bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024–08–04
twelve papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
  2. LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation.
  3. How can we use stem cell-derived cardiomyocytes to understand the involvement of energetic metabolism in alterations of cardiac function?
  4. Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA.
  5. Mitochondrial DNA disorders in neuromuscular diseases in diverse populations.
  6. Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trial.
  7. Mitochondria-derived vesicles: potential nano-batteries to recharge the cellular powerhouse.
  8. Two novel SUCLA2 variants cause mitochondrial DNA depletion syndrome, type 5 in two siblings.
  9. Axonal mitophagy in retinal ganglion cells.
  10. Neonatal Encephalopathy is a Complex Phenotype Representing Reproductive and Pregnancy Exposome Effects on the Maternal-Placental-Fetal Triad.
  11. Programmable DNA pyrimidine base editing via engineered uracil-DNA glycosylase.
  12. In utero delivery of targeted ionizable lipid nanoparticles facilitates in vivo gene editing of hematopoietic stem cells.
  1. Sci Adv. 2024 Aug 02. 10(31): eadp0443
    Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
    Sofia Ahola, Lilli A Pazurek, Fiona Mayer, Philipp Lampe, Steffen Hermans, Lore Becker, Oana V Amarie, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Dietmar Riedel, Hendrik Nolte, Thomas Langer.
      Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.
    DOI:  https://doi.org/10.1126/sciadv.adp0443
  2. Nucleic Acids Res. 2024 Aug 01. pii: gkae662. [Epub ahead of print]
    LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation.
    Diana Rubalcava-Gracia, Kristina Bubb, Fredrik Levander, Stephen P Burr, Amelie V August, Patrick F Chinnery, Camilla Koolmeister, Nils-Göran Larsson.
      In mammals, the leucine-rich pentatricopeptide repeat protein (LRPPRC) and the stem-loop interacting RNA-binding protein (SLIRP) form a complex in the mitochondrial matrix that is required throughout the life cycle of most mitochondrial mRNAs. Although pathogenic mutations in the LRPPRC and SLIRP genes cause devastating human mitochondrial diseases, the in vivo function of the corresponding proteins is incompletely understood. We show here that loss of SLIRP in mice causes a decrease of complex I levels whereas other OXPHOS complexes are unaffected. We generated knock-in mice to study the in vivo interdependency of SLIRP and LRPPRC by mutating specific amino acids necessary for protein complex formation. When protein complex formation is disrupted, LRPPRC is partially degraded and SLIRP disappears. Livers from Lrpprc knock-in mice had impaired mitochondrial translation except for a marked increase in the synthesis of ATP8. Furthermore, the introduction of a heteroplasmic pathogenic mtDNA mutation (m.C5024T of the tRNAAla gene) into Slirp knockout mice causes an additive effect on mitochondrial translation leading to embryonic lethality and reduced growth of mouse embryonic fibroblasts. To summarize, we report that the LRPPRC/SLIRP protein complex is critical for maintaining normal complex I levels and that it also coordinates mitochondrial translation in a tissue-specific manner.
    DOI:  https://doi.org/10.1093/nar/gkae662
  3. Front Mol Med. 2023 ;3 1222986
    How can we use stem cell-derived cardiomyocytes to understand the involvement of energetic metabolism in alterations of cardiac function?
    Sabine Rebs, Katrin Streckfuss-Bömeke.
      Mutations in the mitochondrial-DNA or mitochondria related nuclear-encoded-DNA lead to various multisystemic disorders collectively termed mitochondrial diseases. One in three cases of mitochondrial disease affects the heart muscle, which is called mitochondrial cardiomyopathy (MCM) and is associated with hypertrophic, dilated, and noncompact cardiomyopathy. The heart is an organ with high energy demand, and mitochondria occupy 30%-40% of its cardiomyocyte-cell volume. Mitochondrial dysfunction leads to energy depletion and has detrimental effects on cardiac performance. However, disease development and progression in the context of mitochondrial and nuclear DNA mutations, remains incompletely understood. The system of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) is an excellent platform to study MCM since the unique genetic identity to their donors enables a robust recapitulation of the predicted phenotypes in a dish on a patient-specific level. Here, we focus on recent insights into MCM studied by patient-specific iPSC-CM and further discuss research gaps and advances in metabolic maturation of iPSC-CM, which is crucial for the study of mitochondrial dysfunction and to develop novel therapeutic strategies.
