bims-mitmed 2026-08-30 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–08–30
seventeen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

2000-2025: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future.
COX14 Variants Are Associated With Mitochondrial Complex IV Deficiency Nuclear Type 10 (MC4DN10).
Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials.
Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the ND4 11778G>A mutation.
Concordant mtDNA heteroplasmy between trophectoderm and inner cell mass supports blastocyst-stage PGT-mt for m.14487T>C.
Identification of Nuclear Genetic Loci Linked to Clinical Features of the m.3243A>G Mitochondrial DNA Variant.
Mitochondrial NCLX Couples Glucagon- and PDE2A-Dependent Signals to Regulate Hepatic Lipid Metabolism.
From Single Cells to Diagnosis: Proteomics Technologies in the Multi-Omics Landscape of Rare and Mitochondrial Diseases.
Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.
Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.
Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?
Patient's own mitochondria injected into eyes in attempt to restore vision.
Human Brain Organoid-Enabling Discoveries Reach the Clinic: A Translational Inflection Point.
Reverse electron transport connects tauopathy to mitochondrial dysfunction.
Diagnostic utility of FGF-21 and GDF-15 for differentiating primary mitochondrial diseases from lysosomal storage disorders associated with secondary mitochondrial dysfunction: a machine learning-based multimetabolite approach.
Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis.

Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261473291

2000-2025: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future.

Amel Karaa, Maria Isabel G Lopez Sanchez, Clare Stuart, Luca Bolliger, Kate Murray, Maria E O'Hanlon, Brian Tseng, Philip Yeske, Sean Murray.

  Primary mitochondrial diseases (PMD) are ultra-rare, genetically diverse disorders that impair cellular energy metabolism and typically present with multisystemic symptoms. Over the past decades, the therapeutic landscape of PMD has evolved substantially. Early trials of non-specific antioxidant and metabolic therapies produced largely negative or mixed results, providing important methodological lessons for the field. More recent studies have adopted improved outcome measures, natural history-informed designs, and precision therapeutic approaches, including gene therapy and nucleoside therapy, which have shown encouraging clinical and regulatory progress. Regulatory agencies have only recently begun approving disease-modifying therapies for selected mitochondrial disorders. The European Medicines Agency (EMA) approved idebenone for Leber Hereditary Optic Neuropathy (LHON) in 2015 but only recently, in 2025 did the Food and Drug Administration (FDA) in the US approve a treatment for Barth syndrome and thymidine kinase 2 deficiency (TK2d). Friedreich's ataxia received regulatory approval in 2023 from both the EMA and FDA, marking another milestone in mitochondria-related disorders. To comprehensively review clinical and regulatory developments in PMD over the past two decades, we conducted a structured scoping review and horizon scan of published clinical trials and regulatory approvals in PMD from January 2000 to November 2025. Data sources included PubMed, Embase, https://ClinicalTrials.gov, and regulatory agency websites. Recent accelerated and full FDA approvals validate the feasibility of tailored evidence packages, but sustaining this momentum will require more rigorous alignment of trial design with molecular biology, strengthening of natural history infrastructure, deployment of sensitive biomarkers, and adoption of innovative statistical approaches. Early regulatory engagement and robust patient-community partnerships will be key.

Keywords:  clinical trial; drug development; mitochondrial disease; rare disease

DOI:  https://doi.org/10.1177/26330040261473291
Am J Med Genet A. 2026 Aug 26.

COX14 Variants Are Associated With Mitochondrial Complex IV Deficiency Nuclear Type 10 (MC4DN10).

Elias K Awad, Emily Waskow, Hari Tunuguntla, Joseph Spinner, Hanna J Tadros, Lisa T Emrick, Daniel G Calame, Fernando Scaglia.

