bims-polgdi 2026-03-01 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2026–03–01
thirty papers selected by
Luca Bolliger, lxBio

Linking mitochondrial DNA release to neurodegeneration and cognitive decline.
The endoplasmic reticulum in mitochondrial protein targeting: A neuronal perspective on organelle crosstalk.
Transcriptomic analysis of cells following decreased mitochondrial DNA-copy number reveals compensatory mechanisms in mitochondrial DNA replication and cellular energetics.
Mesenchymal Stromal Cells and Extracellular Vesicles: A Novel Therapeutic Paradigm for Mitochondrial Dysfunctions.
Mitochondrial abnormalities in idiopathic inflammatory myopathies.
Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.
Nutrient and endocrine factors affecting impaired growth in pediatric mitochondrial diseases.
From system building to global engagement: Current significance of and future directions for rare disease research in China.
TFAM-Mediated mtDNA Replication is Essential for Developmental Competence of In Vitro Grown Oocytes.
Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.
Mitochondrial Quality Control in Macrophages during Cardiovascular Disease.
Mainstreaming genomic testing for mitochondrial disease in Australia.
4,5-dihydroxyhexanoic acid is a robust circulating and urine marker of mitochondrial disease and its severity.
The imperative for national legislation on rare diseases in China: A policy review and call to action.
Profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis.
RareArena: a comprehensive benchmark dataset unveiling the potential of large language models in rare disease diagnosis.
Generative AI Accelerates Genotype-Phenotype Characterization of a 1600-Case Leigh Syndrome Virtual Cohort from Published Literature.
Mitochondrial genome editing tools: prospects in animal breeding.
TikTok as a Platform for Patient Education and Health Information in Rare Genetic Diseases: Cross-Sectional Study.
Modeling mitochondrial inheritance enables high-precision single-cell lineage tracing in humans.
Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
Dose-finding and optimization in drug development for rare diseases.
Myoclonus in Pediatric Metabolic Diseases: Clinical Spectrum, Mechanisms, and Treatable Causes-A Systematic Review.
Mitochondrial function-related genes and ionizing radiation-induced intestinal injury: mechanisms and research progress.
DNA methylation as a biomarker of prenatal exposures: current challenges and opportunities.
Mitochondrial insertions/deletions (INDELs) burden in Parkinson's disease: an analysis from a Brazilian cohort.
Mitochondrial dysfunction and disrupted neuronal lipid homeostasis in Parkinson's disease: Potential mechanisms and therapeutic implications.
Regulation of Mitochondrial Biogenesis in Diabetic Retinopathy.
MitoEM 2.0: A Benchmark for Challenging 3D Mitochondria Instance Segmentation from EM Images.
Nature-Inspired Surface Modification Strategy Reverses the Autophagic Flux Impairment of Mitochondrial Transplantation for Attenuating Ischemic Strokes.

Ageing Res Rev. 2026 Feb 21. pii: S1568-1637(26)00054-1. [Epub ahead of print]117 103062

Linking mitochondrial DNA release to neurodegeneration and cognitive decline.

Zongwei Fang, Catarina Barbosa, Daniela Marinho, Rita Peixoto, Ildete Luísa Ferreira, João Laranjinha, A Cristina Rego.

  Mitochondrial DNA (mtDNA) has been recognized as a key link between mitochondrial dysfunction and neuroinflammation in neurodegenerative diseases. Beyond being a vulnerable target of oxidative damage, mtDNA can act as a damage-associated molecular pattern when released from mitochondria, triggering innate immune signaling pathways in the nervous system. This review synthesizes current evidence on the mechanisms regulating mtDNA escape from mitochondria into the cytosol and its subsequent intracellular and extracellular effects, reframing mtDNA as an active driver of inflammatory processes rather than a passive by-product of mitochondrial injury. We discuss how defects in mitochondrial quality control, particularly impaired mitophagy and macroautophagy, promote the accumulation of damaged mtDNA, including its release via mitochondria-derived vesicles, exosomes or as cell-free mtDNA. By integrating mitochondrial dysfunction, immune activation, and clearance pathways, this review highlights the mitochondria-immune axis as a central contributor to neurodegeneration and cognitive decline, identifying upstream molecular targets with potential for therapeutic intervention.

Keywords:  Damage-associated molecular patterns (DAMPs); Inflammation; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Neurodegenerative diseases; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.arr.2026.103062
Protein Sci. 2026 Mar;35(3): e70506

The endoplasmic reticulum in mitochondrial protein targeting: A neuronal perspective on organelle crosstalk.

J Tabitha Hees, Angelika B Harbauer.

  Neurons depend on tightly regulated spatial proteostasis to maintain function across their extended morphology. The endoplasmic reticulum (ER), traditionally known for its function in protein synthesis, folding, and trafficking, has long been recognized as a central platform for directing proteins to organelles of the secretory and endocytic pathways. In contrast, its involvement in the targeting of mitochondrial proteins, which are not directly connected to classical trafficking routes, remains less well understood and has only recently gained attention. Growing evidence implicates the ER in post-translational delivery of mitochondrial precursors through mechanisms that integrate local translation, chaperone activity, and dynamic organelle contact sites. ER-mitochondria contacts form dynamic platforms for precursor translation, stabilization and transfer, as exemplified by pathways such as ER-SURF. Endolysosomes add an additional layer of regulation by influencing both ER function and mitochondrial proteostasis. However, how these processes are mechanistically coordinated, particularly in neurons with their complex architecture, remains incompletely understood. In this review, we synthesize the current understanding on ER-mediated mitochondrial protein targeting, highlight the role of membrane contact sites between ER, mitochondria and endolysosomes, and discuss how chaperone networks and signaling pathways shape mitochondrial precursor handling. We further explore how disruption of these systems might contribute to neurodegeneration, positioning organelle crosstalk as a critical determinant of mitochondrial proteostasis and neuronal health.

Keywords:  ER‐SURF; endoplasmic reticulum; mitochondrial protein targeting; neurodegeneration; organelle crosstalk

DOI:  https://doi.org/10.1002/pro.70506
Exp Cell Res. 2026 Feb 25. pii: S0014-4827(26)00068-6. [Epub ahead of print] 114951

Transcriptomic analysis of cells following decreased mitochondrial DNA-copy number reveals compensatory mechanisms in mitochondrial DNA replication and cellular energetics.

Jiaqi Xie, Phyo W Win, Charles Newcomb, Shaopeng Zeng, Christina A Castellani, Dan E Arking.

  Mitochondrial DNA copy number (mtDNA-CN) is a metric of mitochondrial function that has been associated with a variety of diseases including cardiovascular disease and all-cause mortality. To investigate genes and pathways affected by mtDNA-CN variation, we perturbed HEK 293T cells with ethidium bromide to deplete mtDNA. Using RNASeq and methylation microarrays, we evaluated transcriptomic and methylomic changes in treated cell lines. We observed an 8-fold decrease in mtDNA-CN and compensatory shifts in mitochondrial transcription to support mtDNA replication. Nuclear transcriptomic and methylomic analysis highlighted changes in metabolic pathways, including oxidative phosphorylation and canonical glycolysis. Longitudinal analyses revealed that the identified genes and pathways have different response timing, with nuclear response lagging behind mitochondrial response. These findings further elucidate the mechanisms behind mtDNA maintenance and responses to cellular energetics as well as mitochondrial-nuclear crosstalk dynamics.

