bims-mitmed 2026-08-02 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–08–02
eighteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.
Limiting intestinal iron absorption rescues glial defects and extends lifespan in a Drosophila model of Friedreich's ataxia.
Therapeutic Advances in Major NBIA Disorders: Current Strategies and Translational Challenges.
Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.
Loss of LipT2 disrupts mitochondrial protein lipoylation and metabolic homeostasis in Drosophila melanogaster.
Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.
Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.
Late-onset PSP/FTD-like atypical parkinsonism as a novel phenotype of POLG-related disease: a case report.
Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
ATL2 Recruits TRAK1 to Promote Mitochondrial Transport at ER-Mitochondria Contact Sites.
An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.
Mitochondrial metabolism and epigenetic crosstalk drive SASP.
In utero gene editing and precision medicine.
Managing Pregnancy in Inherited Metabolic Disorders: Experience From a Single Tertiary Metabolic Center.
Mitochondrial Dysfunction, Cerebral Metabolic Crisis, and Exploratory Bioenergetic Biomarkers in a Translational Swine Model of Acute Carbon Monoxide Poisoning.
Multi-generational mitochondrial complex V deficiency due to the recurrent ATP5F1A c.620G>A (p.Arg207His) pathogenic variant: A novel family and a review of the literature.

Signal Transduct Target Ther. 2026 Jul 29. pii: 295. [Epub ahead of print]11(1):

Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.

Agustina Creus, Shrestha Mohapatra, Leonardo Ortega, David Sebastián.

Mitochondria are essential for cellular homeostasis, integrating various signals to control key cellular functions such as metabolism, apoptosis, inflammation, cell proliferation and redox balance. Given their multifaceted functions, it is not surprising that mitochondrial dysfunction has been implicated as a key contributor to the pathogenesis of numerous human diseases. Consequently, preserving mitochondrial integrity and functionality is vital for overall organismal health. Mitochondrial health is safeguarded by a sophisticated and tightly regulated network of quality control systems. These include mitochondrial proteostasis, which ensures proper protein folding and degradation; mitochondrial biogenesis, which governs the synthesis of new mitochondria; mitochondrial dynamics, encompassing fusion and fission processes; and mitophagy, the selective autophagic removal of damaged mitochondria. Additionally, these core systems are intricately connected to other crucial mitochondrial processes, such as the maintenance of mitochondrial DNA integrity, the regulation of cristae architecture, and the control of mitochondrial permeability transition, all of which are indispensable for optimal mitochondrial performance. Preclinical and clinical studies consistently demonstrate a strong link between impairments in these quality control mechanisms and both aging and the development of a wide spectrum of diseases. These include cancer, metabolic disorders, cardiovascular conditions, neurodegenerative diseases and autoimmune pathologies. In this review, we explore the different facets of mitochondrial quality control and discuss their implications in disease progression and aging. Furthermore, we highlight recent advances in interventions and therapies aimed at modulating mitochondrial quality control, providing an overview of their potential to mitigate disease burden and promote healthy aging.

DOI: https://doi.org/10.1038/s41392-026-02813-2
Neurobiol Dis. 2026 Jul 29. pii: S0969-9961(26)00295-0. [Epub ahead of print] 107550

Limiting intestinal iron absorption rescues glial defects and extends lifespan in a Drosophila model of Friedreich's ataxia.

Ema Turki, Estelle Jullian, Pierre Delamotte, Anne Filipe, Laura Tixier-Cardoso, Sandrine Middendorp, Elodie Martin, Véronique Monnier.