  COX14 encodes a transmembrane protein essential for cytochrome c oxidase (COX) complex assembly. A homozygous missense variant in COX14 was reported in three siblings from a single consanguineous family with severe, fatal infantile mitochondrial complex IV deficiency nuclear type 10 (MC4DN10; MIM# 619053). No additional cases have been identified since, and the ClinGen Mitochondrial Disease Gene Curation Expert Panel classified the COX14-MC4DN10 gene-disease association as having limited evidence. We report a 9-year-old male with biallelic COX14 variants (c.82delT, p.Tyr28Thrfs*83, and c.3G>A, p.Met1?) representing the second unrelated family with MC4DN10. In contrast to the fatal neonatal course previously described, this individual demonstrates an attenuated encephalomyopathic phenotype with prolonged survival. Initial presentation at 6 months included hypotonia, feeding difficulties, and developmental delay. Previously unreported features included growth hormone deficiency, ascending aortic dilation, and distinct neuroradiological findings. At age 8 years, he developed neurological regression and ataxia with brain MRI findings consistent with Leigh syndrome. Muscle biopsy confirmed reduced COX enzymatic activity (33% of mean). Identification of a second unrelated family with biallelic COX14 variants and biochemically confirmed complex IV deficiency strengthens the gene-disease association for MC4DN10. This individual presents an attenuated encephalomyopathic phenotype with novel endocrine and cardiovascular manifestations, underscoring the importance of genomic evaluation in suspected mitochondrial disorders even in the absence of classic biochemical markers such as lactic acidosis.

Keywords:   COX14 ; Leigh syndrome; MC4DN10; ascending aortic dilation; cytochrome c oxidase deficiency; encephalomyopathy; growth hormone deficiency; mitochondrial complex IV deficiency nuclear type 10

DOI:  https://doi.org/10.1002/ajmg.a.70260
Genes (Basel). 2026 Jul 23. pii: 850. [Epub ahead of print]17(8):

Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials.

Albert Z Lim, Aye-Myat Moe, Renae J Stefanetti, Yi Shiau Ng.

  Primary mitochondrial diseases (PMDs) are one of the most common genetic disorders with an estimated prevalence of 1 in 4300. This review article summarises the latest updates in the field of mitochondrial medicine over the last decade. The availability of exome and genome sequencing in clinical practice has empowered clinicians to unravel the phenotypic heterogeneity of PMD and to end the diagnostic odyssey experienced by many patients and families. In unresolved cases, the detection of variant(s) of unknown significance by next-generation sequencing creates diagnostic and clinical uncertainties, and integrating a multi-omics approach can improve diagnostic yield. Alongside breakthroughs in genomic technologies, there is growing interest in using fluid biomarkers to guide diagnosis, monitor disease progression, and potentially serve as clinical trial endpoints. However, the clinical application of these fluid biomarkers in unselected patient cohorts with different disease onset and phenotypes would require more robust evidence. Natural history studies derived from national and international collaborations have provided insights into genotype-phenotype relationships and prognostic factors across several genotypes, including m.3243A>G, MT-ATP6, POLG, and TK2. Advances in therapeutic discoveries and clinical trials are challenging the obsolete dogma that PMDs are untreatable and bringing hope to patients; four compounds have been licensed, and many trials are in progress. Many barriers and challenges to translating laboratory discoveries into clinical therapy in PMD remain, including preclinical models for efficacy and safety testing, sample size, trial design, and the selection of outcome measures and trial endpoints.

Keywords:  fluid biomarkers; outcome measures; phenotypes; trial endpoints; whole-genome sequencing

DOI:  https://doi.org/10.3390/genes17080850
Sci Adv. 2026 Aug 28. 12(35): eaeg8792

Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.

Anastasia Rumyantseva, Trevor S Tippetts, Alissa Wilhalm, William Carter, Marco Moedas, Florian A Rosenberger, David Moore, Ákos Végvári, Yvonne Hinze, Linden Muellner-Wong, David Alsina, Rolf Wibom, Rainah Winston, Thomas P Mathews, Lars H Lund, Daniel C Andersson, Gianluigi Pironti, Anna Wedell, Ralph J DeBerardinis, Christoph Freyer, Anna Wredenberg.

