bims-mitmed 2026-02-15 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–02–15
sixteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Short telomeres in mitochondrial DNA depletion disorders.
Optic neuropathy arising from the synergy between YARS2 and mitochondrial COX1 mutations.
Mechanisms and disease relevance of mitochondrial translation in humans.
Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy.
Mitochondrial Ca2+ efflux controls neuronal metabolism and long-term memory across species.
ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation.
A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
Muscle-Specific DNM2 Overexpression Improves Charcot-Marie-Tooth Disease In Vivo and Reveals a Narrow Therapeutic Window in Skeletal Muscle.
Remimazolam-based anesthesia with intraoperative motor evoked potential monitoring in a patient with Leigh syndrome undergoing scoliosis surgery: a case report.
Early diagnosis of fetal ganglionic eminence cysts: imaging, outcome and genetic associations, revealing role of mitochondrial dysfunction.
Mitochondrial Heterogeneity in a Patient with Preeclampsia.
STIM1-containing contact sites promote direct calcium flux from the endoplasmic reticulum to mitochondria.
Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.
Progeny effects of rotenone exposure depend on parental toxicity.
AQP4-IgG-Induced Astrocyte-Derived Small Extracellular Vesicles Carrying Mitochondrial DNA Regulate the TLR9/MyD88/NF-κB Pathway to Drive Microglial Activation and Neuromyelitis Optica.
Structural basis of TACO1-mediated efficient mitochondrial translation.

Mitochondrion. 2026 Feb 10. pii: S1567-7249(26)00021-8. [Epub ahead of print]88 102131

Short telomeres in mitochondrial DNA depletion disorders.

Yumi Dille, Emmanouil Rampakakis, Geraldine Aubert, Christelle Dassi, William Mannherz, Saoussen Berrahmoune, Myriam Srour, Daniela Buhas, Suneet Agarwal, Kenneth A Myers.

  Mitochondrial DNA (mtDNA) depletion disorders (MDDs) are rare, genetically diverse conditions marked by a significant reduction in mtDNA, primarily affecting energy-demanding tissues such as muscle, liver, and brain, sometimes leading to catastrophic multisystem failure. In a cohort of patients with MDDs, we measured telomere length in lymphocytes, granulocytes, T cells, and B cells, and compared to healthy controls. Telomere length was shorter overall in patients with MDDs, with the most significant differences observed in granulocytes. The observation that mtDNA depletion is associated with shorter telomeres may provide insight into MDD pathophysiology. Telomere length may have potential as a biomarker in mitochondrial disease, but further study is needed.

Keywords:  C10orf2; DGUOK; Mitochondrial DNA depletion disorders; POLG; RRM2B; SUCLA2; SUCLG1; TK2; TYMP; Telomere length; Telomeres

DOI:  https://doi.org/10.1016/j.mito.2026.102131
J Genet Genomics. 2026 Feb 08. pii: S1673-8527(26)00047-0. [Epub ahead of print]

Optic neuropathy arising from the synergy between YARS2 and mitochondrial COX1 mutations.

Huiying Li, Cheng Ai, Xiaofen Jin, Jing Wang, Jun Yu, Yinlong Gao, Douglas C Wallace, Min-Xin Guan.

  Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy. Here, we investigate the mechanism underlying the interaction between nuclear modifier and mtDNA mutation(s) that manifests optic neuropathy in vivo to develop an effective therapeutic approach for this disease using mouse models bearing LHON-linked Yars2G186V or COIV421A mutation alone and double mutations. Yars2G186V alters mitochondrial translation and assembly and activities of complex I, III, and IV, while COIV421A reduces complex IV activity. However, a single Yars2G186V or COIV421A mutation causes mild declines in ATP production and yields relatively mild degeneration of retinal ganglion cells (RGCs). Notably, the synergy between COIV421A and Yars2G186V mutations aggravates mitochondrial dysfunction and oxidative stress. Interestingly, COIV421A mainly promotes apoptosis, and Yars2G186V contributes to ferroptosis. The combination of two mutations accelerates the degeneration of RGCs and photoreceptors. Strikingly, AAV-mediated Yars2 expression in the mouse retina carrying both Yars2G186V and COIV421A mutations corrects the defective translation and ferroptosis arising from the Yars2G186V mutation and remarkably improves mitochondrial function and causes morphologic and functional recovery of RGCs and photoreceptors. These findings provide mechanistic insights into the pathophysiology of LHON arising from nuclear modifiers and mtDNA mutation(s) and potential therapeutic strategies for LHON and other mitochondrial diseases.