  Friedreich ataxia (FRDA) is a neurodegenerative and cardiac disease caused by GAA repeat expansions within the first intron of the FXN gene, leading to reduced frataxin expression. Frataxin is involved in iron sulfur cluster (ISC) biosynthesis, and its deficiency results in multiple cellular dysfunctions, including mitochondrial iron overload. Although altered iron homeostasis has been reported in several frataxin-deficient models and in FRDA patients, its contribution to disease progression remains debated. Here, we used a GAA expansion-based Drosophila model of FRDA, termed fh-GAAs, to investigate the impact of reducing intestinal iron absorption on disease progression. We first found that iron accumulation was tissue-specific and predominantly affected the central nervous system. Furthermore, glial cells were affected more severely than neurons, suggesting an increased vulnerability of glia to frataxin deficiency. Reducing intestinal iron uptake, either through treatment with bathophenanthroline disulfonic acid (BPS), an extracellular iron chelator, or by gut-specific silencing of the iron transporter Malvolio, nearly doubled fly survival. BPS treatment also improved sensitivity to dietary iron, enhanced locomotor performance, fully restored normal brain size, and prevented glial alterations. Altogether, our findings identify glial cells as early and preferential targets of frataxin deficiency in an iron-dependent manner and support the in vivo relevance of intestinal iron uptake as a potential modulator of disease severity in FRDA.

Keywords:  Drosophila melanogaster; Frataxin; Friedreich Ataxia; Glia; Gut-brain communication; Iron homeostasis

DOI:  https://doi.org/10.1016/j.nbd.2026.107550
Neurol Int. 2026 Jul 10. pii: 133. [Epub ahead of print]18(7):

Therapeutic Advances in Major NBIA Disorders: Current Strategies and Translational Challenges.

Floriana Cascone, Gemma Gasparini, Valeria Tiranti, Ivano Di Meo.

  Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare genetic movement disorders characterized by progressive neurological deterioration, dystonia, parkinsonism, spasticity, and abnormal iron deposition in the basal ganglia. Although iron accumulation is the shared neuroradiological hallmark, most NBIA genes do not directly regulate iron metabolism. Instead, major NBIA forms arise from disruption of distinct but converging cellular pathways, including coenzyme A (CoA) biosynthesis, lipid metabolism, mitochondrial function, and autophagy. This narrative review aims to examine the pathogenic mechanisms of major NBIA disorders, namely pantothenate kinase-associated neurodegeneration (PKAN), COASY protein-associated neurodegeneration (CoPAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), and beta-propeller protein-associated neurodegeneration (BPAN), and how these insights are guiding therapeutic development. Preclinical strategies aimed at restoring CoA metabolism, improving mitochondrial function, limiting lipid peroxidation, modulating autophagy, or correcting the underlying genetic defect have shown encouraging results, although none have yet reached robust clinical validation. Clinical translation remains limited by disease rarity, clinical heterogeneity, absence of validated biomarkers, and preclinical models that only partially recapitulate human pathology. Advancing the field will depend on earlier molecular diagnosis, biomarkers capable of tracking disease stage, and trial designs suited to ultra-rare populations. NBIA thus offers a paradigm for how mechanistic classification of a genetically defined disease group can redirect therapeutic strategy away from a shared radiological feature and toward pathway-specific intervention.

Keywords:  BPAN; CoA biosynthesis; CoPAN; MPAN; Neurodegeneration with brain iron accumulation; PKAN; PLAN; autophagy; lipid metabolism

DOI:  https://doi.org/10.3390/neurolint18070133
Autophagy. 2026 Jul 31.

Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.

Laura Kristine Rasmussen, Diana Gomes Moreira, Justyna Okarmus, Anne Simonsen, Morten Meyer.

  Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.

Keywords:  Autophagy receptors; E3 ubiquitin ligases; PINK-PRKN/parkin pathway; PRKN-independent mitophagy; mitochondrial dysfunction; mitochondrial quality control; mitophagy; neurodegeneration; therapeutic targets

DOI:  https://doi.org/10.1080/15548627.2026.2711596
FEBS Lett. 2026 Jul 29.

Loss of LipT2 disrupts mitochondrial protein lipoylation and metabolic homeostasis in Drosophila melanogaster.

