bims-mitmed 2026-06-21 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–06–21
eighteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
Editorial: Beyond energy production: exploring mitochondrial dynamics and disease.
Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders.
Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency.
Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.
Enrichment of Rare Mitochondrial DNA Variants Among Individuals With Kidney Disease Reveals Undiagnosed Mitochondrial Disease.
Mitochondrial proteases maintain cellular protein homeostasis and tissue integrity.
Efficient prime editing in vivo and in vitro using lipid nanoparticles.
Beyond proteostasis: LONP1 as an immunometabolic checkpoint in health and disease.
Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset.
AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial.
Aberrant mitochondria in endometriosis: From pathogenic mechanisms to therapeutic opportunities.
The role of energy deficit in autophagy failure in Parkinson's disease.
Post-translational modifications of mitochondrion-related proteins: integrative orchestrators of cell fate networks in cardiovascular disease.
Cerebellar cognitive-affective syndrome in Friedreich Ataxia.
Mesenchymal Stromal Cell-Derived Extracellular Vesicles Mediate Mitochondrial Delivery in Injury: Mechanistic Insights, Evidentiary Tiers, and Translational Challenges.
Agnuside Stabilizes the Complex I Assembly Factor NDUFAF6 to Reinforce Mitochondrial Efficiency and Thermogenic Responsiveness.

EMBO Mol Med. 2026 Jun 17.

Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.

Aniketh Bishnu, Juan Zapata-Muñoz, Robert W Taylor, Kei Sakamoto, Ian G Ganley.

Distinct mitophagy pathways can eliminate not only damaged mitochondria but also healthy ones. In Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), dysregulated BNIP3/NIX-driven mitophagy of functional mitochondria is thought to be the key pathological driver. Patient mutations in the E3 ubiquitin ligase FBXL4 impair the proteasomal degradation of the mitophagy receptors BNIP3 and NIX, causing their accumulation and excessive mitophagy. As a result, mitochondrial content and oxidative phosphorylation decline sharply across multiple tissues, leading to early mortality, with no effective treatments currently existing. Here, we build on our work showing that AMPK can inhibit mitophagy via sequestration of the ULK1 autophagy-initiating kinase ULK1 and demonstrate that it is also critically relevant for mitophagy induced by FBXL4 disruption. Using FBXL4-deficient cells, as well as fibroblasts derived from MTDPS13 patients and a chemically-induced mouse model, we show that small molecule AMPK activation inhibits BNIP3/NIX-mediated mitophagy and recovers functional mitochondrial content. This work therefore validates AMPK as a realistic target in treating MTDPS13.

DOI: https://doi.org/10.1038/s44321-026-00471-z
Front Cell Dev Biol. 2026 ;14 1872916

Editorial: Beyond energy production: exploring mitochondrial dynamics and disease.

Nahid A Khan, Ruben Torregrosa-Muñumer.



Keywords:  cell fate regulation; metabolic signaling; mitochondria; mitochondrial disease; mitochondrial dynamics; mitochondrial quality control; mitochondrial therapy; redox metabolism

DOI:  https://doi.org/10.3389/fcell.2026.1872916
Neurotherapeutics. 2026 Jun 15. pii: S1878-7479(26)00115-7. [Epub ahead of print]23(4): e00945

Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders.

Anthony C T Cheung, Saoussen Berrahmoune, Christelle Dassi, Heather Pekeles, Tommy Gagnon, Paula J Waters, Ralf Eberhard, Daniela Buhas, Kenneth A Myers.

  We evaluated the safety and efficacy of enteral deoxycytidine/deoxythymidine combination therapy in treatment of POLG-related disorders, genetic mitochondrial diseases characterized by progressive neurological degeneration. A single-centre open-label phase II trial was conducted. Inclusion criteria included: age 3 months to 60 years, clinical diagnosis of POLG-related disorder, and biallelic pathogenic POLG variants. Participants received deoxycytidine/deoxythymidine initially at 100 mg/kg/day (50 mg/kg deoxycytidine and 50 mg/kg deoxythymidine), titrated to 400 mg/kg/day over three weeks. The current protocol is a 60-month treatment period with primary outcomes the Newcastle Mitochondrial Disease Scale sections I-III and serum growth differentiation factor 15. Secondary outcomes include quality of life questionnaires, seizure diary, EEG, and blood and urine laboratory tests assessing end organ function. Outcomes were assessed at baseline, 1-month, 2-month, 3-month, and 6-month timepoints, then every 6 months thereafter. Twenty-five individuals (14 male, 11 female; mean age 12.3 years) started deoxycytidine/deoxythymidine. Five died during the trial and five withdrew. The most common treatment-related adverse event was diarrhea. Newcastle Mitochondrial Disease Scale sections I-III score decreased (improved) from baseline at all timepoints from 1 month to 24 months (p < 0.05). Serum growth differentiation factor 15 significantly decreased (improved) from baseline at 1-month, 2-month, and 3-month timepoints (p < 0.05). Quality of life score improved at 3-month, 12-month, and 18-month timepoints (p < 0.05). In summary, our data suggest deoxycytidine/deoxythymidine is safe and effective for POLG-related disorders; however, further study is needed to clarify the therapeutic mechanism(s) so that the treatment can be refined and optimized.