Keywords:  Apoptosis; Ferroptosis; Gene therapy; Mitochondrial DNA mutation; Mitochondrial tyrosyl-tRNA synthetase; Optic neuropathy; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.jgg.2026.02.003
Nat Rev Mol Cell Biol. 2026 Feb 13.

Mechanisms and disease relevance of mitochondrial translation in humans.

Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.

Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.

DOI: https://doi.org/10.1038/s41580-026-00948-2
Int J Mol Sci. 2026 Jan 29. pii: 1375. [Epub ahead of print]27(3):

Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy.

Savas Baris, Rojan Ipek, Saniye Tugba Baris, Ibrahim Baris.

  Biallelic variants in NDUFS6, encoding an accessory subunit of mitochondrial complex I, were initially associated with lethal neonatal mitochondrial encephalopathy and Leigh syndrome. Recent studies have demonstrated that NDUFS6 variants can also cause childhood- or adolescent-onset axonal neuropathy and Charcot-Marie-Tooth (CMT)-like phenotypes, indicating marked clinical heterogeneity. Here, we report a patient with a novel homozygous truncating NDUFS6 variant presenting with a neuropathy-predominant phenotype accompanied by epilepsy, in the absence of neonatal metabolic decompensation. The patient presented with childhood-onset progressive gait abnormality, pes cavus deformity, distal weakness requiring Achilles tendon-release surgery, pyramidal signs, urinary incontinence, and focal epileptiform EEG findings. Brain MRI showed bilateral lenticular nucleus abnormalities. Whole-exome sequencing identified a novel homozygous NDUFS6 nonsense variant (c.130C>T, p.Gln44*). While neuropathy has previously been reported primarily in association with the recurrent splice-site variant c.309+5G>A, our findings demonstrate that truncating NDUFS6 mutations can also underlie a neuropathy-predominant phenotype. Together with previously published cases, our findings support a phenotypic heterogeneity ranging from lethal encephalopathy to neuropathy and reinforce the role of NDUFS6 as a disease-causing gene for inherited peripheral neuropathy. These data support inclusion of NDUFS6 among established neuropathy and Charcot-Marie-Tooth genes.

Keywords:  CMT; NDUFS6; epilepsy; neuropathy

DOI:  https://doi.org/10.3390/ijms27031375
Nat Metab. 2026 Feb 11.

Mitochondrial Ca2+ efflux controls neuronal metabolism and long-term memory across species.

Anjali Amrapali Vishwanath, Typhaine Comyn, Rodrigo G Mira, Claire Brossier, Carlos Pascual-Caro, Maya Faour, Kahina Boumendil, Chaitanya Chintaluri, Carla Ramon-Duaso, Ruolin Fan, Kishalay Ghosh, Helen Farrants, Jean-Paul Berwick, Riya Sivakumar, Mario Lopez-Manzaneda, Eric R Schreiter, Thomas Preat, Tim P Vogels, Vidhya Rangaraju, Arnau Busquets-Garcia, Pierre-Yves Plaçais, Alice Pavlowsky, Jaime de Juan-Sanz.

From insects to mammals, essential brain functions, such as forming long-term memories (LTMs), increase metabolic activity in stimulated neurons to meet the energetic demand associated with brain activation. However, while impairing neuronal metabolism limits brain performance, whether expanding the metabolic capacity of neurons boosts brain function remains poorly understood. Here, we show that LTM formation of flies and mice can be enhanced by increasing mitochondrial metabolism in central memory circuits. By knocking down the mitochondrial Ca2+ exporter Letm1, we favour Ca2+ retention in the mitochondrial matrix of neurons due to reduction of mitochondrial H+/Ca2+ exchange. The resulting increase in mitochondrial Ca2+ over-activates mitochondrial metabolism in neurons of central memory circuits, leading to improved LTM storage in training paradigms in which wild-type counterparts of both species fail to remember. Our findings unveil an evolutionarily conserved mechanism that controls mitochondrial metabolism in neurons and indicate its involvement in shaping higher brain functions, such as LTM.

DOI: https://doi.org/10.1038/s42255-026-01451-w
Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2523367123

ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation.