Yoshihito Kishita, Manabu Tsuda, Yukiko Sato-Miyata, Satomi Takeo, Toshiro Aigaki.

  Lipoic acid is an essential cofactor for mitochondrial multienzyme complexes involved in central metabolism. In humans, mutations in the lipoyl transferase LIPT2 impair mitochondrial protein lipoylation and cause severe metabolic disease. Here, we investigated the Drosophila homolog, lipT2, in vivo. lipT2 mutants exhibited locomotor defects and shortened lifespan, accompanied by markedly reduced lipoylation of pyruvate dehydrogenase (PDH) and 2-oxoglutarate dehydrogenase (OGDH). Loss of lipT2 impaired glucose oxidation and disrupted tricarboxylic acid (TCA) cycle activity, leading to reduced mitochondrial energy production. Metabolomic analysis revealed altered amino acid homeostasis, including a marked reduction in aspartate, a key TCA cycle-derived metabolite. These findings demonstrate that defective lipoylation disrupts central metabolic processes and energy homeostasis.

Keywords:  Drosophila melanogaster; LipT2; carbon flux; energy metabolism; metabolic homeostasis; mitochondrial protein lipoylation

DOI:  https://doi.org/10.1002/1873-3468.70422
Sci Adv. 2026 Jul 31. 12(31): eaef0140

Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.

Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.

Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.

DOI: https://doi.org/10.1126/sciadv.aef0140
Antioxidants (Basel). 2026 Jun 25. pii: 793. [Epub ahead of print]15(7):

Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.

Hsu-Hung Chang, Phebe Ting Syuan Chang, Chung-Che Tsai, Chan-Yen Kuo.

  Mitochondrial Lon peptidase 1 (LONP1) is an ATP-dependent AAA+ (ATPases associated with diverse cellular activities) protease that has emerged as a key regulator of mitochondrial proteostasis, with functions extending beyond protein quality control. In addition to degrading misfolded and oxidized proteins, LONP1 coordinates mitochondrial DNA maintenance, metabolic remodeling, and stress-responsive signaling. Recent structural and functional advances have expanded the biological significance of LONP1 beyond protein quality control, highlighting its roles in mitochondrial metabolism, genome maintenance, and stress responses. LONP1 dysregulation is increasingly implicated in cancer, metabolic disorders, neurodegeneration, and aging, where it exerts context-dependent effects on cell survival and disease progression. In cancer, LONP1 supports metabolic plasticity, redox adaptation, and therapeutic resistance, whereas in degenerative conditions, its decline contributes to mitochondrial dysfunction and tissue damage. Here, we synthesize recent insights into the structure, mechanisms, and biological functions of LONP1 and discuss their implications for human disease. We further discuss emerging therapeutic strategies and key challenges for targeting LONP1 in human disease.

Keywords:  LONP1; cancer metabolism; mitochondrial metabolism; mitochondrial proteostasis; stress response

DOI:  https://doi.org/10.3390/antiox15070793
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2602775123

Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.

Wasi Iqbal, Ben Zucker, Xiaoying Liu, Ruiru Wang, Hongfei Zhu, Sijie Chen, Renjie Zhou, Xingguo Liu, Michael M Kozlov, Liting Duan.