Keywords:  Transcriptome; glycolysis; methylome; mito-nuclear crosstalk; mtDNA replication; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.yexcr.2026.114951
Int J Mol Sci. 2026 Feb 19. pii: 1981. [Epub ahead of print]27(4):

Mesenchymal Stromal Cells and Extracellular Vesicles: A Novel Therapeutic Paradigm for Mitochondrial Dysfunctions.

Eman Salem Algariri, Fazlina Nordin, Min Hwei Ng, Izyan Mohd Idris, Norwahidah Abdul Karim, Gee Jun Tye, Wan Safwani Wan Kamarul Zaman.

  Mitochondrial dysfunction is a central pathological feature of a wide range of inherited and acquired disorders and is characterized by impaired oxidative phosphorylation, disrupted cellular energy metabolism, and excessive oxidative stress. Although advances in molecular diagnostics have improved disease recognition, effective disease-modifying therapies remain limited, and clinical outcomes are often suboptimal, highlighting the need for novel therapeutic strategies. Mesenchymal stromal cells (MSCs) and their extracellular vesicles (MSC-EVs) have emerged as promising candidates for targeting mitochondrial dysfunction due to their regenerative, immunomodulatory, and metabolic regulatory properties. In this review, we provide a comprehensive overview of recent in vitro and in vivo studies investigating the capacity of MSCs and MSC-EVs to restore mitochondrial function by enhancing mitochondrial respiration, improving cellular bioenergetics, and reducing oxidative stress across diverse disease models. We further discuss the underlying mechanisms involved, including mitochondrial transfer, delivery of functional mitochondrial components, and modulation of the cellular microenvironment. Finally, we highlight the key advantages, translational potential, and remaining challenges associated with MSC- and MSC-EV-based therapies for mitochondrial dysfunction.

Keywords:  MSC-EVs; MSC-base therapy; exosomes; mitochondrial diseases; mitochondrial transfer; oxidative phosphorylation

DOI:  https://doi.org/10.3390/ijms27041981
Clin Exp Rheumatol. 2026 Feb;44(2): 384-389

Mitochondrial abnormalities in idiopathic inflammatory myopathies.

Francesca Torri, Giulia Ricci, Michelangelo Mancuso, Gabriele Siciliano.

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of acquired muscle disorders characterised by immune-mediated muscle damage and systemic involvement. Increasing evidence highlights mitochondrial abnormalities as a key contributor to muscle weakness, inflammation, and disease progression. This review aims to summarise current knowledge on the mechanisms, histopathological features, and clinical implications of mitochondrial dysfunction in IIMs, as well as to discuss emerging therapeutic strategies targeting mitochondrial impairment.
METHODS: A narrative review of the literature was conducted using PubMed, with no temporal restrictions. Only English-language articles were included. Search terms comprised "inflammatory myopathies," "mitochondrial abnormalities," and "mitochondrial antibodies AND inflammatory myopathies." Studies addressing mitochondrial structure and function, histopathological findings, autoantibodies targeting mitochondrial components, and therapeutic approaches in IIMs were selected and analysed.
RESULTS: Mitochondrial dysfunction in IIMs involves impaired oxidative phosphorylation, increased oxidative stress, disrupted calcium homeostasis, defective mitophagy, and mitochondrial DNA damage. Histopathological findings include cytochrome c oxidase-negative fibres, ragged red fibres, abnormal mitochondrial morphology, and altered mitochondrial distribution, particularly prominent in inclusion body myositis. Inflammatory mechanisms further exacerbate mitochondrial injury through cytokine signalling, cytotoxic immune responses, and interferon-mediated pathways. Autoantibodies targeting mitochondrial components, such as anti-NDUFA11 and anti-mitochondrial antibodies, define subgroups with more severe or refractory disease. Therapeutic strategies reducing inflammation may indirectly improve mitochondrial function, while novel approaches, including interferon blockade, mitochondrial transplantation, and exercise-based interventions, show promise in restoring bioenergetics.
CONCLUSIONS: Mitochondrial dysfunction represents a central pathogenic mechanism in IIMs, tightly interwoven with immune-mediated muscle damage. Targeting both inflammatory and mitochondrial pathways may offer more effective and personalised therapeutic strategies for patients with inflammatory myopathies.

DOI: https://doi.org/10.55563/clinexprheumatol/qctyi2
Cells. 2026 Feb 20. pii: 372. [Epub ahead of print]15(4):

Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.

Sonila Alia, Gaia Pedriali, Paolo Compagnucci, Yari Valeri, Valentina Membrino, Tiziana Di Crescenzo, Elena Tremoli, Laura Mazzanti, Arianna Vignini, Paolo Pinton, Michela Casella.

  Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control-encompassing fusion-fission dynamics, PINK1/Parkin- and receptor-mediated mitophagy, biogenesis, and proteostasis-compromise mitochondrial integrity and amplify cardiomyocyte injury. Excess reactive oxygen species, mitochondrial DNA release, and calcium overload further activate cGAS-STING, NLRP3 inflammasomes, and mPTP-driven cell death pathways, perpetuating maladaptive remodeling. Therapeutic strategies targeting mitochondrial dysfunction have rapidly expanded, ranging from mitochondria-targeted antioxidants (such as MitoQ and SS-31), nutraceuticals, metabolic modulators (SGLT2 inhibitors, metformin), and mitophagy or biogenesis activators to innovative approaches including mtDNA editing, nanocarrier-based delivery, and mitochondrial transplantation. These interventions aim to restore organelle structure, improve bioenergetics, and reestablish balanced quality control networks. This review integrates recent mechanistic insights with emerging translational evidence, outlining how mitochondria function as bioenergetic and inflammatory hubs in CVD. By synthesizing established and next-generation therapeutic strategies, it highlights the potential of precision mitochondrial medicine to reshape the future management of cardiovascular disease.

Keywords:  cardiovascular disease; inflammation; mitochondrial dysfunction; mitochondrial quality control; mitochondrial signaling; mitophagy; oxidative stress

DOI:  https://doi.org/10.3390/cells15040372
Endocrinol Diabetes Metab Case Rep. 2026 Jan 01. pii: EDM250140. [Epub ahead of print]2026(1):

Nutrient and endocrine factors affecting impaired growth in pediatric mitochondrial diseases.

Hideaki Yagasaki, Hiromune Narusawa, Daisuke Watanabe, Fumikazu Sano, Kaoru Fujioka, Sonoko Mizorogi, Yoshimi Kaga, Takeshi Inukai.

   Summary: Mitochondrial diseases cause systemic failure of energy production and can manifest as various disorders of hormone production and secretion from endocrine organs. These effects can prevent normal growth in children, resulting in adults of short stature. We therefore explored the nutritional and endocrinological status of pediatric mitochondrial disease patients with impaired growth. Four Japanese patients with genetically diagnosed mitochondrial disease were studied (one male and three females, aged 4-22 years). The age of onset ranged from 0 months to 7 years, and the causal genes identified were mtDNA, PDHA1, and NARS2 (in two sibling patients). Two patients were diagnosed with small for gestational age at birth, and their current height standard deviation scores ranged from -1.9 SD to -6.4 SD. Mitochondrial diseases can present as impaired growth with dysfunction of various organs, depending on the causal gene and the degree of heteroplasmy. Our patients had demonstrated low T3 syndrome and reduced IGF1 levels, which appeared to be influenced by impaired nutritional status. These findings emphasize the need for careful monitoring of growth trajectories alongside nutritional and endocrine evaluations to improve clinical management.
Learning points: Mitochondrial diseases can disrupt endocrine function involving the GH-IGF1 axis and the thyroid and gonadal systems, leading to impaired growth during childhood. Patients with early-onset mitochondrial disease tend to experience severe symptoms and pronounced growth impairment. Children with mitochondrial diseases often show low IGF1 levels, low T3 syndrome, and delayed bone age, reflecting endocrine dysfunction commonly observed in chronic systemic diseases and the further influence of suboptimal nutritional status.