Navroop K Dhaliwal, Octavia Yifang Weng, Ai Tian, Aditi Aggarwal, Mai Ahmed, Guoria Sun, Afrin Bhattacharya, Wendy W Y Choi, Haruka Nishimura, Pragnya Chakraborty, Xiaoxue Dong, Yuncheng Wu, Michael D Wilson, Lu-Yang Wang, Luis F Parada, Julien Muffat, Yun Li.

  Mutations in the phosphatase and tensin homolog (PTEN) gene are linked to severe neurodevelopmental disorders. Loss of PTEN causes hyperactivation of both mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2. Recent studies have shown that this dual hyperactivation is required for the neuropathology observed in PTEN-deficient human stem cell-derived neural cells. However, the molecular effectors that integrate these synergistic signals remain unknown. Here, we identify the actin-regulating ARP2/3 complex as a critical point of convergence downstream of mTORC1 and mTORC2. We show that concurrent hyperactivation of both complexes drives increased filamentous actin and elevated levels of the ARP2/3 complex subunits in PTEN-deficient human neural precursors (NPs) and neurons. Pharmacological or genetic inhibition of ARP2/3 is sufficient to rescue multiple disease-relevant phenotypes, including NP hyperproliferation, neuronal hypertrophy, and electrical hyperactivity, without affecting the upstream mTORC1 or mTORC2 hyperactivation. Together, these findings reveal the PTEN-mTOR-ARP2/3 signaling axis as a core mechanism of neuropathology and highlight ARP2/3 inhibition as a potential therapeutic strategy for PTEN-related neurodevelopmental disorders.

Keywords:  PTEN; actin; human pluripotent stem cells; mTOR signaling; neurodevelopmental disorders

DOI:  https://doi.org/10.1073/pnas.2523367123
Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00036-7. [Epub ahead of print]45(2): 116958

A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.

Ying Wang, Xinwan Su, Yu Chen, Yijian Chen, Chengyu Shi, Fangzhou Liu, Yuqi Ye, Panyi Sun, Manman Tan, Meng Yu, Ya Wang, Shanshan Xie, Jian Liu, Qingfeng Yan, Qiming Sun, Dante Neculai, Wei Liu, Jianzhong Shao, Yang Liu, Weiqiang Lin, Aifu Lin.

  Mitochondrial genetic diseases arise from mitochondrial DNA (mtDNA) defects, which gene therapy tools may rectify. However, delivering single-guide RNAs (sgRNAs) into mitochondria remains a challenge limiting CRISPR-mediated mtDNA therapy. Here, through network analysis of mitochondrion-localized long noncoding RNAs (lncRNAs) and RNA-binding proteins (RBPs), we found that lncRNA RP11-46H11.3 translocates into mitochondria via binding mitochondria-associated RBPs using its key RNA recognition motifs (RRMs); its derived 30 nt ST2-RNA mitochondrial targeting sequence (RMTS) showed the highest mitochondrial localization efficiency. We engineered the RMTS-CRISPR tool by fusing ST2-RMTS to sgRNA, verifying its ability to target and cleave mtDNA. Strikingly, our results demonstrated that RMTS-CRISPR could achieve heteroplasmic mtDNA shifting efficiencies of up to 26.37% in m.3243A>G mutant cell models and 26.79% in vivo, offering a technological approach for the correction of heterogeneous mtDNA mutations. Taken together, our findings reveal a CRISPR-based mitochondrial gene intervention strategy that may have applications in mitochondrial disorders.

Keywords:  CP: genomics; CRISPR-Cas system; RNA recognition motif; mitochondrial DNA; mitochondrial disorder; organelle-associated RNA

DOI:  https://doi.org/10.1016/j.celrep.2026.116958
Int J Mol Sci. 2026 Feb 02. pii: 1471. [Epub ahead of print]27(3):

Muscle-Specific DNM2 Overexpression Improves Charcot-Marie-Tooth Disease In Vivo and Reveals a Narrow Therapeutic Window in Skeletal Muscle.

Marie Goret, Gwenaelle Piccolo, Jocelyn Laporte.