    Keywords:  Barth syndrome; Friedreich’s ataxia; iPSC-cardiomyocytes; lysosomal storage disorders; maturation strategies; mitochondrial cardiomyopathy
    DOI:  https://doi.org/10.3389/fmmed.2023.1222986
  4. Nat Aging. 2024 Jul 29.
    Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA.
    Yanfei Ru, Xiaoling Deng, Jiatong Chen, Leping Zhang, Zhe Xu, Qunyu Lv, Shiyun Long, Zijian Huang, Minghua Kong, Jing Guo, Min Jiang.
      Mitochondrial diseases, caused mainly by pathogenic mitochondrial DNA (mtDNA) mutations, pose major challenges due to the lack of effective treatments. Investigating the patterns of maternal transmission of mitochondrial diseases could pave the way for preventive approaches. In this study, we used DddA-derived cytosine base editors (DdCBEs) to generate two mouse models, each haboring a single pathogenic mutation in complex I genes (ND1 and ND5), replicating those found in human patients. Our findings revealed that both mutations are under strong purifying selection during maternal transmission and occur predominantly during postnatal oocyte maturation, with increased protein synthesis playing a vital role. Interestingly, we discovered that maternal age intensifies the purifying selection, suggesting that older maternal age may offer a protective effect against the transmission of deleterious mtDNA mutations, contradicting the conventional notion that maternal age correlates with increased transmitted mtDNA mutations. As collecting comprehensive clinical data is needed to understand the relationship between maternal age and transmission patterns in humans, our findings may have profound implications for reproductive counseling of mitochondrial diseases, especially those involving complex I gene mutations.
    DOI:  https://doi.org/10.1038/s43587-024-00672-6
  5. Ann Clin Transl Neurol. 2024 Aug 02.
    Mitochondrial DNA disorders in neuromuscular diseases in diverse populations.
    ICGNMD Consortium
      Neuromuscular features are common in mitochondrial DNA (mtDNA) disorders. The genetic architecture of mtDNA disorders in diverse populations is poorly understood. We analysed mtDNA variants from whole-exome sequencing data in neuromuscular patients from South Africa, Brazil, India, Turkey and Zambia. In 998 individuals, there were two definite diagnoses, two possible diagnoses and eight secondary findings. Surprisingly, common pathogenic mtDNA variants found in people of European ancestry were very rare. Whole-exome or -genome sequencing from undiagnosed patients with neuromuscular symptoms should be re-analysed for mtDNA variants, but the landscape of pathogenic mtDNA variants differs around the world.
    DOI:  https://doi.org/10.1002/acn3.52141
  6. EClinicalMedicine. 2024 Aug;74 102740
    Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trial.
    Heather Pekeles, Saoussen Berrahmoune, Christelle Dassi, Anthony C T Cheung, Tommy Gagnon, Paula J Waters, Ralf Eberhard, Daniela Buhas, Kenneth A Myers.
       Background: DNA polymerase gamma (POLG)-related disorders are a group of rare neurodegenerative mitochondrial diseases caused by pathogenic variants in POLG, the gene encoding POLG. Patients may experience a range of signs and symptoms, including seizures, vision loss, myopathy, neuropathy, developmental impairment or regression, and liver failure. The diseases follow a progressive, degenerative course, with most affected individuals dying within 3 months-12 years of diagnosis. At present, there are no effective treatments for POLG-related disorders.