Keywords:  diabetes; impaired growth; insulin-like growth factor 1; mitochondria

DOI:  https://doi.org/10.1530/EDM-25-0140
Intractable Rare Dis Res. 2026 Feb 28. 15(1): 1-3

From system building to global engagement: Current significance of and future directions for rare disease research in China.

Wei Tang.

  Rare disease research is undergoing a gradual shift from a primary focus on single-disease mechanisms and drug development toward a more comprehensive agenda encompassing healthcare systems, policy frameworks, and patient engagement. The themed issue of Intractable & Rare Diseases Research (IRDR), entitled "Rare Diseases and Orphan Drugs in China: From System Building to Global Engagement," systematically presents China's recent efforts in building governance structures for rare diseases, strengthening clinical collaboration networks, increasing the use of real-world data, and fostering multi-stakeholder participation. Emerging within the context of a large population and pronounced regional disparities, the Chinese experience offers new analytical perspectives and practical reference points for global rare disease research. It also contributes to an ongoing paradigm shift-from isolated, single-disease breakthroughs toward the development of sustainable, system-level capacity.

Keywords:  international collaboration; policy and governance; rare diseases; real-world evidence; strengthening of the healthcare system

DOI:  https://doi.org/10.5582/irdr.2026.01015
Reprod Med Biol. 2026 Jan-Dec;25(1):25(1): e70031

TFAM-Mediated mtDNA Replication is Essential for Developmental Competence of In Vitro Grown Oocytes.

Son Quang Do, Hidetaka Tasaki, Hiroaki Funahashi, Takuya Wakai.

   Purpose: Mitochondria are essential for oocyte maturation and early embryonic development, supplying ATP and maintaining mitochondrial DNA (mtDNA) integrity. During oogenesis, mtDNA undergoes dramatic amplification, but the mechanisms and functional significance of this process remain unclear. The purpose of this study was to elucidate the role of mitochondrial transcription factor A (TFAM) in mouse oocytes using an in vitro growth (IVG) system.
Methods: Oocytes at different growth stages were analyzed for mtDNA copy number and expression of mitochondrial biogenesis genes. To assess TFAM function, siRNA targeting Tfam was microinjected into secondary follicles, which were then cultured for 12 days under IVG conditions. Following culture, oocyte growth, mtDNA content, mitochondrial membrane potential, and developmental competence after in vitro fertilization (IVF) were evaluated.
Results: mtDNA copy number increased nonlinearly during oocyte growth, with a pronounced rise at the secondary follicle stage accompanied by TFAM upregulation. TFAM knockdown reduced mtDNA copy number and mitochondrial function without affecting oocyte size or meiotic maturation, but significantly decreased blastocyst formation and total cell numbers per blastocyst.
Conclusions: TFAM-mediated mtDNA replication is crucial for mitochondrial function and developmental competence of IVG-derived oocytes, underscoring its importance in early embryonic development.

Keywords:  TFAM; in vitro growth; mitochondrial biogenesis; mtDNA; oogenesis

DOI:  https://doi.org/10.1002/rmb2.70031
Biomolecules. 2026 Feb 14. pii: 302. [Epub ahead of print]16(2):

Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.

Fanny Fontaine, Romain Pénicaud, Stéphane Allouche.

  Coenzyme Q10 (CoQ10) is an essential lipid-soluble molecule that plays a central role in mitochondrial energy production as a mobile electron carrier. In addition to its bioenergetic function, CoQ10 participates in antioxidant defense, redox homeostasis, lipid and nucleotide metabolism, and mitochondrial quality control. Primary CoQ10 deficiencies are rare inherited mitochondrial disorders caused by pathogenic variants in nuclear genes involved in CoQ10 biosynthesis. These defects lead to reduced CoQ10 levels and impaired mitochondrial functions. Clinically, primary CoQ10 deficiencies display remarkable phenotypic heterogeneity, ranging from isolated organ involvement, notably renal or cerebellar disease, to severe multisystemic disorders affecting the nervous system, skeletal muscle, heart, and other organs. Disease onset spans from the antenatal period to adulthood, and clinical severity varies widely, even among patients carrying variants in the same gene. This diversity cannot be fully explained by defective ATP production alone. Growing evidence indicates that disruption of non-bioenergetic functions of CoQ10, including oxidative stress regulation and CoQ-dependent metabolic pathways, contributes significantly to disease pathophysiology and tissue vulnerability. In this review, we summarize current knowledge on CoQ10 biology, biosynthesis, and the clinical spectrum of primary CoQ10 deficiencies, and we discuss emerging mechanisms linking CoQ10 depletion to mitochondrial dysfunctions and human diseases.

Keywords:  coenzyme Q10; metabolism; mitochondrial disorders; mitophagy; oxidative phosphorylation; oxidative stress; primary coenzyme Q10 deficiency

DOI:  https://doi.org/10.3390/biom16020302
Can J Cardiol. 2026 Feb 23. pii: S0828-282X(26)00152-2. [Epub ahead of print]

Mitochondrial Quality Control in Macrophages during Cardiovascular Disease.

Ryan C Falconer, Emily A Day.

  Macrophages are key cells of the innate immune system. Within the cardiovascular system, macrophages exhibit marked phenotypic plasticity, enabling them to sense local cues and regulate vascular inflammation, myocardial injury, and tissue remodeling. Mitochondria serve as multifunctional organelles in macrophages, integrating cellular metabolism with the production of immunogenic signals that shape inflammatory responses. In cardiovascular disease (CVD), mitochondrial dysfunction in macrophages drives maladaptive inflammatory responses that when unresolved, lead to chronic inflammation and tissue injury underlying adverse cardiovascular outcomes. To preserve mitochondrial integrity under diverse conditions, cells engage an interconnected network of mitochondrial quality control (MQC) mechanisms, namely mitochondrial biogenesis, maintenance of mitochondrial DNA (mtDNA), remodelling by fission and fusion, mitophagy, and the mitochondrial unfolded protein response. This review examines how these MQC systems govern macrophage polarization, inflammatory signalling, and survival in CVD, focusing on atherosclerosis, myocardial infarction, and heart failure. We discuss evidence demonstrating that the dysregulation of these mechanisms in macrophages, contributes to cardiovascular impairment, with particular emphasis on how dysregulated mitochondrial dynamics, heightened mitochondrial oxidative stress, and mtDNA release converge to amplify inflammation in CVD. We further highlight clinical evidence suggesting that current therapies, such as statins, SGLT2 inhibitors, and GLP-1 receptor agonists enhance macrophage MQC to alleviate stress, improve metabolic function, and dampen inflammation, which may contribute to their cardiovascular benefit. By examining the role of MQC in macrophages within the cardiovascular system, this review establishes the mechanisms governing mitochondrial homeostasis and dysfunction as a critical immunometabolic axis and potential therapeutic avenue underlying cardiovascular disease.

Keywords:  Immunometabolism; Macrophages; Mitochondria; Mitochondrial Quality Control; cGAS-STING

DOI:  https://doi.org/10.1016/j.cjca.2026.02.034
Eur J Hum Genet. 2026 Feb 26.