  Charcot-Marie-Tooth disease (CMT), caused by dominant loss-of-function mutations in DNM2, encoding the GTPase dynamin-2, impairs motor and sensory function. However, the respective contributions of muscle and nerve pathology, and the therapeutic potential of increasing DNM2 expression, remain unresolved. We evaluated tissue-targeted and systemic approaches to increase DNM2 in a mouse model carrying the common K562E-CMT mutation. Muscle-specific DNM2 overexpression from embryogenesis in Dnm2K562E/+ mice ameliorated desmin and integrin mislocalization, membrane trafficking defects, mitochondrial abnormalities, and fibrosis in skeletal muscle, resulting in improved locomotor coordination despite persistent muscle atrophy. Conversely, systemic postnatal AAV delivery of human DNM2 increased DNM2 in muscle but failed to transduce nerves and paradoxically worsened the muscle pathology, producing centronuclear myopathy-like features. These findings reveal a primary pathogenic impact of DNM2-CMT mutation within skeletal muscle, independent of nerve involvement. Collectively, they underscore that precise DNM2 dosage is critical for neuromuscular homeostasis and reveal a narrow therapeutic window for safe and effective therapeutic intervention. This paradox, in which efforts to compensate for a loss-of-function neuropathy risk inducing a gain-of-function myopathy, highlights the need for tightly controlled modulation of DNM2 activity in future therapeutic strategies.

Keywords:  AAV; CMT; Charcot–Marie–Tooth neuropathy; GTPase; HMSN; Hereditary motor and sensory neuropathy; adeno-associated virus; dynamin; gene therapy; muscle; myopathy

DOI:  https://doi.org/10.3390/ijms27031471
JA Clin Rep. 2026 Feb 13.

Remimazolam-based anesthesia with intraoperative motor evoked potential monitoring in a patient with Leigh syndrome undergoing scoliosis surgery: a case report.

Takahiro Kuwabara, Takahiro Tamura, Masashi Takakura, Tasuku Fujii, Kanako Ozeki, Koichi Akiyama.



Keywords:  Leigh syndrome; Mitochondrial encephalomyopathy; Motor evoked potential monitoring; Remimazolam

DOI:  https://doi.org/10.1186/s40981-026-00851-x
Ultrasound Obstet Gynecol. 2026 Feb 12.

Early diagnosis of fetal ganglionic eminence cysts: imaging, outcome and genetic associations, revealing role of mitochondrial dysfunction.

R Birnbaum, G Malinger, H Miremberg, M Brusilov, R K Pooh, M Rybak-Krzyszkowska, F Viñals, T-S Vo, R Gupta, S Gupta, N Dimri, J H Ochoa, T Weissbach, V Lanzarone, A Quinton, M Levy, D Kidron, K K Haratz.

   OBJECTIVES: To characterize the sonographic features of fetal ganglionic eminence (GE) cysts diagnosed during the late first and early second trimesters, assess their association with additional brain and extracranial malformations, investigate their genetic etiologies and evaluate fetal outcomes.
METHODS: This retrospective, multicenter case series included fetuses with a diagnosis of GE cyst, following referral for targeted transvaginal ultrasound examination, before 23 + 0 weeks' gestation at one of nine medical centers across eight countries between January 2015 and April 2023. All fetuses had been referred after either the first-trimester ultrasound screening examination or an early second-trimester anatomical scan diagnosed a GE cyst or raised suspicion of a cystic brain anomaly. All ultrasound images and three-dimensional ultrasound volumes for each case were retrieved and reviewed to identify brain and extracranial anomalies. Associated brain anomalies were classified into: cerebral midline; hemispheric parenchyma and lamination; lateral ventricles; sulcation pattern; and midbrain-hindbrain abnormalities. Genetic evaluations included chromosomal microarray analysis, exome sequencing and/or whole-genome sequencing, when available. Pregnancy outcomes and postnatal or autopsy data were reviewed when available.
RESULTS: In total, 25 fetuses with a diagnosis of GE cyst were included in the study. Cysts were bilateral in 64.0% of cases. In 36.0% of cases, the diagnosis was made between 11 + 3 and 13 + 6 weeks' gestation. Additional brain abnormalities were identified in 18 of the 22 (81.8%) cases in which these were assessed. These included midline anomalies in 72.2% of those with additional brain abnormalities, hemispheric abnormalities in 77.8%, abnormalities of the lateral ventricles in 55.6%, midbrain-hindbrain abnormalities in 72.2% and sulcation abnormalities in 55.6%. Extracranial anomalies were present in 17/25 (68.0%) fetuses, of which fetal growth restriction was observed in 35.3%. Genetic testing revealed pathogenic or likely pathogenic variants in 70.6% of the 17 cases tested, predominantly affecting mitochondrial functions. The pregnancy was terminated in 64.0% of cases and the fetus was liveborn in 32.0%; one case was lost to follow-up during pregnancy. Of the seven surviving neonates with follow-up, five (71.4%) experienced adverse outcomes. Four of the 25 fetuses were initially diagnosed with an isolated unilateral GE cyst. In three of these cases, the cyst regressed and transformed into a GE enlargement, though their clinical courses differed: two cases developed growth restriction, of which one also had a postnatally repaired ventricular septal defect and the other a short femur length, and the third case had additional extracranial findings. In the fourth case, the cyst resolved completely, with an apparently normal brain observed at follow-up fetal magnetic resonance imaging.
CONCLUSIONS: Late first- or early second-trimester suspicion of GE cysts should trigger a transvaginal neurosonographic examination. The presence of early GE cysts appears to be associated with additional severe brain and extracranial anomalies, including fetal growth restriction. Comprehensive genetic testing is crucial for identifying underlying etiologies, which are often linked to mitochondrial dysfunction. © 2026 International Society of Ultrasound in Obstetrics and Gynecology.