Keywords:  DNA polymerase gamma; Deoxynucleoside; Mitochondrial DNA depletion disorder; Mitochondrial disorder; POLG

DOI:  https://doi.org/10.1016/j.neurot.2026.e00945
Brain Commun. 2026 ;8(3): fcag201

Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency.

Michio Hirano, Caterina Garone, Richard Haas, Carmen Paradas, Fernando Scaglia, Irene Rebollo Mesa, Carl Chiang, Anny-Odile Colson, Susan VanMeter, Cristina Domínguez-González.

  Thymidine kinase 2 deficiency (TK2d) (MIM 609560) is an ultra-rare, autosomal recessive mitochondrial myopathy caused by TK2 variants, leading to mitochondrial DNA depletion and/or multiple deletions. People with thymidine kinase 2 deficiency experience progressive myopathy, bulbar weakness and respiratory insufficiency, often losing the ability to walk, eat and breathe independently. Doxecitine and doxribtimine represents the first approved treatment for patients with thymidine kinase 2 deficiency with age of symptom onset ≤12 years by the US Food and Drug Administration and the European Medicines Agency; previously, disease management was limited to supportive care. We investigated the efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency. Patients treated with pyrimidine nucleos(t)ides were pooled from retrospective (NCT03701568, NCT05017818) and prospective (NCT03845712) studies and company-supported Expanded Access Programs. Untreated patients were pooled from literature reviews and a retrospective chart review study (NCT05017818). Patient subgroups were stratified by age of thymidine kinase 2 deficiency symptom onset (≤12 years and >12 years). The primary outcome was survival in 50th-percentile matched pairs of treated and untreated patients. Other outcomes included status of developmental motor milestones, ventilatory and feeding tube support, and safety. In total, 218 patients were included (treated: 104; untreated: 114). Baseline demographics and characteristics were comparable between subgroups. Most patients had an age of symptom onset ≤12 years [treated: 82/104 (78.8%); untreated: 93/114 (81.6%)]. In the age-of-symptom-onset-≤12-years subgroup, restricted mean survival time (95% confidence interval) was 29.2 (28.2, 30.3) years over the 30 years after symptom onset for treated patients and 14.4 (11.1, 17.6) years for untreated patients. Loss of ≥1 acquired motor milestone was more frequent before treatment start than after. Substantially more patients regained ≥1 lost motor milestone after treatment start than before. Ventilatory and feeding support were used across all age-of-symptom-onset subgroups, but some patients reduced or discontinued support after starting treatment and fewer patients initiated support after treatment start than before. Most treatment-emergent adverse events (TEAEs) did not lead to discontinuation. The most frequent TEAE was diarrhoea [43/50 patients (86.0%)], which was generally mild or moderate and resolved with dose reduction. Serious TEAEs occurred in 28/50 patients (56.0%); few were considered to be drug related [4/50 (8.0%)]. In total, 3/67 patients (4.5%) experienced a fatal serious TEAE, which were not considered to be drug related. These findings indicate that pyrimidine nucleos(t)ide therapy improves survival and functional outcomes in people with thymidine kinase 2 deficiency, especially those with age of symptom onset ≤12 years, and has an acceptable safety profile.

Keywords:  mitochondrial myopathy; pyrimidine nucleos(t)ide therapy; survival; thymidine kinase 2 deficiency; treatment efficacy

DOI:  https://doi.org/10.1093/braincomms/fcag201
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2530774123

Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.

Marine Tessier, Zeinab Hamze, Nathalie Bonello-Palot, Nathalie Roeckel-Trévisiol, Nathalie Da Silva, Ilian Verlet, Natacha Broucqsault, Karine Bertaux, Emilien Delmont, Shahram Attarian, Marc Bartoli, Valérie Delague, Bernard L Schneider, Nathalie Bernard-Marissal.

  Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor neuropathy. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 affect mitochondrial dynamics. We previously demonstrated that mutated MFN2 further disrupts contacts between the ER and the mitochondria, leading to axonal degeneration. There are no treatments for CMT2A, and those currently under development primarily focus on restoring mitochondrial function. Here, we provide proof of concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice as well as in CMT2A-motor neurons derived from induced pluripotent stem cells. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved by administering the vector after the onset of symptoms. Importantly, AAV administration was well tolerated, with no evidence of hepatotoxicity or dorsal root ganglion inflammation. We further show that CMT2A pathology can be corrected in vitro and in vivo using an ER-targeting MFN1 isoform that selectively enhances ER-mitochondria contacts. These results establish that restoring contacts between the ER and mitochondria using gene therapy is a promising therapeutic avenue for CMT2A.

