelke.
       BACKGROUND: Patients with mutations in the monocarboxylate transporter 8 (MCT8, SLC16A2) suffer from X-linked recessive Allan-Herndon-Dudley syndrome (AHDS), which is characterized by developmental delay and a severe movement disorder. Current trials using thyroid hormone derivatives to overcome the transporter defect have failed to achieve patient-oriented therapeutic goals.
    OBJECTIVES: Our aim was to define the type of movement disorder in AHDS in an observational cohort study and to investigate the causative role of the dopaminergic system.
    METHODS: We present longitudinal clinical data from the DEEPTYPE registry of 11 patients with video documentation, standardized phenotyping, cerebrospinal fluid (CSF) analysis, neuroimaging data, and the treatment response to levodopa/carbidopa supplementation.
    RESULTS: Children presented with signs of childhood parkinsonism, including hypokinesia, hypomimia, inability to sit or stand, rigidity, dystonia, and autonomic dysfunction. CSF homovanillic acid concentrations were decreased (n = 12), suggesting an isolated dopamine pathway impairment. Seven out of 8 patients responded favorably to l-dopa/carbidopa supplementation and we did not observe any adverse drug reactions.
    CONCLUSIONS: AHDS is associated with childhood parkinsonism, which is linked with biochemical abnormalities of dopamine metabolism. It can be treated with l-dopa/carbidopa supplementation. However, further research is needed to elucidate the exact effect of MCT8 deficiency on dopamine metabolism. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  MCT8; SLC16A2; dopamine; movement disorder; neurodevelopment; parkinsonism
    DOI:  https://doi.org/10.1002/mds.30152
  11. Stem Cell Res. 2025 Mar 13. pii: S1873-5061(25)00045-5. [Epub ahead of print]85 103695
    Generation of the human iPSC line UNIPDi006-A from a patient with arrhythmogenic cardiomyopathy carrying the DSG2 c.1672C > T pathogenic variant.
    Claudia Sacchetto, Martina Rabino, Marianna Paulis, Sabina Ferron, Barbara Bauce, Libero Vitiello, Alessandra Rampazzo, Leon J de Windt, Elisa Di Pasquale, Martina Calore.
      Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by arrhythmias, risk of sudden cardiac death, and progressive fibro-fatty replacement in the myocardium. DSG2, encoding the desmosomal protein desmoglein-2, is one of the most frequently mutated genes in patients with ACM. We generated human induced pluripotent stem cells (hiPSCs) from epithelial renal cells of one ACM patient carrying the heterozygous nonsense DSG2 c.1672C > T mutation. The generated hiPSCs showed normal karyotype, expression of pluripotency markers, and trilineage differentiation potential. The reported line (UNIPDi006-A) might represent a useful tool for in vitro modeling of ACM.
    DOI:  https://doi.org/10.1016/j.scr.2025.103695
  12. Nature. 2025 Mar;639(8055): 549
    How extreme lethargy can promote healthy ageing.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-00707-x
  13. J Assist Reprod Genet. 2025 Mar 17.
    Mitochondrial FIS1 level in cumulus cells correlates with morphological grades of human cleavage-stage embryos.
    Yizhen Sima, Sanbao Shi, Zhunyuan Min, Yuning Chen, Yongning Lu, Hongying Sha, Suying Liu.
       PURPOSE: Advanced-age women have a lower good-quality embryo rate (GQER) compared to young women. However, GQER varies widely within the same age group, suggesting that factors beyond age influence embryo quality. Mitochondria regulate cellular metabolism through dynamic fission and fusion alterations. Specifically, cumulus cell (CC) mitochondria regulate not only the metabolism of CCs but also of adjacent oocytes. This study aims to investigate the relationship between CC mitochondrial dynamics and oocyte developmental potential post-fertilization.
    METHODS: CCs were collected from 183 women aged 25-45 undergoing single sperm intracytoplasmic injection-embryo transfer treatments. Samples were stratified by age into young (< 35) and advanced age (≥ 35) groups. Each group was further subdivided into high and low subgroups based on day 3 GQER. Mitochondrial morphology, dynamics, fission-fusion gene expression, and mitochondrial functions were compared among groups and subgroups.
    RESULTS: Consistent with the literature, data analysis from our laboratory revealed significant variances in GQER among individuals of the same age group. Morphological analysis suggested a negative correlation between GQER and mitochondrial length in CCs (P < 0.0001, r = - 0.38). Live-cell imaging showed that both fission and fusion frequencies of CC mitochondria in the advanced-age group were lower than those in the young group (P = 0.009, P = 0.01). Additionally, within the advanced-age group, CC mitochondria from the low GQER subgroup exhibited lower fission frequency and fission-fusion ratios compared to the high GQER subgroup (P = 0.04, P = 0.01). Consequently, GQER positively correlated with mitochondrial fission-fusion ratio in CCs (P = 0.01, r = 0.44). Notably, there were no significant differences in the expression of mitochondrial fusion-related proteins (OPA1, MFN1, and MFN2) between the advanced-age and young groups or among the subgroups. However, levels of fission proteins, including FIS1 and MFF, were significantly lower in the advanced-age group compared to the young group and in the low GQER subgroup compared to their high GQER counterparts. qPCR results further indicated that fis1 and mff mRNA levels in CCs were positively correlated with GQER (P < 0.0001, r = 0.55; P = 0.0025, r = 0.41). The CCs from the low GQER subgroup exhibit a higher level of mitochondrial dysfunction.
    CONCLUSIONS: Mitochondrial morphology, fission-fusion balance, and fission-fusion gene expression in CCs influence early embryonic development, independent of age. Of these factors, the FIS1 level shows the most robust correlation with GQER.
    Keywords:  Cumulus cells; Maternal age; Mitochondrial dynamics; Preimplantation embryonic development
    DOI:  https://doi.org/10.1007/s10815-025-03431-7
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