Mainstreaming genomic testing for mitochondrial disease in Australia.

Megan Ball, Naomi Baker, Sze Chern Lim, Sarah Casauria, Sebastian Lunke, Alison G Compton, David R Thorburn, John Christodoulou, Zornitza Stark.

Genomic sequencing has transformed the diagnostic approach for mitochondrial disease, yet integration into standard clinical practice is limited by access and funding. We conducted a post-implementation evaluation of genome sequencing (GS) for mitochondrial disease in Australia, which became publicly funded through the Medicare Benefits Scheme (MBS) in November 2023, to allow for broader access to testing. Test request data, including demographics, phenotypic information, and the diagnostic outcomes, were collected from November 2023 to May 2025 from the Victorian Clinical Genetics Services, the current laboratory provider of the MBS-funded service. Test uptake was 26% of predicted, with lower test rates in regional and remote areas. Over the first 19 months, 300 individuals suspected of mitochondrial disease underwent GS with a median turnaround time of 84 days (8 days-218 days). The diagnostic yield was 20%, with 56% of diagnoses in known mitochondrial disease genes. Of these, 70% (24 of 34) were in mitochondrial DNA. Seventeen diagnoses were in individuals who had prior non-diagnostic testing (exome sequencing or gene panel). We demonstrate that publicly-funded GS can deliver meaningful diagnostic outcomes for mitochondrial disease on a national scale. To maximise its impact, attention must now shift towards ensuring equitable access, particularly for regional and remote areas, and embedding sustainable mainstreaming models that support both genetic and non-genetic clinicians.

DOI: https://doi.org/10.1038/s41431-026-02053-6
bioRxiv. 2026 Feb 12. pii: 2026.02.10.705117. [Epub ahead of print]

4,5-dihydroxyhexanoic acid is a robust circulating and urine marker of mitochondrial disease and its severity.

Owen S Skinner, Maria Miranda, Fangcong Dong, Tessa Struhl, Melissa A Walker, Grigorij Schleifer, Matthew T Henke, Jon Clardy, Michio Hirano, Darryl C De Vivo, Eric A Schon, Kristin Engelstad, Stephanie E Siegmund, Catherine Laprise, Christine Des Rosiers, Vamsi K Mootha, Rohit Sharma.

Management of patients with mitochondrial respiratory chain diseases is challenging, in part because of our incomplete understanding of pathogenesis and a lack of biomarkers. Unknown metabolites account for >90% of detected features in modern metabolomics experiments and hold immense untapped promise for new basic and biomedical research. We recently used mass spectrometry-based metabolomics to identify and validate 19 circulating blood-based biomarkers for patients with the mitochondrial DNA (mtDNA) m.3243A>G pathogenic variant, which is the most frequent cause of the mitochondrial disorder MELAS ( m itochondrial e ncephalomyopathy, lactic a cidosis, and s troke-like episodes). However, the most significantly changing biomarker corresponded to an "unknown" metabolite. Here, we combine cheminformatics with analytical chemistry and identify that feature as 4,5-dihydroxyhexanoic acid (4,5-DHHA), a metabolite previously associated with inherited defects of gamma-aminobutyric acid (GABA) catabolism, but with no prior links to mitochondrial respiratory chain disorders. We validate this finding in an independent MELAS cohort and further show that 4,5-DHHA levels correlate with disease severity and are elevated in patients with other forms of mitochondrial disease and sepsis. Furthermore, brain 4,5-DHHA levels were elevated in two genetic mouse models of mitochondrial disease. In vitro and tissue culture experiments indicate that 4,5-DHHA is generated when the GABA catabolite succinic semialdehyde reacts with an intermediate of the pyruvate dehydrogenase reaction and is sensitive to mitochondrial complex I function. Our work identifies 4,5-DHHA as a robust plasma and urine marker of mitochondrial dysfunction in humans and reveals new connections between the respiratory chain and GABA metabolism.
Significance Statement: Inborn errors of the mitochondrial respiratory chain cause severe, progressive diseases, yet effective treatments and biomarkers remain limited. Modern metabolomics detects thousands of molecules in biofluids, but the vast majority are unidentified. In this study, we investigate the most significantly altered blood metabolite in patients with the most common mitochondrial disease - MELAS ( m itochondrial e ncephalomyopathy, lactic a cidosis, and s troke-like episodes) - and identify it as an 4,5-dihydroxyhexanoic acid (4,5-DHHA). We show that 4,5-DHHA is reproducibly elevated and correlates with severity. Levels are increased across multiple mitochondrial disorders as well as in sepsis and rise when respiratory chain function is impaired. These findings establish 4,5-DHHA as a promising biomarker of mitochondrial dysfunction and reveal a link to dysregulated GABA metabolism.

DOI: https://doi.org/10.64898/2026.02.10.705117
Intractable Rare Dis Res. 2026 Feb 28. 15(1): 4-10

The imperative for national legislation on rare diseases in China: A policy review and call to action.

Yangyang Li, Zheng Liu, Rufang Huang, Yugang Liu.

  Rare diseases represent a significant public health challenge in China, affecting an estimated 20 million individuals. Despite incremental policy improvements over the past decade, including the publication of two National Rare Disease Lists, an increasing number of available treatments, and the inclusion of some therapies in the Nationally Reimbursed Drug List (NRDL), patients continue to face systemic challenges in diagnosis, treatment access, and sustainable protection. That said, China has very limited rare disease research & development (R&D) and industrial development, so the market potential is far from being tapped. This policy review argues that the lack of a national legal definition for rare diseases and orphan drugs, an unsustainable payment mechanism for high-value innovative therapies, and insufficient incentives for domestic research and development have collectively hindered the creation of a sustainable rare disease ecosystem. Drawing on an analysis of patient registry data, policy documents, and proposals from China's National People's Congress (NPC) sessions, we demonstrate a growing societal consensus on the need for comprehensive national legislation on rare diseases, which is not only a moral imperative to safeguard the rights of patients but also a strategic necessity for a national population strategy and biomedical industrial development. We consider systemic rare disease legislation in China to be imperative, and now is the optimal time to promote rare disease legislation in China. We propose nine key initiatives, including establishment of a working committee on national legislation, creating a standardized definition of rare diseases and orphan drugs, creating a dedicated national rare disease fund, and robust R&D incentives.

Keywords:  China; biomedical industry; health policy; legislation; orphan drug; rare diseases

DOI:  https://doi.org/10.5582/irdr.2025.01058
J Neurol Sci. 2026 Feb 06. pii: S0022-510X(26)00079-1. [Epub ahead of print]483 125797

Profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis.

Jiongming Bai, Xinyuan Pang, Hongfen Wang, Ying Zhang, Yahui Zhu, Jiarui Zhao, Yifan Li, Mao Li, Xusheng Huang.