Keywords:  Charcot–Marie–Tooth disease; MFN2; endoplasmic reticulum; gene therapy; mitochondria

DOI:  https://doi.org/10.1073/pnas.2530774123
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2612098123

SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.

Mohammad Zulkifli, Ifrah Farid, Laura E Oldfather, Vinit C Shanbhag, Scot C Leary, Michael J Petris, Paul A Cobine, Vishal M Gohil.

  Copper (Cu) is an essential cofactor for cytochrome c oxidase (CcO), a mitochondrial respiratory chain enzyme that is metalated in the intermembrane space (IMS) primarily using Cu derived from the mitochondrial matrix pool. While Cu import into the matrix depends on the inner membrane carrier SLC25A3, the route by which matrix Cu is exported to the IMS for insertion into CcO has remained a major, unresolved step in intramitochondrial Cu trafficking. Here, we leveraged our recent discovery that the Cu ionophore elesclomol (ES) releases Cu directly into the mitochondrial matrix to show that SLC25A3 is required for exporting Cu to the IMS for CcO metalation. Loss of SLC25A3 decreases mitochondrial Cu content and CcO activity as expected. Strikingly, bypassing the loss of SLC25A3 with ES-mediated Cu delivery to the matrix fails to restore CcO function; rather, it drives toxic Cu retention and triggers cuproptosis, revealing that SLC25A3-facilitated Cu export is the limiting determinant of CcO metalation. Heterologous expression in Lactococcus lactis confirms that SLC25A3 can mediate Cu export. These results suggest that SLC25A3 is the long-sought mitochondrial Cu exporter with a dual role in enabling CcO metalation and gating susceptibility to cuproptosis.

Keywords:  SLC25A3; copper; cuproptosis; cytochrome c oxidase; elesclomol

DOI:  https://doi.org/10.1073/pnas.2612098123
Kidney Int Rep. 2026 Jul;11(7): 106578

Enrichment of Rare Mitochondrial DNA Variants Among Individuals With Kidney Disease Reveals Undiagnosed Mitochondrial Disease.

Daniel R Schecter, Rory J Tinker, Patrick O'Connell, Jiuhong Pang, Simon SzeKing Lee, Meltem Ece Kars, Aysegul Guvenek, Michael Preuss, Yuval Itan, Eva Morava, Tamas Kozicz, Michio Hirano, Ali Naini, Jaya Ganesh.

   Introduction: Pathogenic mitochondrial DNA (mtDNA) variants cause multisystem disease, yet their contribution to kidney disease remains incompletely characterized, partly because of exclusion of the mitochondrial genome from genetic studies.
Methods: We evaluated mtDNA variation in 27,747 participants from the Mount Sinai Million Health Discoveries Program (MSM), an ancestrally diverse biobank with whole-exome sequencing and linked electronic health records (EHR). mtDNA variants were identified using MitoVerse and classified with MITOMAP. Kidney disease was defined using renal PheCodes for glomerular disease (GU_580) and renal failure (GU_582). Previous mitochondrial diagnoses were ascertained from EHR to identify undiagnosed individuals. Associations were adjusted for age, self-reported gender, and ancestry, with genotype-phenotype review.
Results: Among 3935 individuals with kidney disease, 45 carried clinically associated mtDNA variants, 42 of whom had no previous clinical mitochondrial diagnosis. mtDNA variants were enriched among individuals with kidney disease and associated with increased odds of renal involvement (odds ratio [OR] = 1.72). Associations were strongest for chronic kidney disease (CKD; GU_582.2; OR = 1.55) and renal failure (GU_582; OR = 1.53). Among undiagnosed carriers, genotype-phenotype review identified concordant manifestations in 14%, including mitochondrial CKD with hyperuricemia. Variant-level analysis identified enrichment of m.1630A>G in MT-TV (OR = 5.56), with additional variants showing trends. Both renal- and nonrenal-associated pathogenic mtDNA variants were observed.
Conclusion: Pathogenic mtDNA variants are overrepresented among individuals with kidney disease, often without a known mitochondrial diagnosis. These findings support a contributory role for mtDNA in renal disease and highlight the value of mtDNA analysis into kidney disease research and clinical evaluation, particularly for identifying unrecognized mitochondrial disease with renal involvement.