Keywords:  exome sequencing; fetal brain; fetal growth restriction; ganglionic eminence; mitochondrial disease; neurosonography; prenatal genetic analysis; transvaginal ultrasound; tubulinopathy

DOI:  https://doi.org/10.1002/uog.70180
Free Radic Biol Med. 2026 Feb 11. pii: S0891-5849(26)00122-X. [Epub ahead of print]

Mitochondrial Heterogeneity in a Patient with Preeclampsia.

Vasanthi Rajasekaran, Shubham Dubey, Teshi Kaushik, Annalese G Neuenschwander, Namakkal-Soorappan Rajasekaran, Dan E Berkowitz, Praveen K Dubey.

  Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria after the 20th week. In this condition, reduced blood flow to the placenta leads to placental ischemia and oxidative stress, resulting in mitochondrial DNA damage and dysfunction. In this case of preeclampsia, a unique feature is observed: the presence of mitochondrial heterogeneity and heteroplasmy in the preeclamptic placenta, but not in circulating plasma. We found a single nucleotide addition (m.310C) in the MT-D-loop region and a heteroplasmic mutation (m.7681C<T) in the Cytochrome C Oxidase Subunit II (MT-COX2) gene. This heteroplasmic mutation causes a phenylalanine (F) to serine (S) substitution in the MT-COX2 protein. A cost-effective Tetra ARMS PCR assay was developed to screen this heteroplasmic variation, producing distinctive 269-bp, 197-bp (T), and 132-bp (C) bands. Additionally, mitochondrial mutational burden measurement in placental tissue indicated a higher number of mutant mitochondria than in WT, suggesting a significant mutational burden. Ultrastructural examination of the patient's placenta via electron microscopy demonstrated a mix of healthy oval mitochondria alongside stressed (rounded mitochondria) and increased vacuolization and collagen fibril formation. These findings suggest that mtDNA mutations that may play a role in altered mitochondrial morphology may contribute to mitochondrial dysfunction in the patient's placental pathology, which needs to be further investigated.

Keywords:  Mitochondrial Heteroplasmy and Heterogeneity; Oxidative stress; Preeclampsia; ROS production; Tetra ARMS PCR

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.025
EMBO J. 2026 Feb 11.

STIM1-containing contact sites promote direct calcium flux from the endoplasmic reticulum to mitochondria.

Yolanda Orantos-Aguilera, Irene Sanchez-Lopez, Carlos Pascual-Caro, Patricia Gómez-Suaga, Estela Area-Gomez, Eulalia Pozo-Guisado, Jorge Montesinos, Francisco Javier Martin-Romero.