The neonatal heart experiences rapid metabolic growth after birth to meet increasing energetic and biosynthetic demands. How mitochondrial cofactor availability limits this transition remains unclear. Here, we demonstrate that mitochondrial S-adenosylmethionine (mitoSAM) import through SLC25A26 becomes limiting shortly after birth and specifically restricts protein lipoylation, although other mitoSAM-dependent processes are partially preserved. Loss of Slc25a26 impaired lipoylation-dependent flux through pyruvate and α-ketoglutarate dehydrogenases, restricting tricarboxylic acid cycle carbon entry and depleting aspartate and nucleotide pools. Conversely, mitochondrial gene expression remained intact, and respiratory chain enzyme activities showed partial impairment, indicating that lipoylation is the most mitoSAM-sensitive pathway during postnatal heart adaptation. These metabolic limitations were linked to sustained cardiomyocyte cell-cycle activity, delayed structural maturation, and early cardiomyopathy. Supplementing with medium-chain triglycerides during the suckling-to-weaning transition partially stabilized metabolism and prolonged survival. Overall, our findings identify a stage-specific metabolic vulnerability in the postnatal heart characterized by hierarchical mitoSAM utilization within the mitochondria.

DOI: https://doi.org/10.1126/sciadv.aeg8792
J Genet Genomics. 2026 Aug 22. pii: S1673-8527(26)00272-9. [Epub ahead of print]

Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the ND4 11778G>A mutation.

Yanchun Ji, Feilong Meng, Yinglong Gao, Zhipeng Nie, Yunfan He, Juanjuan Zhang, Ya Li, Minglian Zhang, Jianyong Wang, Yongming Zhang, Shihui Wei, Jun Qin Mo, Min-Xin Guan.

  Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease mainly driven by the m.11778G>A mutation, and its incomplete penetrance and diverse inheritance patterns remain unclear. This study integrates clinical and genetic analyses of 419 Han Chinese pedigrees carrying this mutation, covering 5262 matrilineal relatives. Distinct phenotypic heterogeneity emerges, including sporadic, maternal and complex transmission patterns; 209 pedigrees contain only single affected individuals, which suggests that the m.11778G>A mutation alone fails to cause disease. Full mitochondrial DNA sequencing and haplogroup screening identify multiple mitochondrial genetic modifiers. Haplogroups D4j, M7, M9, and M10 are significantly enriched in maternally inherited families with elevated disease penetrance. Haplotype-specific variants ND4 11696G>A, ND1 3394T>C, and ND6 14502T>C synergistically aggravate mitochondrial dysfunction together with m.11778G>A, and secondary mtDNA mutations disrupting complex I or mitochondrial tRNA metabolism also raise disease susceptibility. Nuclear modifiers PRICKLE3 and YARS2, as well as X-linked sex-specific regulatory factors, are also identified. Overall, LHON results from the interaction of mitochondrial and nuclear genetic factors. This research constructs a comprehensive genetic landscape of LHON, highlights the vital role of modifier genes, and provides theoretical support for precision therapies targeting mitochondrial and nuclear pathways.

Keywords:  Chinese; Inheritance pattern; Leber hereditary optic neuropathy (LHON); Mitochondrial DNA mutation; Mitochondrial haplogroup; Nuclear modifier gene

DOI:  https://doi.org/10.1016/j.jgg.2026.08.007
J Assist Reprod Genet. 2026 Aug 27.

Concordant mtDNA heteroplasmy between trophectoderm and inner cell mass supports blastocyst-stage PGT-mt for m.14487T>C.

Maria Tofilo, Ilya Volodyaev, Evgenii Tretiakov, Olga Kokorina, Svetlana Avdeichik, Anna Smirnova, Elena Grechenko, Anna Filimonova, Natalia Sudarikova, Anastasia Kirillova, Ilya Mazunin.