Keywords:  mitochondrial DNA; mitochondrial disease; population biobank; precision medicine; variant-level association

DOI:  https://doi.org/10.1016/j.ekir.2026.106578
Cell Biosci. 2026 Jun 19.

Mitochondrial proteases maintain cellular protein homeostasis and tissue integrity.

Kexin Shi, Hao Liu, Hong Xu, Weina Shang, Liquan Wang, Chao Tong.

   BACKGROUND: Mitochondrial proteases are essential for mitochondrial protein import and constitute the core of the organelle's intrinsic protein quality control system. However, their physiological functions across tissues, as well as their influence on cytosolic proteostasis, remain incompletely understood.
RESULTS: We generated loss- and gain-of-function alleles for 15 conserved mitochondrial proteases in Drosophila melanogaster to systematically dissect their in vivo functions. Disruption of specific proteases caused male sterility or organismal lethality, whereas tissue-specific knockouts in the eye, muscle, or fat body led to mitochondrial protein aggregates, structural defects, and age-dependent degeneration. Loss of UQCR-C1 or Afg3l2 robustly increased mitophagy, while overexpression of several proteases severely impaired muscle integrity. Loss of UQCR-C1, Mppa, or CG11771 promoted HTT72Q aggregation, and reducing UQCR-C1 or Afg3l2 markedly elevated cytosolic HTT72Q levels. Conversely, overexpressing Mppa-but with reduced efficacy in its disease-associated variants-suppressed HTT96Q aggregation and neuronal toxicity. Mppa forms a complex with UQCR-C1 to regulate mitochondrial pre-protein processing and import, indicating that enhancing mitochondrial protein import is sufficient to alleviate cytosolic proteotoxic stress caused by HTT polyglutamine (polyQ) proteins.
CONCLUSIONS: This work establishes a comprehensive in vivo resource for mitochondrial protease functions and their roles in shaping cytosolic proteostasis.

Keywords:   Drosophila ; Huntington disease (HTT) polyQ proteins; Mitochondria; Protease

DOI:  https://doi.org/10.1186/s13578-026-01612-0
Nat Nanotechnol. 2026 Jun 15.

Efficient prime editing in vivo and in vitro using lipid nanoparticles.

Allen Y Jiang, Ana Cristian, Dominique L Brooks, Emily R Feierman, Paul Z Chen, Madelynn N Whittaker, Sarah E Pierce, Holt A Sakai, Hongyu Chen, Dangliang Liu, Peyton B Randolph, Angus H Li, Alvin Hsu, Serena O Omo-Lamai, Y Allen Tao, Benista Owusu-Amo, Xiao Wang, Xiao Wang, Kiran Musunuru, David R Liu.

Prime editing is a versatile clinical genome editing method that enables precise substitutions, small insertions and deletions at specified locations in the genomes of living systems including human cells. Although non-viral lipid nanoparticle (LNP) delivery of RNA in vivo has become a preferred method for gene editing in animals and patients, its application to complex, three-component prime editing systems has yielded low editing efficiencies. Here we developed a systematic prime editing LNP (PE-LNP) optimization platform that addresses key bottlenecks in cargo design that limit editing efficiency. This generalizable workflow yielded PE-LNPs that can achieve 49% average in vivo prime editing in the bulk mouse liver with a single dose of 2 mg kg-1. We applied our workflow to the correction of PAH R408W, a cause of phenylketonuria, in a mouse model and achieved prime editing efficiencies and serum phenylalanine levels anticipated to be curative. We also show that PE-LNPs minimize off-target editing compared with DNA delivery methods, induce only transient elevation of liver enzymes and can be dosed repeatedly to improve editing efficiencies. These PE-LNP systems provide an attractive alternative to viral delivery by offering transient expression that minimizes off-target editing, no observed long-term toxicity and high levels of non-viral in vivo liver prime editing.

DOI: https://doi.org/10.1038/s41565-026-02200-6
Biochem Pharmacol. 2026 Jun 16. pii: S0006-2952(26)00508-3. [Epub ahead of print]251(Pt 2): 118170

Beyond proteostasis: LONP1 as an immunometabolic checkpoint in health and disease.

Lin Xie, Li-Hong Wu, Xin-Cheng Ni, Jiang-Nan Zhang.