  Membrane pearling, the transformation of a smooth tubule into a chain of bead-like swellings connected by narrow membrane tethers, is a widely observed shape change. While it has been well studied for synthetic lipid and unilamellar intracellular membranes, the mechanism underlying the pearling of the peculiar double-membrane architecture of tubular mitochondria remained elusive. Here, we addressed the role of the strongly convoluted inner mitochondrial membrane (IMM) in pearling driven by stretching. Using a light-gated, mitochondria-specific mechanostimulator to apply stretching forces to mitochondria in live cells, we demonstrated that stretching triggers pearling of whole tubular mitochondria. Moreover, we found that pearling requires the presence of the IMM, as unilamellar tubules derived solely from the mitochondrial outer membrane elongate uniformly under stretching and never undergo pearling. To understand the physical mechanism by which IMM controls pearling, we developed a theoretical model that considers the lumen, effectively spanned and volumetrically stiffened by cristae, as an elastic continuum. Our computations show that pearling requires the luminal volume to be sufficiently resistant to change, with its effective bulk rigidity modulus exceeding a critical value. Our experimental observations further revealed the functionally important consequences of stretching-induced pearling. mtDNA nucleoids partitioned into the bulges of pearled configurations, suggesting a role for pearling in the reorganization of luminal components. In addition, the membrane fission GTPase DRP1 accumulated at the constrictions of pearled shapes, leading to membrane scission and mitochondrial fragmentation. Our work uncovers the unique biophysical mechanism of mitochondrial pearling and its functional significance for organelle dynamics.

Keywords:  membrane elasticity; membrane pearling; membrane tension; mitochondria; mitochondrial fission

DOI:  https://doi.org/10.1073/pnas.2602775123
Acta Neurol Belg. 2026 Jul 27.

Late-onset PSP/FTD-like atypical parkinsonism as a novel phenotype of POLG-related disease: a case report.

Gloria Rožmarić, Mario Hero, Eliša Papić, Nadja Grozdanić, Vladimira Vuletić.

  POLG-related disease is a multisystem mitochondrial disorder that may mimic primary neurodegenerative syndromes. We report a 70-year-old man with progressive cognitive decline, rigid-akinetic parkinsonism, postural instability, vertical supranuclear gaze palsy, and prominent executive and semantic fluency deficits, forming a PSP/FTD-like phenotype. Brain MRI showed frontotemporal-predominant cortical atrophy and a hummingbird sign, while FDG-PET demonstrated frontal and bilateral parietotemporal hypometabolism with preserved occipital metabolism. Alzheimer disease CSF biomarkers were normal and RT-QuIC was negative. Pancytopenia with macrocytosis, liver cirrhosis, and myelodysplastic syndrome indicated multisystem involvement. Genetic testing identified biallelic POLG variants, one pathogenic and one likely pathogenic, confirming POLG-related disease. Levodopa produced partial improvement. This case expands the recognised late-onset POLG spectrum and supports POLG testing in atypical parkinsonism accompanied by cognitive, hepatic, or haematological abnormalities. Early diagnosis may prevent valproate-associated severe hepatotoxicity.

Keywords:  Atypical parkinsonism; Frontotemporal dementia; Mitochondrial disease; POLG; Progressive supranuclear palsy

DOI:  https://doi.org/10.1007/s13760-026-03145-2
Science. 2026 Jul 30. 393(6810): eady0832

Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.

Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.

Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.

DOI: https://doi.org/10.1126/science.ady0832
Adv Sci (Weinh). 2026 Jul 30. e76972

ATL2 Recruits TRAK1 to Promote Mitochondrial Transport at ER-Mitochondria Contact Sites.

Yiru Cheng, Peiyuan Chai, Xiayuhe Pei, Yiwen Chen, Xiaoshuai Huang, Bei Liu, Yiqian Wu, Junlin Teng, Pengli Zheng, Jianguo Chen.

  Mitochondrial transport and distribution are crucial for cellular homeostasis, yet whether and how they are regulated by endoplasmic reticulum (ER)-mitochondria contact sites remains unclear. Here, we demonstrate that the ER protein atlastin-2 (ATL2) orchestrates mitochondrial transport and distribution by promoting assembly of the transport machinery at ER-mitochondria contact sites. Mechanistically, ATL2 recruits the adaptor trafficking kinesin-binding protein 1 (TRAK1) to the ER membrane, strengthening the interaction of TRAK1 with the mitochondrial transport adaptor MIRO1 to promote anterograde mitochondrial transport. Loss of ATL2 disrupts this process, leading to perinuclear mitochondrial clustering. We further find that ATL2 stabilizes ER-mitochondria contact sites by interacting with MFN2, providing a platform for mitochondrial transport complex assembly. Moreover, in hypoxia, ATL2 is ubiquitinated at lysine 567 by the E3 ligase SYVN1, leading to its degradation and a resulting defect in mitochondrial distribution. Our findings elucidate a novel ER-mediated mechanism for mitochondrial transport.