   PURPOSE: Is blastocyst-stage trophectoderm (TE) biopsy informative for preimplantation genetic testing of the mitochondrial DNA (mtDNA) variant m.14487 T > C (MT-ND6), by providing heteroplasmy estimates representative of the inner cell mass (ICM), within a combined PGT-A/PGT-mt workflow?
METHODS: Single IVF/ICSI cycle study in one carrier woman; six blastocysts were obtained and underwent day 5-6 TE biopsy followed by combined PGT-A and targeted mtDNA heteroplasmy assessment.
RESULTS: Six blastocysts underwent combined PGT-A/PGT-mt (day 5, n = 2; day 6, n = 4). PGT-A classified three embryos as euploid, two as aneuploid, and one as mosaic. PGT-mt showed a bimodal distribution of m.14487 T > C heteroplasmy: three embryos were < 18% (11.4-13.5%) and three were > 70% (73.2-99.6%); only one embryo met the predefined transfer criteria (euploid; 11.4% heteroplasmy). After warming and embryo fractionation, heteroplasmy estimates from the original TE biopsy and the corresponding post-warming embryo fraction (the remaining TE, ICM, or combined TE + ICM) were closely concordant, with only small paired differences.
CONCLUSION: These findings provide variant-specific evidence that blastocyst TE biopsy can be representative of the ICM for m.14487 T > C, supporting combined PGT-A/PGT-mt at the blastocyst stage. Nevertheless, given the possibility of heteroplasmy shifts later in development, prenatal diagnosis and postnatal follow-up remain advisable when a heteroplasmic embryo is transferred.

Keywords:  Heteroplasmy; ICM; Leigh syndrome; MT-ND6; Mitochondrial DNA; PGT-mt; TE; m.14487T>C

DOI:  https://doi.org/10.1007/s10815-026-04012-y
Neurol Genet. 2026 Aug;12(4): e200411

Identification of Nuclear Genetic Loci Linked to Clinical Features of the m.3243A>G Mitochondrial DNA Variant.

Róisín M Boggan, Theodora-Dafni Michalettou, Yi Shiau Ng, Imogen G Franklin, Lucas T Cortés, Charlotte L Alston, Emma L Blakely, Boriana Büchner, Enrico Bugiardini, Kevin Colclough, Catherine Feeney, Michael G Hanna, Andrew T Hattersley, Thomas Klopstock, Cornelia Kornblum, Michelangelo Mancuso, Kashyap A Patel, Robert D S Pitceathly, Chiara Pizzamiglio, Holger Prokisch, Jochen Schäfer, Andrew M Schaefer, Maggie H Shepherd, Annemarie Thaele, Rhys H Thomas, Doug M Turnbull, Cathy E Woodward, Robert McFarland, Robert W Taylor, Heather J Cordell, Sarah J Pickett.

Background and Objectives: Mitochondrial DNA (mtDNA) disorders exhibit striking clinical variability that is poorly explained by known factors such as variant heteroplasmy, age, or sex. Nuclear genetic modifiers likely play a significant role in this heterogeneity. We aimed to characterize the nature of nuclear genetic involvement for 2 common syndromic presentations of the common pathogenic mtDNA variant, m.3243A>G: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD).
Methods: We assembled a multicenter cohort of clinically ascertained carriers of m.3243A>G (total n = 488), identifying 198 individuals across 76 pedigrees suitable for genetic linkage analysis. We investigated 4 clinical features characteristic of MELAS and MIDD: diabetes, hearing impairment, stroke-like episodes, and encephalopathy. Haseman-Elston regression-based genetic linkage analysis was performed to identify regions of the nuclear genome cosegregating with these features. The effects of m.3243A>G heteroplasmy, age, and sex were accounted for using logistic regression; empirical significance thresholds were determined through feature-specific gene-dropping simulations. Association analyses were performed in 247 individuals using single-variant (SAIGE) and gene-based approaches (SAIGE-GENE+ and MAGMA) to refine candidate loci within a significant linkage region.
Results: We identified significant genetic linkage to encephalopathy (chromosome 7q22; LOD = 3.72), and regions suggestive of genetic linkage on chromosomes 1, 5, 6, 11, and 13, for encephalopathy and stroke-like episodes. No linkage was identified for diabetes or hearing impairment. Association analysis within the chromosome 7 region identified variant rs62500792 (intergenic between SDHAF3 and TAC1) with the lowest p value (3.7 × 10-5), yet no variants reached the proportional significance threshold (5.3 × 10-6). Gene-based analyses highlighted PLOD3 (p = 3.9 × 10-3) and IMMP2L (p = 6.4 × 10-3) as candidates, as each showed the strongest gene-level signals within the linkage region across complementary burden-testing methods, although neither reached corrected significance thresholds.
Discussion: The nuclear genetic architecture modifying m.3243A>G differs across clinical features. Severe neurologic features (encephalopathy and stroke-like episodes) may be influenced by a small number of nuclear genes with relatively large effect sizes, whereas the nuclear contribution to diabetes and hearing impairment appears more polygenic. This study highlights the value of large, well-characterized patient cohorts in identifying modifier loci and advancing knowledge of the mechanisms underlying phenotypic variability in mtDNA disease.