    Methods: In this study we report the interim 6-month data from a long term open-label, single arm phase 2 trial, in which we assessed the safety and efficacy of combination therapy with deoxycytidine and deoxythymidine (dC/dT) in children with POLG-related disorders. dC/dT was given enterally in powder form, dissolved in water. The primary outcome measures included Newcastle Mitochondrial Disease Scale (NMDS) score, serum growth differentiation factor 15 (GDF-15; a biomarker of mitochondrial dysfunction), electroencephalography (EEG), seizure diary, and blood and urine tests to assess end organ and mitochondrial function. Secondary outcome measures included recording of all adverse events to evaluate the safety of the intervention. The trial is registered with ClinicalTrials.gov, NCT04802707 (https://clinicaltrials.gov/ct2/show/NCT04802707). Data were collected from 14 October, 2021 to 13 December, 2023.
    Findings: We present 6-month interim data from the first ten people with POLG-related disorders enrolled in the trial, six with Alpers-Huttenlocher syndrome, two with ataxia-neuropathy spectrum, and two who do not fit into a classical POLG-related phenotype. During the 6 months of treatment, NMDS score improved from a mean of 27.3 at baseline to 20.7 at 6 months (estimated difference 6.0; 95% CI 2.5-∞). GDF-15 values remained stable or decreased in all patients; the mean decreased from 1031 pg/ml to 729 pg/ml (estimated difference 200; 95% CI 12-∞). 8/10 patients had abnormal baseline EEG; improvement in EEG was seen in 5 of these 8. There were no significant changes in other blood and urine testing. Regarding adverse events, two patients experienced diarrhea that spontaneously resolved.
    Interpretation: dC/dT is a promising treatment option for people with POLG-related disorders. Further research is needed to assess the long-term safety and efficacy in POLG-related disorders, as well as safety and efficacy in other mitochondrial DNA depletion disorders.
    Funding: This study was primarily funded by the Liam Foundation, with additional funding from the Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec - Santé.
    Keywords:  Deoxycytidine; Deoxynucleosides; Deoxythymidine; POLG; Thymidine
    DOI:  https://doi.org/10.1016/j.eclinm.2024.102740
  7. Extracell Vesicles Circ Nucl Acids. 2024 Jun;5(2): 271-275
    Mitochondria-derived vesicles: potential nano-batteries to recharge the cellular powerhouse.
    Shalini Mishra, Gagan Deep.
      Mitochondria dysfunction is increasingly recognized as a critical factor in various pathogenic processes. The mechanism governing mitochondrial quality control serves as an adaptive response, ensuring the preservation of mitochondrial morphology, quantity, and overall function, crucial for cell survival. The generation of mitochondria-derived vesicles (MDVs) is one of the processes of mitochondrial quality control. Recent literature has suggested MDV heterogeneity; however, the detailed characteristics of various MDV subtypes still need to be studied better. Recent studies have shown that MDVs also play a role in inter-organelle communication for mitochondria besides quality control. For instance, Hazan et al. demonstrated that functional mitochondria from Saccharomyces cerevisiae release vesicles independent of the fission machinery. These vesicles, falling within the typical size range of MDVs, were selectively loaded with mitochondrial proteins, especially with functional ATP synthase subunits. Intriguingly, these MDVs maintained membrane potential and could generate ATP. Moreover, MDVs could fuse with naïve mitochondria, transferring their ATP generation machinery. Lastly, this study revealed a potential delivery mechanism of ATP-producing vesicles, presenting a promising avenue to rejuvenate ATP-deficient mitochondria. Overall, this study unveils a novel mechanism for inter-organelle communication by vesicles, which is crucial for maintaining cellular homeostasis and could also be important in pathological conditions.
    Keywords:  F1-F0 ATP synthase; Mitochondria; inter-organelle communication; mitochondria-derived vesicle
    DOI:  https://doi.org/10.20517/evcna.2023.71
  8. Front Neurol. 2024 ;15 1394150
    Two novel SUCLA2 variants cause mitochondrial DNA depletion syndrome, type 5 in two siblings.