Keywords:  ATL2; ER–mitochondria contact sites; TRAK1; hypoxia; mitochondrial transport

DOI:  https://doi.org/10.1002/advs.76972
Science. 2026 Jul 30. 393(6810): eads5397

An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.

Thomas Cottle, Lydia Joh, Cori Posner, Adam DeCosta, Dean R Campagna, Mark D Fleming, Sarah Ducamp, Julia R Kardon.

Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.

DOI: https://doi.org/10.1126/science.ads5397
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2608102123

Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.

Jingwen Chen, Lili Su, Bangze Pan, Junhao Sang, Linlin Li, Junsong Huang, Zhao-Lan Hu, Lixin Wang, Xiaojie Zhang, Jun Jin.

  Mitochondrial dysfunction drives T cell aging in mice. Yet, due to fundamental differences in T cell aging mechanisms between species, whether human T cells exhibit similar mitochondrial alterations remains unclear, with existing evidence often conflicting. Using cryoelectron tomography, we resolved the structure and spatial organization of mitochondrial ribosomes in primary human CD8+ T cells under physiological conditions. Comparative analysis with human aging models revealed an age-related reduction in mitoribosome abundance and in higher-order mitoribosome organization, which is necessary for cooperative translation. Defective mitochondrial translation suppressed cytosolic ribosomal protein expression, thereby limiting mitochondrial biogenesis. The consequent reduction in mitochondrial mass induced an aged T cell phenotype characterized by compromised memory phenotypes and proliferative capacity. Enhancing mitochondrial translation via overexpression of the mitoribosomal component Mrps5 reversed aged T cell phenotypes in a mouse model of viral infection or tumor. Together, our findings provide nanoscale-resolution views of internal mitochondrial structures in situ, revealing an age-related loss of mitoribosomes. This loss contributes to mitochondrial dysfunction and the subsequent decline in T cell function observed in older individuals. Restoring mitochondrial translation may therefore represent a strategy for mitigating T cell dysfunction in the aging population.

Keywords:  T cell aging; cryo-electron tomography; mitoribosome

DOI:  https://doi.org/10.1073/pnas.2608102123
Nature. 2026 Jul 29.

Mitochondrial metabolism and epigenetic crosstalk drive SASP.

Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L Rowsey, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M Espe, Taro Hitosugi, Ya Li, Alexander M Washington, Aaron Havas, Rabi Murad, Xue Lei, Rebecca A Porritt, Oliver D K Maddocks, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari, Alexandre Gaspar-Maia, Peter D Adams, João F Passos.

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.

DOI: https://doi.org/10.1038/s41586-026-10791-2
Semin Pediatr Surg. 2026 Jul 16. pii: S1055-8586(26)00094-6. [Epub ahead of print] 151678

In utero gene editing and precision medicine.

Olivia L Katz, Kara Kennedy, Natalie F Berger, Nada Fadl, William H Peranteau.

  Advances in preconception and prenatal genetic testing, in combination with the rapid evolution and regulatory acceptance of targeted gene therapy technologies, has unveiled promising opportunities for the antenatal treatment of genetic disease by way of in utero gene editing and precision medicine. Recent regulatory guidance, put forth by the Federal Drug Administration (FDA), on gene editing has the exciting potential to accelerate the development and implementation of therapeutics for rare and ultrarare diseases. In this review, we highlight recent advances that have occurred in the fields of in utero gene editing and precision medicine and the opportune regulatory landscape that may facilitate the clinical translation of therapeutics in the future. We additionally review the indispensable role of prenatal genetic diagnosis, including chorionic villus sampling, amniocentesis, and noninvasive prenatal testing, as the diagnostic gateway through which candidates for in utero gene and precision therapies will be identified.