   BACKGROUND: Recent studies increasingly implicate mitochondrial DNA (mtDNA) alterations in neurodegenerative diseases, but findings across studies remain inconsistent. We aimed to characterize mtDNA indices across whole blood, plasma and CSF compartments and evaluate their clinical relevance.
METHODS: We enrolled two study cohorts: (1) a whole blood cohort of 102 ALS patients; and (2) a plasma and cerebrospinal fluid (CSF) cohort including 132 ALS patients and 62 non-neurodegenerative controls. The D-loop and COX3 regions were selected as representative mtDNA fragments, while B2M was used as a nuclear reference. Quantification was performed using SYBR Green-based quantitative PCR.
RESULTS: In whole blood, higher D-loop/COX3 ratios were associated with better functional status and longer survival. In the cell-free compartments, CSF ccf-mtDNA markers (D-loop and COX3) were significantly higher in ALS than in controls, whereas plasma abundance showed no significant group difference. Within ALS, higher ccf-mtDNA indices tended to correlate with greater disease severity and more rapid functional decline. In addition, higher plasma and CSF D-loop/COX3 ratios showed marginal trends toward association with faster disease progression.
CONCLUSIONS: This study systematically characterizes mtDNA alterations in whole blood, plasma and CSF samples of ALS, offering new insights into mtDNA involvement in neurodegeneration.

Keywords:  Amyotrophic lateral sclerosis (ALS); Circulating cell-free mitochondrial DNA (ccf-mtDNA); Mitochondrial dysfunction; mtDNA copy number

DOI:  https://doi.org/10.1016/j.jns.2026.125797
Lancet Digit Health. 2026 Feb 25. pii: S2589-7500(25)00135-9. [Epub ahead of print] 100953

RareArena: a comprehensive benchmark dataset unveiling the potential of large language models in rare disease diagnosis.

Haichao Chen, Zhengyun Zhao, Songchi Zhou, Shikai Hu, Jinyuan Wang, Ye Jin, Xianghong Jin, Yih Chung Tham, Xiaofei Wang, Weizhi Ma, Honghan Wu, Bin Sheng, Shuyang Zhang, Sheng Yu, Tien Yin Wong.

Rare diseases pose a substantial clinical and public health burden, with timely and accurate diagnoses remaining a formidable challenge in many countries and settings. Large language models (LLMs) have the potential to enhance the screening and diagnosis of rare diseases. However, existing evaluations of such capacities of LLMs are insufficient due to the low sample sizes, poor coverage of different rare diseases, and weak real-world clinical relevance. To address these issues, we developed an automated data collection pipeline, RareArena, to curate a comprehensive rare disease dataset from PubMed Central case reports. Two tasks were considered: rare disease screening (RDS), which involved rare disease recognition before confirmatory diagnostic tests; and rare disease confirmation (RDC), which required diagnosis with complete information. The constructed RDS task comprised 49 760 cases of 4597 rare diseases, whereas the RDC task comprised 22 901 cases of 3522 rare diseases. Human evaluations by two physicians across three dimensions-leakage, fidelity, and complexity-validated the high quality of our dataset. We systematically benchmarked ten state-of-the-art LLMs of varying sizes (GPT-4o, Llama3·1-70B, Llama3·1-8B, Qwen2·5-72B, Qwen2·5-7B, Gemma2-9B, Phi3-7B, Llama3-70B-UltraMedical, Llama3-8B-UltraMedical, and MedLlama-7B) and found that GPT-4o achieved the best performance in both the tasks (RDS: 33·1% top-1 recall, 56·9% top-5 recall; RDC: 64·2% top-1 recall, 85·9% top-5 recall). Additionally, GPT-4o performed better on genetically inherited diseases than on non-genetically inherited diseases in both the tasks, with its highest performance observed in systemic or rheumatologic diseases (RDS: 48·5% top-1 recall, 76·5% top-5 recall; RDC: 76·0% top-1 recall, 93·5% top-5 recall). To our knowledge, our dataset represents the largest rare disease diagnostic benchmark to date, featuring broad and deep disease coverage and reflecting clinically relevant scenarios. RareArena highlights the potential of LLMs in rare disease screening and diagnosis, providing a foundation for improved care for individuals with rare diseases around the world.

DOI: https://doi.org/10.1016/j.landig.2025.100953
Biology (Basel). 2026 Feb 14. pii: 334. [Epub ahead of print]15(4):

Generative AI Accelerates Genotype-Phenotype Characterization of a 1600-Case Leigh Syndrome Virtual Cohort from Published Literature.

Lishuang Shen.

  Leigh Syndrome Spectrum (LSS) is a rare and heterogeneous disease continuum with most published cohorts in small sizes that limit the statistical power. Large-scale meta-analyses with published case-level clinical data extracted from the literature are essential for robust population analysis but are hindered by the burden of manually standardizing the unstructured, heterogeneous, and sparse case-level data from the literature. We developed a novel workflow which is among the first to combine Generative AI (GenAI) with human-in-the-loop curation to overcome this barrier. This pipeline utilized Google's Gemini-2.5-pro and rapidly processed over 2300 cases from published case data tables in two weeks and achieved >90% accuracy in mapping raw clinical data to Human Phenotype Ontology (HPO) terms. This process rapidly yielded a harmonized LSS virtual cohort of 1679 data-rich cases, which is the largest LSS virtual cohort reported so far, and thus enables characterization of LSS phenotypic and genetic architectures, revealing that autosomal recessive (932 cases) and mitochondrial (752 cases) inheritance are the most common. The most frequently mutated genes were SURF1 (240 cases), MT-ATP6 (199), and MT-ND3 (183). HPO term consolidation identified common hallmark phenotypes, including lactic acidosis, hypotonia, bilateral basal ganglia lesions, and mitochondrial respiratory chain deficiency. The cohort's scale enabled large-scale survival analysis, revealing that defects in mitochondrial translation are associated with the poorest prognosis (84% mortality in this group) and early onset (0.23 years). Among the deceased group, patients with Complex V mutations were linked to a significantly shorter mean survival time (1.77 years) than those with Complex I (3.70 years) or IV (3.57 years) mutations. This GenAI-driven methodology establishes a scalable framework for rapidly creating analysis-ready virtual cohorts from heterogeneous literature and accelerating population-level study for rare diseases including Leigh Syndrome and other mitochondrial diseases.

Keywords:  Leigh Syndrome Spectrum (LSS); Leigh disease; generative AI (GenAI); human phenotype ontology (HPO); large language model; rare disease

DOI:  https://doi.org/10.3390/biology15040334
J Genet Genomics. 2026 Feb 25. pii: S1673-8527(26)00062-7. [Epub ahead of print]

Mitochondrial genome editing tools: prospects in animal breeding.

Xu Yan, Mingyue Chen, Shunkai Yang, Yuyang Guo, Yichao Dai, Yutong Chen, Haijiang Zhong, Taisen Ma, Dingrui Zha, Yutao He, Baiyu Li, Xinyu Jia, Long Guo, Jianhong Hu, Yinghui Wei, Xiaoxu Chen.

  Mitochondria are vital organelles responsible for driving cellular energy metabolism and regulating key biological processes. Their circular mitochondrial DNA (mtDNA) encodes 13 subunits of the respiratory chain proteins but is susceptible to mutations due to high levels of reactive oxygen species and limited repair mechanisms. Mutant phenotypes manifest only when heteroplasmy surpasses a critical threshold. Understanding the consequences of mtDNA mutations has long been hampered by the lack of precise editing tools. Recently, CRISPR-free, protein-only mitochondrial base editors have enabled C·G-to-T·A and A·T-to-G·C transitions. These breakthroughs facilitate the creation of relevant disease models and offer unique opportunities for animal breeding, as specific mtDNA variants are known to influence economically important traits in livestock, including production, reproduction, and stress tolerance. This review summarizes recent advances in mitochondrial genome editing technologies, including CRISPR/Cas-based systems, restriction endonucleases, double-stranded DNA deaminase toxin A (DddA)-based cytosine and adenine base editors, and DddA-free base editors, along with their delivery strategies and optimization avenues. Furthermore, we outline the associations between mtDNA polymorphisms, copy number variation, and economic traits in livestock and poultry. Finally, we discuss the potential applications of mitochondrial genome editing in animal breeding and highlight the critical safety and ethical considerations that require careful attention.