  Mitochondrial Lon protease 1 (LONP1) is an ATP-dependent protease involved in mitochondrial protein quality control, mitochondrial DNA (mtDNA) maintenance, and stress adaptation. Beyond this canonical role, accumulating evidence links LONP1 to metabolic rewiring, inflammatory signaling, immune-cell polarization, and disease-associated mitochondrial dysfunction. Recent human LONP1 cryo-electron microscopy (cryo-EM) structures have revealed nucleotide- and substrate-dependent conformational states, including fold-sensing intermediates, pore-loop rearrangements, and catalytic-site organization, providing a structural framework for substrate processing and state-dependent ligandability. Functionally, LONP1 regulates the turnover or stability of metabolic enzymes such as pyruvate dehydrogenase kinase 4 (PDK4), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), and aconitase 2 (ACO2), thereby influencing carbon flux, epigenetic regulation, and immune-related metabolic programs. LONP1 deficiency or dysfunction can promote mitochondrial stress responses, including mtDNA release and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-dependent inflammation, with implications for aging, pulmonary fibrosis, developmental disorders such as cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS) syndrome, and organ injury. Conversely, increased LONP1 activity or expression has been associated with tumor progression, desmoplastic remodeling, ferroptosis resistance, and viral pathogenesis in selected models, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coxsackievirus B3 (CVB3). Pharmacological studies, including activators, dual-target inhibitors, and bortezomib-bound structural complexes, support the potential ligandability of LONP1 but also highlight unresolved issues in selectivity, target engagement, mitochondrial toxicity, and context-dependent therapeutic windows. This review summarizes current structural, mechanistic, and pharmacological evidence for LONP1 as a context-dependent immunometabolic regulatory node and discusses limitations and open questions that must be addressed before clinical translation.

Keywords:  Enzyme activators; Immunity; LONP1protease; Metabolic reprogramming; Mitochondria

DOI:  https://doi.org/10.1016/j.bcp.2026.118170
Brain Commun. 2026 ;8(3): fcag200

Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset.

Cristina Domínguez-González, Caterina Garone, Andrés Nascimento, Yuanjun Ma, Nada Boudiaf, Richard Kim, Susan VanMeter, Marcus Brunnert, Michio Hirano.

  Thymidine kinase 2 deficiency (MIM 609560) is an ultra-rare, autosomal recessive mitochondrial disease, resulting in progressive myopathy, respiratory insufficiency and increased risk of early death. Doxecitine and doxribtimine represents the first approved treatment for thymidine kinase 2 deficiency in the USA and the EU; previously, management was restricted to supportive care. The overall understanding of the natural history of thymidine kinase 2 deficiency is limited. Our study describes the baseline characteristics, survival and disease progression of untreated patients with thymidine kinase 2 deficiency as part of one of the largest international datasets to date. Data from individuals with thymidine kinase 2 deficiency identified through the review of published literature and a retrospective chart review study (NCT05017818) were pooled with pretreatment data from patients later treated with pyrimidine nucleos(t)ides (NCT03701568; NCT03845712; NCT05017818; company-supported Expanded Access Programs). Subgroups were stratified by age of thymidine kinase 2 deficiency symptom onset (≤12 years and >12 years). Key outcomes measured included survival, developmental motor milestone attainment, loss, regain and use of ventilatory and feeding support. In total, 257 patients were included in the study. Most patients [n = 199 (77.4%)] had an age of symptom onset ≤12 years, while 49 (19.1%) had an age of symptom onset >12 years; age of onset was missing for 9 (3.5%). Kaplan-Meier survival analyses estimated that the median time (95% confidence interval) from symptom onset to death was 2.6 (1.3, 6.4) years with age of symptom onset ≤12 years and 24.0 (16.0, not applicable) years with age of symptom onset >12 years. Loss of previously acquired motor milestones was observed across both subgroups, though most frequently in those with age of symptom onset ≤12 years [61/75 patients (81.3%) lost ≥1 motor milestone]. Spontaneous regain of lost motor milestones was rare [3/71 patients (4.2%), all with age of symptom onset ≤12 years]. Use of ventilatory support was observed for both subgroups [81/199 patients (40.7%) with age of symptom onset ≤12 years (missing data, n = 73); 23/49 patients (46.9%) with age of symptom onset >12 years (missing data, n = 11)]. Use of feeding tube support was also reported [28/199 patients (14.1%) with age of symptom onset ≤12 years (missing data, n = 121); 4/49 patients (8.2%) with age of symptom onset >12 years (missing data, n = 21)]. This study confirms the severe disease burden and high mortality associated with thymidine kinase 2 deficiency, underscoring the devastating impact on quality of life. This comprehensive dataset provides a valuable resource for informing clinical management and future therapeutic strategies.

Keywords:  mitochondrial myopathy; motor milestones; natural history; survival; thymidine kinase 2 deficiency

DOI:  https://doi.org/10.1093/braincomms/fcag200
JAMA Cardiol. 2026 Jun 17.

AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia: A Nonrandomized Clinical Trial.