Keywords:  Amniocentesis; CRISPR; Chorionic villus sampling; Enzyme replacement; Fetal; Gene editing; Gene therapy; Genetic disease; In utero; Noninvasive prenatal testing; Precision medicine; Prenatal diagnosis

DOI:  https://doi.org/10.1016/j.sempedsurg.2026.151678
J Obstet Gynaecol Res. 2026 Aug;52(8): e70419

Managing Pregnancy in Inherited Metabolic Disorders: Experience From a Single Tertiary Metabolic Center.

Elif İşler-Soylu, Tanyel Zubarioglu, Esma Uygur, Tuğçe Aras-Çöl, Hanım Babazade-Aghakishili, Kağan Çalışgan, Ertuğrul Kıykım, Çiğdem Aktuğlu-Zeybek.

   AIM: Improved newborn screening and critical care allow more individuals with inherited metabolic disorders (IMDs) to survive to adulthood and reach reproductive age. However, given the rarity of these conditions, evidence on pregnancy management is limited and clinical practice is largely informed by case reports and expert opinions. This study aims to evaluate pregnancy outcomes and metabolic management strategies in women with IMDs, addressing a critical gap in evidence-based care for this unique and growing patient population.
METHODS: This retrospective, single-center study included female patients aged 15-49 years with genetically confirmed IMDs who initiated treatment before conception and gave birth.
RESULTS: Seven pregnancies in six women were included. The median maternal age at conception was 29.0 years and the median gestational age of infants was 38.4 weeks. In two patients with glutaric aciduria type I, individualized peripartum management protocols were successfully implemented. Enzyme replacement therapy was continued without complications throughout pregnancy in the woman with Gaucher disease. A previously unreported congenital heart defect was detected in the infant of a mother with tyrosinemia type II. Notably, one patient with 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency, whose first pregnancy ended in a healthy birth despite peripartum metabolic instability, experienced fatal metabolic decompensation following a miscarriage in her second pregnancy.
CONCLUSIONS: These findings indicate that while successful pregnancies are possible, severe maternal complications and fetal anomalies can still occur. These observations highlight the urgent need for structured adult care pathways and disease-specific pregnancy management strategies as this population continues to grow.

Keywords:  Glutaric acidemia type 1; Tyrosinemia type II; gyrate atrophy; mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA Lyase deficiency; pregnancy

DOI:  https://doi.org/10.1111/jog.70419
Toxicol Sci. 2026 Jul 29. pii: kfag093. [Epub ahead of print]

Mitochondrial Dysfunction, Cerebral Metabolic Crisis, and Exploratory Bioenergetic Biomarkers in a Translational Swine Model of Acute Carbon Monoxide Poisoning.

Abigail Insana, Alistair Lewis, John C Greenwood, Matthew Kelly, Frances S Shofer, Shih-Han Kao, McKenna Mason, Stephen Baak, Jonathan Starr, Jarelis Cabrera, Johannes K Ehinger, Todd J Kilbaugh, Tiffany Ko, Angela N Viaene, Wesley B Baker, David H Jang.