Keywords:  Animal breeding; Economic traits; Mitochondria; Mitochondrial gene editing; mtDNA

DOI:  https://doi.org/10.1016/j.jgg.2026.02.018
JMIR Form Res. 2026 Feb 24. 10 e79978

TikTok as a Platform for Patient Education and Health Information in Rare Genetic Diseases: Cross-Sectional Study.

Jackson Montgomery Wahman, Rhoda Mariam Hijazi, Hosam Gharib Abdelhady.

   Background: Rare genetic diseases pose significant diagnostic and therapeutic challenges, often leading to delayed diagnoses, misinformation, and patient isolation. Social media platforms have emerged as prominent spaces for health information dissemination and community building among patients with rare diseases.
Objective: This study aimed to evaluate the role of TikTok videos in patient education, community engagement, and information quality related to 5 rare genetic conditions: Ehlers-Danlos syndrome, Marfan syndrome, cystic fibrosis, Wilson disease, and Gaucher disease.
Methods: A cross-sectional analysis was conducted on 184 TikTok videos identified via disease-specific hashtags. Included videos were 15 seconds to 4 minutes long and directly discussed the target diseases. Advertisements, promotional content, and product marketing were excluded. Videos were categorized by creator type: physicians, medical professionals, patients, influencers, nonprofit organizations, and others. Content quality was assessed using the Global Quality Scale (GQS) and a modified DISCERN tool (mDISCERN). Engagement metrics (views, likes, and shares) were recorded. Kruskal-Wallis and chi-square tests evaluated differences across creator categories.
Results: Of the 184 TikTok videos, 88 (47.8%) were created by patients or family members; 31 (16.8%) by influencers, 24 (13.0%) by physicians, 17 (9.2%) by nonprofit organizations, 15 (8.2%) by general users, and 9 (4.9%) by others. Collectively, the videos amassed more than 123 million views. Influencer-generated content accounted for the highest cumulative view count, totaling approximately 60.9 million views. Content produced by medical professionals and physicians demonstrated higher information quality, with mean GQS scores of 3.89 (SD 0.66) and 3.62 (SD 0.71) and mDISCERN scores of 3.11 (SD 0.58) and 3.21 (SD 0.65), respectively. In contrast, videos by influencers and patients exhibited lower quality scores (influencers: GQS mean 1.48, SD 0.60; mDISCERN mean 1.42, SD 0.55; patients: GQS mean 1.57, SD 0.58; mDISCERN mean 1.38, SD 0.52). For Ehlers-Danlos syndrome (n=40 videos, 21.7%), Wilson disease (n=40 videos, 21.7%), and cystic fibrosis (n=34 videos, 18.5%), significant differences in quality scores among creator types were observed (P<.001, P<.001, and P≤.04, respectively). For Marfan syndrome (n=40 videos, 21.7%) and Gaucher disease (n=30 videos, 16.3%), no significant differences were observed (P=.43 and P=.07, respectively). Chi-square analysis indicated no association between creator type and inclusion of peer-reviewed references (χ25=10.6; P=.07). Overall, only 7 (3.8%) videos cited scientific literature.
Conclusions: TikTok serves as a key platform for rare disease awareness and community engagement, although the quality and accuracy of health information vary widely. Although medical professionals produced higher-quality content, it tended to receive less visibility. Increasing the presence of health care professionals and improving visibility of evidence-based content could enhance patient education and safer health information sharing.

Keywords:  Ehlers-Danlos syndrome; Gaucher disease; Marfan syndrome; TikTok; cystic fibrosis; health misinformation; patient education; rare diseases; social media

DOI:  https://doi.org/10.2196/79978
bioRxiv. 2026 Feb 18. pii: 2026.02.12.705660. [Epub ahead of print]

Modeling mitochondrial inheritance enables high-precision single-cell lineage tracing in humans.

Teng Gao, Chen Weng, Isaac Johnson, Michael Poeschla, Jonas Gudera, Emily King, Christopher Rouya, Adriana Donovan, Lauren Bourke, Ying Shao, Eladio Marquez, Rahul Tyagi, Leonard I Zon, Jonathan S Weissman, Vijay G Sankaran.

Somatic mutations in mitochondrial DNA (mtDNA) provide natural barcodes that enable engineering-free lineage tracing in human tissues, but the complex dynamics of mtDNA inheritance across cell divisions and incomplete sampling of mtDNA introduce uncertainty in reconstructed lineages. Here, we present MitoDrift, a probabilistic framework that integrates Wright-Fisher drift dynamics with sparse single-cell measurements to produce confidence-refined lineage trees enriched for accurate clonal relationships. Validation with gold-standard lentiviral barcoding and whole-genome sequencing demonstrates that MitoDrift outperforms existing tree reconstruction methods in precision while maintaining high clonal recovery, enabling robust analyses linking lineage to cell state. Applying MitoDrift to human hematopoiesis reveals an age-associated decline in clonal diversity with differential impact across cell types and identifies heritable regulatory programs in hematopoietic stem cells in vivo, linking AP-1/stress-associated programs to clonal expansions. In multiple myeloma, MitoDrift captures therapy-associated clonal remodeling undetectable by copy number analysis, revealing phenotypic transitions and linking gene regulatory programs to differential drug sensitivity. Collectively, MitoDrift enables high-precision lineage tracing at scale and establishes quantitative lineage-state analysis in primary human tissues, linking clonal history to transcriptional and epigenetic programs in tissue homeostasis, aging, and disease.

DOI: https://doi.org/10.64898/2026.02.12.705660
Nat Struct Mol Biol. 2026 Feb 27.

Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.

Lara Kroczek, Hendrik Nolte, Yvonne Lasarzewski, Ishita Agrawal, Thibaut Molinié, Daniel Curbelo Piñero, Kathrin Lemke, Elena Rugarli, Thomas Langer.

Mitochondria dynamically adapt to cellular stress to ensure cell survival. The stress-regulated mitochondrial peptidase OMA1 orchestrates these adaptive responses, which limit mitochondrial fusion and promote mitochondrial stress signaling and metabolic rewiring. Here, we show that cellular stress adaptation involves OMA1-mediated regulation of mitochondrial protein import and OXPHOS biogenesis. OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response. Our results demonstrate stress-dependent changes in mitochondrial protein import as part of the OMA1-mediated mitochondrial stress response and highlight the interdependence of proteostasis regulation between different organelles.

DOI: https://doi.org/10.1038/s41594-026-01756-0
Nat Rev Drug Discov. 2026 Feb 26.

Dose-finding and optimization in drug development for rare diseases.

Robert N Schuck, Ruo-Jing Li, Mia Williams, Valerie J Parker, Michael Pacanowski.

DOI: https://doi.org/10.1038/d41573-026-00035-3
Metabolites. 2026 Jan 28. pii: 98. [Epub ahead of print]16(2):

Myoclonus in Pediatric Metabolic Diseases: Clinical Spectrum, Mechanisms, and Treatable Causes-A Systematic Review.

Elżbieta Majewska, Zofia Zdort, Aleksandra Ochocka, Justyna Paprocka.