DOI: https://doi.org/10.1212/NXG.0000000000200411
Mol Metab. 2026 Aug 25. pii: S2212-8778(26)00117-1. [Epub ahead of print] 102433

Mitochondrial NCLX Couples Glucagon- and PDE2A-Dependent Signals to Regulate Hepatic Lipid Metabolism.

Essam A Assali, Mahmoud Taha, Ahmad Salhab, Johnny Amer, Karthickeyan Chella Krishnan, Marko Kostic, Michaela Veliova, Alexandra J Brownstein, Orian S Shirihai, Rifaat Safadi, Israel Sekler.

  Mitochondrial calcium signaling, particularly its glucagon-mediated oscillatory dynamics, plays a pivotal role in regulating hepatic metabolism and is known to be disrupted in steatotic liver disease. We recently identified the mitochondrial Na+/Ca2+ exchanger NCLX as a key mediator of glucagon-induced mitochondrial calcium oscillations, essential for proper gluconeogenic function. Here, using hepatocyte-specific NCLX knockout (cKO) mice, we demonstrate that NCLX is critical for intrahepatic lipolysis and fatty acid oxidation (FAO); its loss impairs glucagon-stimulated lipid droplet catabolism and blunts FAO. Mechanistically, we find that NCLX deficiency disrupts allosteric activation of lipolytic enzymes and increases CPT1 sensitivity to malonyl-CoA-mediated inhibition, resulting in defective lipolysis and FAO. We further show that glucagon regulates hepatic NCLX via cAMP/PKA-dependent phosphorylation at NCLX Ser258. Notably, PDE2A acts as a negative regulator of this pathway by degrading mitochondrial cAMP. Hepatic mitochondrial PDE2A abundance and cAMP-degrading activity are elevated in HFD, and in vivo BAY 60-7550 treatment suppresses mitochondrial cAMP degradation and augments PKA signaling in steatosic livers. Pharmacologic inhibition of PDE2A with BAY 60-7550 enhances NCLX phosphorylation, restores mitochondrial calcium efflux and oscillations, and stimulates FAO in an NCLX-dependent manner. Importantly, we uncover that cAMP/PKA-dependent phosphorylation of NCLX at Ser258 is suppressed in human steatotic livers, and that pharmacologic inhibition of PDE2A ameliorates hepatic FAO and steatosis in both dietary and genetic MASLD models. Collectively, our findings establish the glucagon-PKA-PDE2A-NCLX signaling axis as a key metabolic rheostat integrating mitochondrial calcium dynamics with lipid homeostasis, providing a promising therapeutic target for MASLD.

Keywords:  Glucagon signaling; Hepatic steatosis; MASLD (Metabolic dysfunction-associated steatotic liver disease); NCLX; PDE2A (Phosphodiesterase 2A); fatty acid oxidation; lipolysis; mitochondrial bioenergetics; mitochondrial calcium signaling

DOI:  https://doi.org/10.1016/j.molmet.2026.102433
J Inherit Metab Dis. 2026 Sep;49(5): e70236

From Single Cells to Diagnosis: Proteomics Technologies in the Multi-Omics Landscape of Rare and Mitochondrial Diseases.

Simon Wetzel, Sebastian Porsdam Mann, Florian A Rosenberger.