  Carbon monoxide (CO) poisoning remains a major cause of toxicologic morbidity and mortality and is a leading cause of acute neurologic injury among poisoned patients, yet the mechanisms underlying cerebral bioenergetic dysfunction remain incompletely understood. In addition to impaired oxygen delivery through carboxyhemoglobin (COHb) formation, CO poisoning is associated with mitochondrial respiratory dysfunction and cerebral metabolic injury. We characterized systemic physiology, cerebral metabolism, mitochondrial bioenergetics, and exploratory translational biomarkers in a swine model of acute CO poisoning. Yorkshire swine underwent sham exposure or inhalational CO exposure at 1000 or 2000 ppm with serial physiologic monitoring, arterial blood gas analysis, cerebral microdialysis, high-resolution mitochondrial respirometry, ATP quantification, western blotting, and histologic/immunohistochemical analyses. Peripheral blood mononuclear cell (PBMC) mitochondrial respiration was explored as a systemic correlate of cerebral mitochondrial function. CO exposure produced dose-dependent elevations in COHb and lactate with associated metabolic acidosis and hemodynamic impairment. Cerebral microdialysis demonstrated variable lactate-to-pyruvate ratios, while extracellular glycerol was significantly increased following severe CO exposure, consistent with membrane injury and metabolic dysfunction. Mitochondrial respiration was impaired in both cortical and hippocampal tissue, with Complex IV-linked respiration among the most consistently affected respiratory states. Cortical ATP content was significantly reduced in severely exposed animals, supporting cerebral bioenergetic failure. Western blot analysis demonstrated increased HO-1 expression without significant reductions in citrate synthase or Complex IV protein abundance, suggesting functional respiratory inhibition rather than loss of mitochondrial content. Collectively, these findings demonstrate that acute CO poisoning produces early cerebral bioenergetic dysfunction characterized by impaired mitochondrial respiration, ATP depletion, and metabolic alterations, while supporting the exploratory potential of PBMC mitochondrial respiration as a translational biomarker of cerebral mitochondrial dysfunction.

Keywords:  bioenergetic biomarkers; carbon monoxide poisoning; cerebral metabolism; cerebral microdialysis; mitochondrial dysfunction; swine model

DOI:  https://doi.org/10.1093/toxsci/kfag093
Mol Genet Metab. 2026 Jul 14. pii: S1096-7192(26)00490-7. [Epub ahead of print]149(1-2): 110207

Multi-generational mitochondrial complex V deficiency due to the recurrent ATP5F1A c.620G>A (p.Arg207His) pathogenic variant: A novel family and a review of the literature.

Undiagnosed Diseases Network

  ATP5F1A encodes part of the catalytic core of mitochondrial complex V, which is responsible for the majority of ATP production. Mitochondrial complex V deficiency, nuclear type 4A (MC5DN4A; MIM#620358) is due to monoallelic pathogenic variants in ATP5F1A. MC5DN4A is a neonatal-onset disorder with features including growth faltering, developmental delay, epilepsy, and a biochemical phenotype indicative of urea cycle dysfunction. Interestingly, patients who have MC5DN4A due to the recurrent pathogenic ATP5F1A c.620G>A (p.Arg207His) variant appear to demonstrate clinical resolution before 18 months of age. All reported cases of MC5DN4A due to the ATP5F1A c.620G>A (p.Arg207His) variant have been de novo. Here we present a mother and her three children with MC5DN4A harboring the ATP5F1A c.620G>A (p.Arg207His) variant. The oldest child has growth faltering, seizures, autism spectrum disorder, global developmental delay, urea cycle dysfunction, and elevated plasma lactate without full clinical resolution. The two younger children have similar biochemical findings with a more severe clinical phenotype including congenital heart disease, growth faltering, sideroblastic anemia, and hypogammaglobulinemia, however both children are showing signs of spontaneous clinical resolution. Additionally, both younger children have a deletion of the entire coding sequence of NDUFA12, which may be contributing to the more severe presentation. The mother is reportedly asymptomatic. In summary, we present the first known instance of transgenerational transmission of the pathogenic ATP5F1A c.620G>A (p.Arg207His) variant. The presence of congenital heart disease, sideroblastic anemia, and hypogammaglobulinemia in two cases may indicate a phenotypic expansion of MC5DN4A or may suggest a modifying effect of the NDUFA12 deletion on the phenotype.

Keywords:  ATP5F1A; Congenital heart disease; Hypogammaglobulinemia; Mitochondria; Sideroblastic anemia

DOI:  https://doi.org/10.1016/j.ymgme.2026.110207