Ronald G Crystal, Jonathan W Weinsaft, Stephen M Kaminsky, Anthony Caragiulo, Niamh Savage, Aarti Patel, Ralitza H Gavrilova, Susan L Perlman, Madeline Galbraith, Udhay Kahlon, Udhay Krishnan, Robert J Kaner, Abraham Sanders, Mary Vo, Harini Sarva, Andrea Yoo, Dolan Sondhi, Bishnu P De, Jason G Mezey, Gregory Aubert, Aashir Khan, Nithya Selvan, Narinder Bhalla, Eric Adler, Theresa Zesiewicz.

Importance: Friedreich ataxia (FA), a fatal, autosomal recessive disorder caused by pathogenic variants in the frataxin (FXN) gene, is characterized by progressive neurologic and cardiac disease, with cardiac disease being the major cause of death. Preclinical studies have demonstrated that systemic administration of AAVrh.10hFXN, an rh.10 serotype cardiotropic adenoassociated virus (AAV) vector expressing the normal human FXN coding sequence, reverses the cardiomyopathy in FXN-deficient mice.
Objective: To assess the safety and preliminary efficacy of administration of AAVrh.10hFXN to adults with FA cardiomyopathy.
Design, Setting, and Participants: This nonrandomized clinical trial evaluates the pooled data of 2 independent, open-label, dose-escalation trials that used the same gene therapy vector and similar clinical protocols among patients with FA cardiomyopathy at academic medical centers. Data were collected from February 22, 2022, to October 4, 2025, for trial 1 and from February 14, 2023, to September 10, 2025, for trial 2 and analyzed together from November 5, 2025, to March 12, 2026.
Intervention: AAVrh.10hFXN, administered intravenously in 3 dose cohorts (1.8 × 1011, 5.6 × 1011, and 1.2 × 1012 vector genomes per kilogram of body weight).
Main Outcomes and Measures: In addition to safety as the primary outcome, multiple parameters of exploratory end points were assessed, including cardiac biopsy levels of FXN protein, cardiac magnetic resonance imaging-derived left ventricular mass index (LVMI), and serum high-sensitivity (hs) troponin I.
Results: Seventeen patients with FA cardiomyopathy (mean [SD] age, 25 [6] years; 11 [65%] female) were followed up for a mean (SD) of 20 (8) months. There were 4 serious adverse events, 3 possibly related to prednisone immunosuppression and 1 possibly vector-related myocarditis 12 months after therapy, all of which resolved. Other adverse events were transient, nonserious, or not treatment related. In all 8 patients with cardiac biopsy 3 months after therapy, there were higher levels of cardiac FXN (dose cohort 1, 20%; cohort 2, 81%; cohort 3, 123%). After therapy, LVMI was lower by at least 10% in 9 patients and stabilized in 8 patients. Excluding the patient with myocarditis, posttherapy values of serum hs troponin I were lower by at least 10% in 15 patients and higher by at least 10% in 2 patients.
Conclusions and Relevance: Findings of this nonrandomized clinical trial suggest that intravenous administration of AAVrh.10hFXN was well tolerated and may be a potential treatment for FA cardiomyopathy, as evidenced by preliminary improvement in exploratory efficacy end points.
Trial Registration: ClinicalTrials.gov Identifiers: NCT05302271 and NCT05445323.

DOI: https://doi.org/10.1001/jamacardio.2026.1699
iScience. 2026 Jun 19. 29(6): 115916

Aberrant mitochondria in endometriosis: From pathogenic mechanisms to therapeutic opportunities.

Yishen S Rong, Jue Zhu, Chi Chiu Wang, Jing Zhang, Yichen C Chen.

  Endometriosis affects about 10% of women of reproductive age and is a major cause of chronic pelvic pain and infertility, yet current therapies often fail to provide lasting relief. Mitochondrial dysfunction has emerged as a potential key contributor that drives disease progression through metabolic reprogramming, oxidative stress (OS), and mitochondrial DNA (mtDNA) abnormalities. These alterations disrupt energy metabolism, promote ectopic cell survival under hypoxia, and increase oxidative damage. This review highlights mitochondrial failure as both a proposed driver and therapeutic target, discussing biomarkers and emerging interventions including antioxidants, metabolic modulation, oxidative phosphorylation (OXPHOS) inhibition, and bioactive substances.

Keywords:  Health sciences; Medicine; Reproductive medicine

DOI:  https://doi.org/10.1016/j.isci.2026.115916
Front Aging Neurosci. 2026 ;18 1846307

The role of energy deficit in autophagy failure in Parkinson's disease.

Mihajlo Bosnjak, Maja Misirkic Marjanovic, Milica Kosic, Milos Mandic, Ljubica Vucicevic, Verica Paunovic, Ljubica Harhaji-Trajkovic.