  Proteomics by mass spectrometry has rapidly matured from a niche method into a standard tool. The recent 10-year trajectory of single-cell proteomics has opened a new biological dimension for studying disease. Mitochondrial diseases, with their pronounced cell-to-cell heterogeneity, are particularly, well-suited to these methods. Here, we discuss how this approach can serve as an orthogonal functional layer for rare disease diagnostics. We trace the evolution of rare disease diagnostics from biochemical enzyme assays through genomics, transcriptomics, proteomics and metabolomics, highlighting incremental gains in diagnostic yield from individual omics layers and their integration. We discuss the limitations of bulk approaches in capturing the functional consequences of genetic perturbations, the new opportunities opened up by single-cell measurements and how spatial single-cell proteomics can further enrich the biological signal of affected cells in diagnostic tissues. We observe that the persisting diagnostic gap reflects not only technological limitations but, increasingly, challenges in data sharing and infrastructure as well as interpretive frameworks for functional molecular evidence. In this context, we consider opportunities for artificial intelligence and the ethical dimensions of single-cell proteomics in rare disease diagnostics. Finally, we propose a single-cell deep visual proteomics (scDVP) framework for clinical diagnostics of rare diseases with cell-to-cell variability, arguing that mitochondrial diseases are an ideal proof-of-concept.

Keywords:  diagnostics; mitochondria; omics ethics; rare diseases; single‐cell proteomics; spatial proteomics

DOI:  https://doi.org/10.1002/jimd.70236
Sci Adv. 2026 Aug 28. 12(35): eadu0632

Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.

Fangbing Chen, Yanhui Liang, Wei Zheng, Aobo Yao, Ning Wang, Huangyao Chen, Zhenpeng Zhuang, Meng Lian, Yu Zhao, Zhen Ouyang, Zhaohai Zhou, Weikai Ge, Qishuai Liu, Yinghua Ye, Liangxue Lai, Kepin Wang.

The accumulation of mitochondrial DNA (mtDNA) mutations is a primary driver of mitochondrial dysfunction, which is intrinsically linked to aging and various pathologies. POLG, the catalytic subunit of DNA polymerase gamma, is essential for mtDNA replication; notably, a deficiency in its proofreading function precipitates the accumulation of mtDNA mutations. In this study, by combining prime editing with somatic cell nuclear transfer technology, we successfully generated a mitochondrial mutator pig model expressing proofreading-deficient POLG. These pigs exhibited elevated somatic mtDNA mutation loads and recapitulated key premature aging phenotypes, including weight loss, rough hair coat, anemia, structural alterations in the skin and testicular interstitium, increased apoptosis, and the up-regulation of senescence-associated markers, culminating in shortened life span. Given the physiological and metabolic similarities between pigs and humans, this mitochondrial mutator pig model represents an ideal preclinical tool for dissecting the mechanistic role of mtDNA mutations in aging and age-related pathologies and for accelerating the translation of therapeutic strategies.

DOI: https://doi.org/10.1126/sciadv.adu0632
Mitochondrion. 2026 Aug 22. pii: S1567-7249(26)00095-4. [Epub ahead of print]91 102205

Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.

Yang Yang, Nirajan Neupane, Jouni Kvist, Jonna Saarimäki-Vire, Matthias Schewe, Kalle Luopajärvi, Pooja Manjunath, Svetlana Konovalova, Rubén Torregrosa-Muñumer, Veijo Kinnunen, Pekka Katajisto, Timo Otonkoski, Eija Pirinen, Jayasimman Rajendran, Henna Tyynismaa.

