Nat Commun. 2026 May 30. doi: 10.1038/s41467-026-73455-9. Online ahead of print. ABSTRACT Primary mitochondrial diseases (PMDs) affect approximately 1 in 4300 individuals and cause early-onset neuromuscular and multisystem dysfunction with reduced lifespan. They result from pathogenic variants in mitochondrial or nuclear DNA that impair oxidative phosphorylation. Cytochrome c oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome c oxidase subunit FA4), formerly NDUFA4, is a nuclear-encoded COX subunit, but its role in disease remains poorly defined. We report the largest genetically confirmed cohort of COXFA4-related PMD to date, comprising 13 individuals from 12 families with biallelic pathogenic COXFA4 variants. All present with Leigh-like encephalopathy and complete loss of COXFA4 protein; however, patient-derived fibroblasts retain residual COX activity, with upregulation of COXFA4L2 (cytochrome c oxidase subunit FA4-like 2), a poorly characterised paralog. Here, we show that COXFA4 is a late-stage COX assembly subunit and identify a paralog-mediated compensatory mechanism with translational potential. PMID:42218136 | DOI:10.1038/s41467-026-73455-9

Crit Care. 2025 Dec 22. doi: 10.1186/s13054-025-05758-0. Online ahead of print. ABSTRACT PURPOSE: Humoral immunity proteins-immunoglobulins, complement proteins, and antimicrobial peptides-have key antimicrobial and immunomodulatory functions in sepsis. We hypothesised that their circulating levels are lower in non-survivors, potentially resulting in impaired bacterial clearance and persistent or recurrent infections. METHODS: We performed a systematic review and meta-analysis evaluating differences in humoral immunity proteins between survivors and non-survivors in adult patients with sepsis. PubMed and Embase were searched without date restrictions. Random-effects meta-analyses were used to estimate pooled standardised mean differences (SMD) with 95% confidence intervals (CI). Sensitivity analyses included data from the MIMIC-IV ICU database, and further supplemented by three proteomic studies. RESULTS: Thirty-six studies including 6,330 patients were analysed. Thirteen reported on immunoglobulins, 17 on complement proteins, and 7 on the antimicrobial peptide heparin-binding protein (HBP). Survivors had significantly higher levels of complement proteins C3 (SMD 0.53 [0.07-0.99]) and C4 (SMD 0.51 [0.09-0.94]) compared to non-survivors. Conversely, C4a (SMD – 1.17 [-1.77 to – 0.56]) and IgA (SMD – 0.21 [-0.39 to – 0.03]) were significantly lower in survivors. No differences were found for IgG (SMD 0.00 [-0.18 to 0.18]), IgM (SMD – 0.02 [-0.13 to 0.08]), C5, C5a, or HBP. Sensitivity analyses using MIMIC-IV (n = 2,452) and proteomic datasets supported these findings. Proteomic data revealed early depletion of classical complement components (C3, C4B) and regulatory proteins in non-survivors. CONCLUSION: Sepsis non-survivors exhibit lower C3 and C4 levels and higher C4a, consistent with complement activation and/or depletion. Complement proteins may serve as potential biomarkers and therapeutic targets in sepsis. PMID:41430733 | DOI:10.1186/s13054-025-05758-0

Cell. 2025 Dec 4:S0092-8674(25)01310-8. doi: 10.1016/j.cell.2025.11.014. Online ahead of print. ABSTRACT Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4^R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer’s-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease. PMID:41349546 | DOI:10.1016/j.cell.2025.11.014

Birth Defects Res. 2025 Oct;117(10):e2533. doi: 10.1002/bdr2.2533. ABSTRACT BACKGROUND: Spina bifida (SB), a common neural tube defects (NTDs), has a complex genetic architecture that remains incompletely understood. Although prior studies have identified rare, deleterious single nucleotide variants (SNVs) in SB, broader contributions to risk remain unclear. Here, we investigated shared genetic risk among 256 SB probands compared with 395 ancestry-matched controls using an unbiased sequencing approach. METHODS: We performed an exome-wide association study (ExWAS) of 46,887 SNVs with minor allele frequencies (MAF) > 0.001 to identify single-variant associations, followed by gene-based burden tests to assess the cumulative effect of SNVs within genes, using all variants and then restricting to rare variants (MAF < 0.05). Both burden tests were repeated in 510 unaffected parents to evaluate excess mutational burden relative to controls. RESULTS: Across all analyses, 16 genes were associated with SB: SRCIN1, PDE4DIP, XCL2, CTAGE10P, GLB1L3, PMS2P4, HSPA4, GLB1L2, FAM90A1, PLA1A, HLA-A, SPIRE2, TVP23B, CHD5, FOXA2, and PIF1. ExWAS identified 11 significant SNVs, nine of which were common (MAF > 0.05). The unrestricted burden test identified seven genes; four remained significant when restricted to rare variants, and two additional genes emerged only in that subset. Five burden-associated genes were not detected in the ExWAS, suggesting cumulative variant effects. Four burden-associated genes also showed enrichment in parents, supporting inherited risk. Three of these showed suggestive transmission disequilibrium (p values ≤ 0.10) and one was attributed to multiple SNVs. CONCLUSION: These results provide new insight into the multifactorial genetic landscape of SB and highlight the importance of unbiased approaches in constructing genetic models of NTD. PMID:41013918 | DOI:10.1002/bdr2.2533

Cancer Discov. 2025 Aug 7:OF1-OF24. doi: 10.1158/2159-8290.CD-24-1738. Online ahead of print. ABSTRACT Extrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number-dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy-number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate decisions in cancer cell lines, patient-derived xenografts, and primary neuroblastomas, illustrating how extrachromosomal oncogene dosage-driven phenotypic diversity offers a strong evolutionary advantage under therapeutic pressure. Furthermore, we identify senescent cells with reduced ecDNA copy numbers as a source of treatment resistance in neuroblastomas and outline a strategy for their targeted elimination to improve the treatment of MYCN-amplified cancers. SIGNIFICANCE: ecDNA-driven tumor genome evolution provides a major challenge to curative cancer therapies. We demonstrate that ecDNA copy-number dynamics drives treatment resistance by promoting oncogene dosage-dependent phenotypic heterogeneity in MYCN-amplified cancers. Exploiting phenotype-specific vulnerabilities of ecDNA cells, therefore, presents a powerful strategy to overcome treatment resistance. See related article by Korsah, p. XX. PMID:40773595 | DOI:10.1158/2159-8290.CD-24-1738