    Xiaohuan Zhang, Guo Zhang, Li Cao, Wenjing Zhou, Chang Tan, Shi Ma, Jiyun Yang.
      Mitochondrial DNA depletion syndrome (MDS), characterized by succinate-CoA ligase deficiency and loss of mitochondrial DNA (mtDNA), is caused by specific variants in nuclear genes responsible for mtDNA maintenance. SUCLA2-related mitochondrial DNA depletion syndrome, type 5 (MTDPS-5), presents as a rare, severe early progressive encephalomyopathy. This report investigates a new family exhibiting clinical manifestations of MTDPS-5 and elucidates the genetic basis of this disorder. In two affected siblings, a novel maternally inherited nonsense variant [c.1234C>T (p.Arg412*)] in the SUCLA2 gene and a unique paternally inherited indel variant (g.48569263-48571020del1758insATGA) were identified. Additionally, the siblings exhibited blood mtDNA content lower than 33% compared to age-matched controls. These findings underscore the importance of assessing SUCLA2 variants in patients with severe early progressive encephalomyopathy, even in the absence of methylmalonic aciduria or mtDNA loss, thereby broaden the mutational spectrum of this gene.
    Keywords:  MTDPS-5; NGS; SUCLA2; mitochondrial DNA; mitochondrial succinate-CoA ligase; rare disease
    DOI:  https://doi.org/10.3389/fneur.2024.1394150
  9. Cell Commun Signal. 2024 Jul 29. 22(1): 382
    Axonal mitophagy in retinal ganglion cells.
    Yang Liang, Yulin Li, Qing Jiao, Muyang Wei, Yan Wang, Aoteng Cui, Zhihui Li, Guangyu Li.
      Neurons, exhibiting unique polarized structures, rely primarily on the mitochondrial production of ATP to maintain their hypermetabolic energy requirements. To maintain a normal energy supply, mitochondria are transported to the distal end of the axon. When mitochondria within the axon are critically damaged beyond their compensatory capacity, they are cleared via autophagosomal phagocytosis, and the degradation products are recycled to replenish energy. When the mitochondria are dysfunctional or their transport processes are blocked, axons become susceptible to degeneration triggered by energy depletion, resulting in neurodegenerative diseases. As the final checkpoint for mitochondrial quality control, axonal mitophagy is vital for neuronal growth, development, injury, and regeneration. Furthermore, abnormal axonal mitophagy is crucial in the pathogenesis of optic nerve-related diseases such as glaucoma. We review recent studies on axonal mitophagy and summarize the progress of research on axonal mitophagy in optic nerve-related diseases to provide insights into diseases associated with axonal damage in optic ganglion cells.
    Keywords:  Axon; Energy; Mitophagy; Optic nerve
    DOI:  https://doi.org/10.1186/s12964-024-01761-0
  10. Clin Perinatol. 2024 Sep;pii: S0095-5108(24)00040-X. [Epub ahead of print]51(3): 535-550
    Neonatal Encephalopathy is a Complex Phenotype Representing Reproductive and Pregnancy Exposome Effects on the Maternal-Placental-Fetal Triad.
    Mark S Scher.
      Reproductive, pregnancy, and placental exposomes influence the fetal neural exposome through toxic stressor interplay, impairing the maternal-placental-fetal (MPF) triad. Neonatal encephalopathy represents different clinical presentations based on complex time-dependent etiopathogenetic mechanisms including hypoxia-ischemia that challenge diagnosis and prognosis. Reproductive, pregnancy, and placental exposomes impair the fetal neural exposome through toxic stressor interplay within the MPF triad. Long intervals often separate disease onset from phenotype. Interdisciplinary fetal-neonatal neurology training, practice, and research closes this knowledge gap. Maintaining reproductive health preserves MPF triad health with life-course benefits.