  Mitochondrial protein homeostasis intersects with metabolic control, but the in vivo roles of specific mitochondrial co-chaperones remain unclear. The chaperone mtHSP70 plays a key role in import and folding of nuclear-encoded proteins targeted to mitochondrial matrix. Its protein folding cycle is regulated by the GrpE-like nucleotide exchange factor GRPEL1. Vertebrates also have a GRPEL2 paralog, postulated as the stress-sensitive counterpart, but its physiological relevance is not known. We show here that GRPEL2 is not essential for viability in mice, and its absence does not induce proteotoxic stress responses in stark contrast to GRPEL1. However, we find that GRPEL2 has a role in regulating body weight homeostasis. GRPEL2 knockout mice are protected from age- and diet-induced weight gain and maintain a better metabolic health and insulin sensitivity. Transcriptional profiling revealed minimal changes in liver and skeletal muscle, whereas white adipose tissue from Grpel2-deficient mice lacked the obesity-associated remodeling seen in controls. We propose that GRPEL2 fine-tunes metabolic setpoints without broadly perturbing mitochondrial protein import, thereby maintaining adipose tissue health during nutritional excess. These findings show that subtle alterations in mitochondrial chaperone systems reshape systemic metabolism and could suggest strategies to mitigate obesity and insulin resistance through targeted modulation of mitochondrial proteostasis.

Keywords:  Adipose tissue; Body weight homeostasis; Grpel2; Mitochondrial protein import; Nucleotide exchange factor; mtHSP70

DOI:  https://doi.org/10.1016/j.mito.2026.102205
Brain Sci. 2026 Aug 20. pii: 890. [Epub ahead of print]16(8):

Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?

Kate Erin Harris, Gerassimos Lascaratos, Kai-Yin Chau.

   BACKGROUND/OBJECTIVES: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders.
METHODS: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue.
RESULTS: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction.
CONCLUSIONS: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target.

Keywords:  ATP hydrolysis; ATP synthase; ATP synthesis; Complex V; bioenergetics; mitochondria; neurodegeneration

DOI:  https://doi.org/10.3390/brainsci16080890
Nature. 2026 Aug 24.

Patient's own mitochondria injected into eyes in attempt to restore vision.

Miryam Naddaf.



Keywords:  Diseases; Sensory systems; Therapeutics

DOI:  https://doi.org/10.1038/d41586-026-02616-z
Stem Cells Dev. 2026 Aug 22. 15473287261481004

Human Brain Organoid-Enabling Discoveries Reach the Clinic: A Translational Inflection Point.

Aline M A Martins, Alysson R Muotri.

  Human brain organoids have evolved from early neurodevelopmental models into platforms for therapeutic discovery. Here, we highlight two cases in which organoid-derived findings enabled FDA-approved clinical trials. Patient-derived organoids modeling Pitt-Hopkins syndrome revealed human-specific, TCF4-dependent abnormalities and supported the development of a regulated AAV gene therapy. In parallel, Rett syndrome organoids cultured aboard the International Space Station uncovered space-induced neural senescence, characterized by retroelement-associated neuroinflammation, prompting evaluation of antiretroviral therapy. These examples illustrate how organoids can reveal disease mechanisms that are inaccessible or incompletely reproduced in animal models, while animal studies remain essential for validation and safety assessment. As the field advances, matching model complexity to experimental purpose-and ensuring reproducibility, scalability, and accessibility-will be critical. Human brain organoids are crossing a translational threshold, emerging as engines of therapeutic discovery and gateways to clinical intervention.

Keywords:  clinical trials; disease modeling; translation

DOI:  https://doi.org/10.1177/15473287261481004
Nat Rev Neurol. 2026 Aug 27.

Reverse electron transport connects tauopathy to mitochondrial dysfunction.

Heather Wood.

DOI: https://doi.org/10.1038/s41582-026-01265-0
Mol Genet Metab. 2026 Aug 21. pii: S1096-7192(26)00529-9. [Epub ahead of print]149(1-2): 110246

Diagnostic utility of FGF-21 and GDF-15 for differentiating primary mitochondrial diseases from lysosomal storage disorders associated with secondary mitochondrial dysfunction: a machine learning-based multimetabolite approach.

Ayla Yildiz, Mehmet Taha Yildiz, Hasan Onal.