  Mitochondrial complex I dysfunction, ATP depletion, and impaired autophagy are key features of Parkinson's disease (PD), but their causal relationship remains unclear. Although energy stress induces autophagy, autophagy execution requires ATP. Available evidence suggests a biphasic effect of ATP depletion on autophagy in PD, with mild early energy decline promoting autophagy and more severe ATP loss, below a critical threshold, suppressing its completion. This mechanism may contribute to the accumulation of dysfunctional mitochondria and other undegraded cargo, creating a vicious cycle in which mitochondrial dysfunction, ATP decline, and autophagy failure progressively reinforce one another in PD. Here, we review current evidence linking cellular energy status to autophagic dysfunction in PD and discuss its pathogenic and therapeutic implications.

Keywords:  ATP depletion; Parkinson’s disease; autophagy; mitochondrial dysfunction; mitophagy; neurodegeneration

DOI:  https://doi.org/10.3389/fnagi.2026.1846307
Cell Commun Signal. 2026 Jun 13.

Post-translational modifications of mitochondrion-related proteins: integrative orchestrators of cell fate networks in cardiovascular disease.

Lei Liu, Saiteng Wu, Lei Zhang, Li Zhong, Rui Guo.

  Cardiovascular disease remains the leading cause of global mortality, with mitochondrial dysfunction playing a central pathogenic role. Post-translational modifications act as fundamental regulators of mitochondrial quality control. Yet, how mitochondrial post-translational modifications integrate stress signals to direct cell fate among diverse regulated cell death pathways in cardiovascular disease remains incompletely understood. This review proposes a conceptual framework in which mitochondrial post-translational modifications act as the master conductors of an integrated network linking mitochondrial homeostasis to cellular demise. We first outline the pivotal roles of mitochondrial quality control in cardiovascular disease and detail their precise mechanisms governed by mitochondrial post-translational modifications over each process. We then delineate how mitochondrial post-translational modifications critically regulate the initiation and execution of apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, evaluating their distinct contributions to cardiovascular pathophysiology. Furthermore, we highlight the extensive crosstalk and convergence among these death modalities at the mitochondrial level, emphasizing the role of mitochondrial post-translational modification signatures in amplifying death signals or triggering modality switching. By synthesizing recent discoveries, this work connects dynamic protein-level modifications to cell fate outcomes, offering a theoretical basis for future therapeutic strategies aimed at rebalancing the network of mitochondrial post-translational modifications to combat heart failure and other cardiovascular diseases.

Keywords:  Cardiovascular disease; Cell death; Dynamic equilibrium.; Mmitochondrial quality control; Post-translational modifications

DOI:  https://doi.org/10.1186/s12964-026-03002-y
J Neurol. 2026 Jun 16. pii: 400. [Epub ahead of print]273(7):

Cerebellar cognitive-affective syndrome in Friedreich Ataxia.

Emilien Petit, Sabrina Sayah, Elisabetta Indelicato, Stéphanie Borel, Marcus Grobe-Einsler, Jennifer Faber, Almut T Bischoff, Thomas Klopstock, Jörg B Schulz, Kathrin Reetz, Ludger Schöls, Brittany Humphries, Mariana Atencio, Rania Hilab, Audrey Iskandar, Maresa Buchholz, Feng Xie, Thomas Klockgether, Bernhard Michalowsky, Sylvia Boesch, Alexandra Durr, Giulia Coarelli.

   BACKGROUND: Increasing evidence suggests that cognition and affect may be affected in Friedreich Ataxia (FA).
OBJECTIVES: To investigate the Cerebellar Cognitive Affective Syndrome (CCAS) in patients with FA and evaluate its correlations with speech and clinical parameters.
METHODS: Patients were recruited from the PROFA study (NCT05943002), a prospective observational cohort in France, Germany, and Austria. Assessments included clinical scales (Friedreich Ataxia Rating Scale-Activities of Daily Living, FARS-ADL, Scale for the Assessment and Rating of Ataxia), the CCAS scale, and patient-reported outcomes. Controls data were obtained from the READISCA study (NCT03487367).
RESULTS: A total of 101 patients with FA and 43 controls with similar ages were included (35.4 ± 14.9 years vs 38.8 ± 9.5 years, p = 0.11). The mean CCAS total raw score was lower in patients than in controls (92.4 ± 13.7 vs 104.0 ± 8.5, p < 0.001), with a higher rate of definite CCAS (47% vs 12%, p < 0.001). The most frequently impaired cognitive functions in FA were phonemic fluency (44% vs 14%, p < 0.001), categoric switching (41% vs 9%, p < 0.001), and semantic fluency (20% vs 2%, p = 0.007). In multivariate models, CCAS total raw score increased with higher education and decreased with FARS-ADL (both p < 0.001). Dysarthria had no significant effect on total or item-level CCAS scores after adjustment for education, FARS-ADL, mean GAA repeats, and study center (all p > 0.15).
DISCUSSION: Definite CCAS is common in FA, with deficits in phonemic fluency, categoric switching, and semantic fluency. Cognitive impairment appears independent of dysarthria severity, suggesting CCAS is an intrinsic manifestation of the disease.