  STIM1 is a transmembrane protein localized in the endoplasmic reticulum (ER), where it acts as a calcium ion sensor, activating store-operated Ca2+ entry upon ER Ca2+ depletion. Via cellular calcium influx, STIM1 is thought to indirectly affect mitochondrial calcium content. Here we show that STIM1 also interacts with mitochondrial proteins such as PTPIP51 and GRP75, suggesting its presence in mitochondria-associated ER membranes (MAMs), which are specialized ER regions that facilitate ER-mitochondria communication. Lowering STIM1 expression disrupts ER-to-mitochondria Ca2+ transfer, reduces basal mitochondrial Ca2+ levels, impairs maximal mitochondrial respiration, and reduces ATP production. The STIM1-GRP75 interaction depends on STIM1's Ca2+-sensing ability. ER Ca2+ depletion or the constitutive-open R429C mutation both reduce STIM1 binding to GRP75, suggesting that conformational changes in STIM1 play a role in this interaction. Deletion analysis revealed that the STIM1 (551-611) segment is crucial for GRP75 binding, as the peptide STIM1(551-611) binds GRP75, while STIM1(Δ551-611) shows reduced binding. These findings reveal a previously unrecognized role of STIM1 in direct inter-organelle communication.

Keywords:  Calcium; GRP75; MAM; Mitochondria; STIM1

DOI:  https://doi.org/10.1038/s44318-026-00700-8
Transl Neurodegener. 2026 Feb 13. 15(1): 5

Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.

Abhishek Jauhari, Tanisha Singh, Diane L Carlisle, Robert M Friedlander.

  Mitochondrial DNA (mtDNA) plays a pivotal role in the regulation of neuroinflammation, acting as a potent trigger of innate immune responses when released into the cytoplasm or extracellular space. mtDNA is structurally similar to bacterial DNA, containing unmethylated CpG motifs that are readily recognized by immune sensors. Under conditions of cellular stress, injury, or mitochondrial dysfunction, mtDNA can escape into the cytoplasm, where it activates the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway, or it can be detected extracellularly by Toll-like receptors on immune cells. These signaling events lead to the production of pro-inflammatory cytokines and type I interferons, amplifying neuroinflammatory responses. In the central nervous system, this process contributes to the pathogenesis of various neurodegenerative and inflammatory conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), etc.. The dual role of mtDNA as both a damage-associated molecular pattern and a signaling molecule underscores its importance as a therapeutic target for modulating neuroinflammation and protecting against progressive neuronal damage. In this review, we will discuss the implications of mtDNA-mediated neuroinflammation in neurodegenerative diseases, including AD, PD, and HD, highlighting its potential as a diagnostic biomarker and therapeutic target.

Keywords:  Mitochondria; Mitochondrial DNA; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1186/s40035-026-00540-w
Toxicol Sci. 2026 Feb 12. pii: kfag011. [Epub ahead of print]

Progeny effects of rotenone exposure depend on parental toxicity.

Christina M Bergemann, Danielle F Mello, Rojin Chitrakar, Kinsey Fisher, Shefali R Bijwadia, Javier Huayta, Ian T Ryde, Rick Presman, Zhiqing Huang, Amy H Herring, Susan K Murphy, L Ryan Baugh, Joel N Meyer.

  Parental exposure to toxicants can affect progeny health. However, laboratory studies often employ exposures that result in loading of pollutants to gametes, or toxic effects to parents which could indirectly affect germ cell or gamete health. Here, we took advantage of the biology of Caenorhabditis elegans to carry out a study in which we minimized the potential for maternal loading of toxicants, and used an exposure paradigm that either did (high concentration) or did not (low concentration) significantly impact the health of the P0 generation. We hypothesized that parental exposure to mitochondrial toxicants during germ cell and gamete development, at levels not causing P0 toxicity, would result in altered mitochondria and organismal health in offspring. In the P0 generation, a high rotenone concentration altered growth, mitochondrial respiration, gene expression, induction of the mitochondrial unfolded protein response, and susceptibility to dopaminergic neurodegeneration induced by a chemical rechallenge later in life. However, we observed minor or no effects in P0 at a low concentration. In high-exposure F1 offspring, we observed altered embryo size, larval developmental stage distribution, spare respiratory capacity, heat shock protein expression, and dopaminergic neurodegeneration after a secondary rotenone challenge. The only effects observed in the F1 offspring of the low exposure were a 1.7% decrease in egg size (size later in development was normal), and moderate evidence of a slightly increased sensitivity to heat shock protein expression and dopaminergic neurodegeneration caused by a secondary later-in-life rotenone exposure. We recommend parental toxicity be carefully assessed to contextualize offspring outcomes.