   OBJECTIVES: Differentiating primary mitochondrial disease (PMD) from disorders associated with secondary mitochondrial dysfunction may be challenging because of overlapping biochemical and clinical features. In the present study, the group designated as secondary mitochondrial dysfunction consisted specifically of lysosomal storage disorders. Single biomarkers, such as FGF-21 and GDF-15, may have limited discriminatory power in this setting. In this study, multivariate metabolite panels distinguishing PMD, lysosomal storage disorders associated with secondary mitochondrial dysfunction (SMD), and healthy controls (HC) were developed and internally validated using a leakage-controlled machine learning framework with interpretable outputs.
METHODS: This prospective study included 88 participants: 28 patients with genetically confirmed PMD, 30 patients with genetically confirmed lysosomal storage disorders associated with secondary mitochondrial dysfunction, and 30 healthy controls (HC). Plasma amino acids were quantified by LC-MS/MS, urinary organic acids by GC-MS, and serum FGF-21 and GDF-15 by ELISA, yielding 77 variables. Three pairwise tasks were modeled using nested cross-validation, stability-ranked feature selection, and elastic net logistic regression. Performance was summarized using mean outer-fold AUC, accuracy, sensitivity, and specificity, with BCa confidence intervals; DeLong confidence intervals were calculated from pooled out-of-fold predictions.
RESULTS: The comparison between the lysosomal storage disorder group and the PMD group showed the highest discrimination within the present cohort (mean outer-fold AUC, 0.988; pooled-OOF DeLong 95% CI, 0.952-1.000; mean outer-fold accuracy, 0.948). Parsimonious panels were identified: SMD vs. PMD-asparagine, lactate, GABA, homocystine, hydroxylysine; SMD vs. HC-asparagine, pyruvate, GDF-15, histidine, urinary 4-hydroxyphenylpyruvic acid; PMD vs. HC-GDF-15 and lactate. SHAP analysis supported the consistency in the mitochondrial redox and amino acid pathways.
CONCLUSIONS: A multivariate metabolomic approach provided discriminatory information between genetically confirmed PMD, selected lysosomal storage disorders associated with secondary mitochondrial dysfunction, and healthy controls. The highest performance was observed between the two patient groups. However, these findings are specific to the diagnostic composition of the present cohort and should not be interpreted as establishing a universal distinction between primary and secondary mitochondrial dysfunction. External validation in larger, independent, and diagnostically broader cohorts is required before clinical implementation.

Keywords:  Biomarkers; Fibroblast growth factor 21; Growth differentiation factor 15; Machine learning; Mitochondrial diseases; Tandem mass spectrometry

DOI:  https://doi.org/10.1016/j.ymgme.2026.110246
Nat Commun. 2026 Jul 24. pii: 9041. [Epub ahead of print]17(1):

Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis.

Xiao-Chen Xie, Yang Guo, Ran Guo, Yong-Ze Li, Shan-Shan Wang, Xiao-You Jiang, Shuang Hao, Ye Zhang, Yu-Han Li, Xi-Yan Liu, Xiao-Xu Wu, Xin-Yue Zhang, Wen-Dong Guo, Yan-Ling Feng, Jia-Bin Li, Chen Liu, Liang Wang, Zhen-Hua Li, Wei-Ping Teng, Zhong-Yan Shan, Liu Cao, Qi-Qiang Guo.

Autoimmune thyroiditis arises from disrupted homeostasis of thyroid follicular epithelial cells and coordinated immune cell activation within the microenvironment. However, its pathogenesis is not fully understood. Here, we identify a mitochondrial (mt) DNA-cGAS-STING inflammatory axis as a driver of autoimmune thyroiditis in mice. By contrast, ubiquitin-dependent mitophagy mediated by PINK1 and Parkin was found to protect mice from disease. Mechanistically, mitochondrial dysfunction elevates mitochondrial reactive oxygen species levels, activating the ATM-CHK2 DNA damage response pathway, which in turn phosphorylates the autophagy adapter TAX1BP1 at Ser722. This modification promotes the recruitment of mitochondria to autophagosomes, thereby facilitating mitophagy. Impairing the ATM-CHK2-TAX1BP1 mitophagy pathway causes mtDNA leakage into the cytosol and triggers cGAS-STING-dependent inflammation. Notably, pharmacological inhibition of STING with C176 effectively slows autoimmune thyroiditis progression. Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target.

DOI: https://doi.org/10.1038/s41467-026-76047-9