    Keywords:  Gene-environment interactions; Hypoxic-ischemic encephalopathy; Maternal-placental-fetal triad; Neonatal encephalopathy; Neural exposome; Placental disease; Social determinants of health
    DOI:  https://doi.org/10.1016/j.clp.2024.04.001
  11. Nat Commun. 2024 Jul 30. 15(1): 6397
    Programmable DNA pyrimidine base editing via engineered uracil-DNA glycosylase.
    Zongyi Yi, Xiaoxue Zhang, Xiaoxu Wei, Jiayi Li, Jiwu Ren, Xue Zhang, Yike Zhang, Huixian Tang, Xiwen Chang, Ying Yu, Wensheng Wei.
      DNA base editing technologies predominantly utilize engineered deaminases, limiting their ability to edit thymine and guanine directly. In this study, we successfully achieve base editing of both cytidine and thymine by leveraging the translesion DNA synthesis pathway through the engineering of uracil-DNA glycosylase (UNG). Employing structure-based rational design, exploration of homologous proteins, and mutation screening, we identify a Deinococcus radiodurans UNG mutant capable of effectively editing thymine. When fused with the nickase Cas9, the engineered DrUNG protein facilitates efficient thymine base editing at endogenous sites, achieving editing efficiencies up to 55% without enrichment and exhibiting minimal cellular toxicity. This thymine base editor (TBE) exhibits high editing specificity and significantly restores IDUA enzyme activity in cells derived from patients with Hurler syndrome. TBEs represent efficient, specific, and low-toxicity approaches to base editing with potential applications in treating relevant diseases.
    DOI:  https://doi.org/10.1038/s41467-024-50012-w
  12. Proc Natl Acad Sci U S A. 2024 Aug 06. 121(32): e2400783121
    In utero delivery of targeted ionizable lipid nanoparticles facilitates in vivo gene editing of hematopoietic stem cells.
    Rohan Palanki, John S Riley, Sourav K Bose, Valerie Luks, Apeksha Dave, Nicole Kus, Brandon M White, Adele S Ricciardi, Kelsey L Swingle, Lulu Xue, Derek Sung, Ajay S Thatte, Hannah C Safford, Venkata S Chaluvadi, Marco Carpenter, Emily L Han, Rohin Maganti, Alex G Hamilton, Kaitlin Mrksich, Margaret B Billingsley, Philip W Zoltick, Mohamad-Gabriel Alameh, Drew Weissman, Michael J Mitchell, William H Peranteau.
      Monogenic blood diseases are among the most common genetic disorders worldwide. These diseases result in significant pediatric and adult morbidity, and some can result in death prior to birth. Novel ex vivo hematopoietic stem cell (HSC) gene editing therapies hold tremendous promise to alter the therapeutic landscape but are not without potential limitations. In vivo gene editing therapies offer a potentially safer and more accessible treatment for these diseases but are hindered by a lack of delivery vectors targeting HSCs, which reside in the difficult-to-access bone marrow niche. Here, we propose that this biological barrier can be overcome by taking advantage of HSC residence in the easily accessible liver during fetal development. To facilitate the delivery of gene editing cargo to fetal HSCs, we developed an ionizable lipid nanoparticle (LNP) platform targeting the CD45 receptor on the surface of HSCs. After validating that targeted LNPs improved messenger ribonucleic acid (mRNA) delivery to hematopoietic lineage cells via a CD45-specific mechanism in vitro, we demonstrated that this platform mediated safe, potent, and long-term gene modulation of HSCs in vivo in multiple mouse models. We further optimized this LNP platform in vitro to encapsulate and deliver CRISPR-based nucleic acid cargos. Finally, we showed that optimized and targeted LNPs enhanced gene editing at a proof-of-concept locus in fetal HSCs after a single in utero intravenous injection. By targeting HSCs in vivo during fetal development, our Systematically optimized Targeted Editing Machinery (STEM) LNPs may provide a translatable strategy to treat monogenic blood diseases before birth.
    Keywords:  CRISPR; congenital disease; hematopoietic stem cell; lipid nanoparticles; mRNA
    DOI:  https://doi.org/10.1073/pnas.2400783121
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