  Background: Myoclonus, a sudden brief shock-like involuntary movement, represents a common yet under-recognized manifestation across many inherited metabolic disorders. Although its occurrence has been reported in case series and small cohorts, the overall spectrum, pathophysiological mechanisms, and therapeutic relevance of metabolic myoclonus have not been systematically summarized. Methods: A systematic search of PubMed was conducted for English-language publications from 2014 to 2025 using predefined MeSH terms related to myoclonus, movement disorders, and inborn errors of metabolism. Titles and abstracts were screened independently by three reviewers. After removal of duplicates, 27 articles were included, complemented by 65 additional references addressing individual disorders. Data were organized according to the International Classification of Inherited Metabolic Disorders (ICIMD). Results: Myoclonus was documented across six ICIMD categories, including intermediary metabolism, mitochondrial energy metabolism, lipid metabolism, disorders of complex molecules and organelles, cofactor and mineral metabolism, and metabolic cell signaling disorders. Clinical presentation ranged from isolated jerks to progressive myoclonic epilepsies. Several conditions-such as GLUT1 deficiency, cerebrotendinous xanthomatosis, and folate receptor α deficiency-are treatable through dietary or pharmacological interventions. Conclusions: Recognition of myoclonus as a presenting feature of inherited errors of metabolism (IEMs) is critical for timely diagnosis and treatment. Metabolic screening should be considered in all unexplained cases of myoclonus, particularly when accompanied by developmental delay or systemic abnormalities.

Keywords:  inherited metabolic disorders; movement disorders; myoclonic seizures; myoclonus; treatable neurometabolic disease

DOI:  https://doi.org/10.3390/metabo16020098
Int J Radiat Biol. 2026 Feb 25. 1-12

Mitochondrial function-related genes and ionizing radiation-induced intestinal injury: mechanisms and research progress.

Zhongwei Zhang, Jun Liu, Qing-Jie Liu.

   PURPOSE: Ionizing radiation-induced intestinal injury (RIII) is a significant complication of radiotherapy and nuclear radiation incidents. Mitochondria, the centers of energy metabolism and apoptosis, are pivotal in the pathogenesis of RIII. Under irradiation conditions, multiple mitochondrial function-related genes modulate the production of reactive oxygen species and ATP, maintain mitochondrial DNA, induce mitophagy, and activate the apoptotic pathway associated with mitochondrial dysfunction, leading to intestinal tissue injury. Mitochondrial function-related genes are pivotal in maintaining the normal function of mitochondria and moderate RIII. This review summarizes the mechanisms of mitochondrial function-related genes in RIII and potential therapeutic strategies, aiming to provide references for further research on RIII and clinical prevention and treatment.
CONCLUSION: Mitochondrial dysfunction driven by the dysregulation of genes related to mitochondrial function (nuclear genes and mitochondrial genome) is a key mechanism of RIII pathogenesis. At present, research on pivotal regulators remains limited, necessitating deeper investigation with multi-omics approaches. Precisely targeting these mitochondrial function-related genes offers a promising therapeutic strategy for reducing mitochondrial damage and treating RIII.

Keywords:  Radiation-induced intestinal injury; apoptosis; electron transport chain; mitochondrial function-related genes; oxidative stress

DOI:  https://doi.org/10.1080/09553002.2026.2630995
Environ Epigenet. 2026 ;12(1): dvag006

DNA methylation as a biomarker of prenatal exposures: current challenges and opportunities.

Rachel B Walkup, Matthew A Nangle, Phillip E Bergmann, Robert J Lipinski.

  The prenatal environment contributes to the risk for congenital conditions, including birth defects, developmental disorders, and diseases that manifest in later life. However, our current understanding of prenatal exposures and their impact on disease risk is extremely limited. DNA methylation (DNAm) is a promising biomarker of prenatal exposures because this epigenetic mechanism is developmentally active, environmentally responsive, and imparts chemically stable marks that can be quantified with increasing accuracy and precision. However, development and utilization of DNAm biomarkers are impeded by inadequate understanding of how environmentally responsive prenatal DNAm changes persist across progenitor cell populations and pre- and postnatal development. This review synthesizes current evidence on the impact of the prenatal environment on DNAm, including specific dietary and chemical influences, and persistence of these changes across life stages. We then evaluate the suitability of common surrogate tissues (blood, saliva, and extra-embryonic tissues) from a developmental cell lineage framework for their applicability in prenatal exposure research and outline key considerations in selecting surrogate tissues for epigenome-wide association studies. Finally, using orofacial cleft etiopathogenesis as a model, we illustrate the conceptual application of DNAm biomarkers and highlight the need for longitudinal studies and comparative analysis of target and surrogate tissues. By identifying key knowledge gaps and proposing actionable strategies to address them, this review is directed at advancing the use of DNAm biomarkers in resolving how prenatal exposures contribute to human disease.

Keywords:  DNA methylation; biomarkers; developmental origins of health and disease; prenatal exposome; surrogate tissues

DOI:  https://doi.org/10.1093/eep/dvag006
Parkinsonism Relat Disord. 2026 Feb 20. pii: S1353-8020(26)00076-3. [Epub ahead of print]145 108250

Mitochondrial insertions/deletions (INDELs) burden in Parkinson's disease: an analysis from a Brazilian cohort.

Gustavo Barra-Matos, Felipe Gouvea de Souza, Caio Santos Silva, Matheus Epifane-de-Assunção, Marcella Vitória Belém Souza, Letícia Cota Cavaleiro de Macêdo, Tatiane Piedade de Souza, Dafne Dalledone Moura, Giovanna C Cavalcante, Ândrea Ribeiro-Dos-Santos, Bruno Lopes Santos-Lobato, Gilderlanio Santana de Araújo.

   INTRODUCTION: Mitochondrial DNA (mtDNA) alterations are increasingly associated with Parkinson's disease (PD), particularly due to their role in oxidative stress. However, the contribution of mtDNA insertions and deletions (INDELs) to PD remains poorly understood, particularly in genetically admixed populations such as Brazilians.
METHODS: To explore this, we sequenced the complete mtDNA from blood samples of 179 admixed individuals from the Brazilian Amazon (104 people with PD and 75 controls). Data processing included FastQC, MultiQC, FastP, BWA, and mtDNA-Server 2.
RESULTS: We identified a significantly higher burden of mtDNA INDELs in PD compared with controls in Complex I genes (OR = 9.23; 95% CI: 2.22-63.55; FDR = 0.044). Differences in heteroplasmy levels were also observed in the ATP6, ND4, and ND5 genes. Importantly, we discovered seven new PD-associated INDELs (m.13763_13763delinsCCA, m.13885_13885delinsCTG, m.13888_13890delinsT, m.13767_13769delinsC, m.13810_13812delinsG, m.13813_13813delinsGCA, and m.13764_13764delinsCAT) that are particularly more frequent among individuals harboring uniparental lineages of Native American origin.
CONCLUSION: Our findings report novel mtDNA INDELs, particularly in Complex I, which may contribute to PD susceptibility and highlight the importance of investigating mitochondrial genomic variation in underrepresented populations. These associations should be interpreted as preliminary, and further longitudinal studies with independent cohorts are required to confirm these observations.

Keywords:  Admixed populations; INDELs; Mitogenome; Parkinson's disease; Underrepresented populations

DOI:  https://doi.org/10.1016/j.parkreldis.2026.108250
Exp Neurol. 2026 Feb 25. pii: S0014-4886(26)00066-X. [Epub ahead of print] 115703

Mitochondrial dysfunction and disrupted neuronal lipid homeostasis in Parkinson's disease: Potential mechanisms and therapeutic implications.