Keywords:  Developmental exposure; antimycin A; intergenerational effects; metabolism; pyraclostrobin; rotenone

DOI:  https://doi.org/10.1093/toxsci/kfag011
Neurochem Res. 2026 Feb 11. 51(1): 73

AQP4-IgG-Induced Astrocyte-Derived Small Extracellular Vesicles Carrying Mitochondrial DNA Regulate the TLR9/MyD88/NF-κB Pathway to Drive Microglial Activation and Neuromyelitis Optica.

Juan Zhou, Haipeng Li, Ying Wen, Lingli He, Yangli He, Heng Meng.

  Neuromyelitis optica spectrum disorder (NMOSD) is a rare but serious inflammatory demyelinating disease. A key characteristic of NMOSD is the presence of a pathogenic autoantibody in serum called aquaporin-4 immunoglobulin G (AQP4-IgG). This study investigates the mechanism of astrocyte-derived small extracellular vesicles (EVs) carrying mitochondrial DNA (mtDNA) to promote AQP4-IgG-induced microglial activation in neuromyelitis optica (NMO) via the toll-like receptor 9 (TLR9)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway. Serum IgG was isolated from NMOSD patients (AQP4-IgG) and healthy controls (Con-IgG). Astrocytes were treated with AQP4-IgG or Con-IgG. EVs were isolated via ultracentrifugation, characterized, and examined for internalization. Microglia were exposed to EVs, and mtDNA levels were assessed. An NMO mouse model was established, with neurological damage, mouse behaviors, tissue damage, and microglial characterization evaluated using modified neurological severity score, open-field test, rotarod test, luxol fast blue staining, and flow cytometry. Inflammatory cytokines, TLR9, MyD88, p65, IκBα, p-p65, and p-IκBα in BV2 cells and spinal cord tissues were analyzed via ELISA, RT-qPCR, and western blot. AQP4-IgG-induced astrocyte-derived EVs increased Iba1-high-expressing and CD86/tumor necrosis factor-α-high-expressing cells, reduced CD206/transforming growth factor-β-high-expressing cells, and boosted inflammatory responses. AQP4-IgG-induced EVs carried mtDNA to activate microglia via the TLR9/MyD88/NF-κB pathway. TLR9/MyD88/NF-κB pathway inhibition reversed AQP4-IgG-induced EVs' promotion on microglial activation. In vivo, AQP4-IgG-induced EVs-mtDNA exacerbated microglial activation and NMO through the TLR9/MyD88/NF-κB pathway. AQP4-IgG-induced EVs carried mtDNA to upregulate TLR9, further activating the MyD88/NF-κB pathway, thereby promoting microglial activation and transition toward pro-inflammatory gene-high-expressing cells to drive NMO progression.

Keywords:  Aquaporin-4 immunoglobulin g; Astrocyte-Derived small extracellular vesicles; Microglia; Mitochondrial DNA; Neuroinflammation; Neuromyelitis optica; Toll-like receptor 9/myeloid differentiation primary response 88/Nuclear factor-kappa b

DOI:  https://doi.org/10.1007/s11064-026-04685-y
Nat Commun. 2026 Feb 09.

Structural basis of TACO1-mediated efficient mitochondrial translation.

Shuhui Wang, Michele Brischigliaro, Yuekang Zhang, Chunxiang Wu, Wei Zheng, Antoni Barrientos, Yong Xiong.

Translation elongation is a universally conserved step in protein synthesis, relying on elongation factors that engage the ribosomal L7/L12 stalk to mediate aminoacyl-tRNA delivery, accommodation, and ribosomal translocation. Using in organello cryo-electron microscopy, we reveal how the mitochondrial translation accelerator TACO1 promotes efficient elongation on human mitoribosomes. TACO1 binds the mitoribosomal region typically bound by elongation factor Tu (mtEF-Tu), bridging the large and small subunits via contacts with 16S rRNA, bL12m, A-site tRNA, and uS12m. While active throughout elongation, TACO1 is especially critical when translating polyproline motifs. Its absence prolongs mtEF-Tu residence in A/T states, causes persistent mitoribosomal stalling and premature subunit dissociation. Structural analyses indicate that TACO1 competes with mtEF-Tu for mitoribosome binding, stabilizes A-site tRNA, and enhances peptidyl transfer through a mechanism distinct from EF-P and eIF5A. These findings suggest that bacterial TACO1 orthologs may serve analogous roles, highlighting an evolutionarily conserved strategy for maintaining elongation efficiency during challenging translation events.

DOI: https://doi.org/10.1038/s41467-026-69156-y