Keywords:  Cerebellar cognitive affective syndrome; Dysarthria; Friedreich Ataxia

DOI:  https://doi.org/10.1007/s00415-026-13786-1
Stem Cell Rev Rep. 2026 Jun 17.

Mesenchymal Stromal Cell-Derived Extracellular Vesicles Mediate Mitochondrial Delivery in Injury: Mechanistic Insights, Evidentiary Tiers, and Translational Challenges.

Tingkun Ma, Yuan He, Jincui Yang, Peng Luo, Qiyi Shen, Junjie Yang, Ding Xu, Xiao Li, Chunchu Deng, Kelu Li, Biao Chen, Yulong Shi.

  While mesenchymal stromal cell (MSC)-derived extracellular vesicles (MSC-EVs) offer a safer, cell-free alternative to stem cell transplantation, their specific role in rescuing recipient cell mitochondrial networks requires precise definition. This review clarifies that scientific landscape by systematically partitioning MSC-EV-mediated mitochondrial delivery into three rigorous, evidence-based categories: (i) the horizontal transfer of intact, bioenergetically active mitochondria, (ii) the lateral delivery of sub-organellar components such as mitochondrial DNA (mtDNA) and transcriptional proteins (e.g., TFAM), and (iii) indirect protective signaling that rejuvenates endogenous networks. Effectively integrated cargo within MSC-EV has been reported to restore mitochondrial membrane potential, contributing to the stabilization of electron transport chain complexes (I-IV), the reactive oxygen species (ROS) balance, and the tricarboxylic acid (TCA) cycle and NAD + /NADH balance to reverse bioenergetic collapse. Across diverse myocardial, pulmonary, hepatic, renal, and neurological injury models, this EV-associated delivery is associated with dampening of hyper-inflammation, enhances macrophage phagocytosis, and supports tissue barrier regeneration. Nevertheless, critical translational barriers remain, including significant EV heterogeneity, a lack of standardized high-purity isolation protocols in line with MISEV (Minimal Information for Studies of Extracellular Vesicles) guidelines, and unverified oncologic risks such as supporting tumor progression or chemoresistance through unintended metabolic rescue. In conclusion, large-scale clinical adoption requires prioritized, well-designed human trials with rigorous cargo characterization to firmly establish long-term safety, durability, and oncologic security.

Keywords:  Extracellular vesicle; Mesenchymal stromal cell; Mitochondrial delivery; Tissue injury

DOI:  https://doi.org/10.1007/s12015-026-11170-0
Adv Sci (Weinh). 2026 Jun 16. e16501

Agnuside Stabilizes the Complex I Assembly Factor NDUFAF6 to Reinforce Mitochondrial Efficiency and Thermogenic Responsiveness.

Qingwen Zhao, Li Xie, Qianzhuo Wang, Shuying Dai, Bei Li, Yingjuan Zhang, Zhe Sun, Yue Gao.

  Brown and beige adipocytes dissipate energy as heat, yet effective strategies to enhance their mitochondrial efficiency remain limited. Here, we identify Agnuside (AGN) as a selective stabilizer of the complex I assembly factor NDUFAF6. AGN directly binds cytosolic NDUFAF6, suppresses its ubiquitination, prolongs its half-life, and facilitates mitochondrial import, thereby reinforcing complex I assembly and promoting coordinated stabilization of complexes III and IV within the respirasome, without altering complex II, complex V, or global mitochondrial biogenesis. Functionally, AGN exhibits a demand-dependent metabolic profile. Under basal conditions, AGN enhances mitochondrial oxidative efficiency without activating overt UCP1-dependent uncoupling. In contrast, cold exposure or chronic high-fat feeding markedly potentiates its thermogenic impact, as evidenced by improved mitochondrial ultrastructure, increased UCP1 abundance, and elevated energy expenditure in brown adipose tissue, with similar mitochondrial reinforcement observed in inguinal white adipose tissue under sustained metabolic stress. Importantly, thermoneutral Ucp1 knockdown does not abolish AGN-mediated enhancement of respiratory complex assembly and ATP production, whereas genetic ablation of Ndufaf6 eliminates these effects. Together, these findings establish AGN-NDUFAF6 stabilization as a key regulatory mechanism governing adipose mitochondrial efficiency and thermogenic responsiveness, and highlight assembly-factor targeting as a promising strategy to restore oxidative metabolism in metabolic dysfunction.

Keywords:  NDUFAF6; agnuside; brown adipocytes; mitochondria; thermogenesis

DOI:  https://doi.org/10.1002/advs.202516501