Zehao Quan, Chun-Yuan Ku, Tian Xie, Ho Tin Fok, Daniel Schweitzer, Isaac Akefe.

   BACKGROUND: Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterised by dopaminergic neuron loss and pathological accumulation of alpha-synuclein. Emerging evidence highlights a crucial interplay between mitochondrial dysfunction and disrupted lipid homeostasis as central mechanisms driving PD pathogenesis.
OBJECTIVE: This scoping review synthesises current evidence on the relationship between mitochondrial dysfunction and neuronal lipid dysregulation in PD and identifies potential therapeutic targets within these intersecting pathways.
METHODS: Following the PRISMA-ScR guidelines, a comprehensive literature search was conducted across PubMed, Embase, and Web of Science for studies published between 2015 and 2025. Two independent reviewers screened and selected eligible studies based on predefined inclusion criteria.
RESULTS: Analysis revealed four central interconnected pathological mechanisms: ferroptosis, alpha-synuclein-lipid interactions, mitochondrial dysfunction, and impaired autophagy/mitophagy. These mechanisms collectively contribute to oxidative stress, membrane destabilisation, and bioenergetic collapse, driving dopaminergic neuronal vulnerability.
CONCLUSIONS: The findings underscore a complex, bidirectional relationship between mitochondrial dysfunction and lipid dysregulation in PD. Therapeutic strategies targeting iron accumulation, lipid peroxidation, and alpha-synuclein aggregation are promising. However, further mechanistic studies are required to clarify these interactions and advance the development of effective disease-modifying interventions.

Keywords:  Alpha-Synuclein; Cholesterol; Lipid homeostasis; Mitochondrial dysfunction; Neurodegeneration; Parkinson's disease

DOI:  https://doi.org/10.1016/j.expneurol.2026.115703
Cells. 2026 Feb 17. pii: 357. [Epub ahead of print]15(4):

Regulation of Mitochondrial Biogenesis in Diabetic Retinopathy.

Jay Kumar, Renu A Kowluru.

  Mitochondrial dysfunction plays a major role in diabetic retinopathy development and in its resistance to halt after the reversal of hyperglycemia (metabolic memory). Diabetes also upregulates many long noncoding RNAs, RNAs with >200 nucleotides with no reading frame, and several of them resist reversal after hyperglycemia cessation. Our aim was to investigate the role of LncRNA HOTAIR, a master regulator of chromatin dynamics, in mitochondrial biogenesis in diabetic retinopathy and in metabolic memory. Using retinal endothelial cells and Müller cells, incubated in high glucose (20 mM D-glucose), the effect of HOTAIR-siRNA on mitochondrial biogenesis was investigated by quantifying mitochondrial mass, copy numbers, and mtDNA replication, structure, and function. HOTAIR's role in metabolic memory was investigated by analyzing mitochondrial biogenesis in HOTAIR-siRNA transfected cells incubated in high glucose for four days, followed by normal glucose (5 mM D-glucose) for four days. HOTAIR was upregulated in both retinal vascular and nonvascular cells, and HOTAIR-siRNA ameliorated decreases in mtDNA biogenesis and protected their mitochondria from structural/functional damage. Reversal of high glucose insult failed to ameliorate HOTAIR upregulation and impaired mtDNA biogenesis in both endothelial and Müller cells, but regulation of HOTAIR during high glucose incubation, which followed normal glucose, prevented a decrease in mitochondrial mass and mtDNA copies. Thus, HOTAIR has a major role in mitochondrial biogenesis and in the continued impaired biogenesis in both vascular and nonvascular cells. Regulating HOTAIR may provide a therapeutic option to inhibit the development/progression of diabetic retinopathy.

Keywords:  Müller cells; diabetic retinopathy; long noncoding RNAs; mitochondria; mitochondrial DNA; retina

DOI:  https://doi.org/10.3390/cells15040357
bioRxiv. 2025 Dec 10. pii: 2025.11.12.687478. [Epub ahead of print]

MitoEM 2.0: A Benchmark for Challenging 3D Mitochondria Instance Segmentation from EM Images.

Peng Liu, Boyu Shen, Liyuan Liu, Qiong Wang, Shulin Zhang, Abhishek Bhardwaj, Ignacio Arganda-Carreras, Kedar Narayan, Donglai Wei.

We present MitoEM 2.0, a curated data resource for training and evaluating three-dimensional (3D) mitochondria instance segmentation in volume electron microscopy. The collection assembles multiscale vEM datasets (FIB-SEM, SBF-SEM, ssSEM) spanning diverse tissues and species, with expert-verified instance labels emphasizing biologically difficult scenarios, including dense mitochondrial packing, hyperfused networks, and thin filamentous connections with ambiguous boundaries. All releases include native-resolution volumes and standardized processed versions, per-volume metadata (voxel size, modality, tissue, splits), and official train/validation/test partitions to enable reproducible benchmarking. Annotations follow a consistent protocol with quality checks and instance reindexing. Data are provided in NIfTI with nnU-Net-compatible layout, alongside machine-readable split files and checksums. Baseline scripts support common training pipelines and size-stratified evaluation. By consolidating challenging volumes and harmonized labels, MitoEM 2.0 facilitates robust model development and fair comparison across methods while supporting reuse in bioimage analysis, algorithm benchmarking, and teaching.

DOI: https://doi.org/10.1101/2025.11.12.687478
Adv Sci (Weinh). 2026 Feb 25. e18969

Nature-Inspired Surface Modification Strategy Reverses the Autophagic Flux Impairment of Mitochondrial Transplantation for Attenuating Ischemic Strokes.

Nisha Wang, Qiyang Ding, Lei Shi, Ji Xia, Shuyue Zhang, Chenxin Jian, Yixiao Yan, Xiuhua Luo, Jiarui Wang, Ming Cheng, Yiqiong Jia, Hao Tian, Wei Gao.

  Mitochondrial transplantation has emerged as a promising therapeutic intervention for ischemic strokes (IS). Although previous studies have demonstrated the therapeutic breakthroughs of mitochondrial transplantation facilitated by advances in biotechnology, in-depth investigations into the exact mechanisms underlying its beneficial effects remain insufficient. Here, we investigate how exogenous mitochondria interact with recipient cells to optimize therapeutic protocols and improve outcomes. Emerging evidence indicates that exogenous mitochondria act as triggers of mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin pathway. However, excessive reactive oxygen species (ROS) generated during ischemia-reperfusion injury activate the receptor-interacting protein (RIP)1/RIP3 pathway, leading to the blockage of autophagic flux. Hence, we devised a novel mitochondrial transplantation platform (MLSR) that utilizes functionalized starch as a stable coating for exogenous mitochondria and enables the co-delivery of the antioxidant resveratrol through the helical structure of the starch. Following internalization by recipient neurons, the exogenous mitochondria rapidly initiate mitophagy, while resveratrol escapes from the lysosome to inhibit the ROS-RIP1/RIP3-exosome axis. Experimental results demonstrate that MLSR effectively triggers and maintains positive autophagic flux, thereby suppressing the release of undegraded autophagosomes in the form of exosomes and preventing proinflammatory crosstalk between neurons and microglia. Therefore, our findings provide important implications for renewing the therapeutic potential of mitochondrial transplantation.

Keywords:  ROS‐RIP1/RIP3‐exosome axis; autophagic flux; mitochondrial transplantation; mitophagy

DOI:  https://doi.org/10.1002/advs.202518969