bims-polgdi 2025-06-08 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–06–08
sixteen papers selected by
Luca Bolliger, lxBio

The low endoribonuclease activity and lack of rNMP preference of human mitochondrial topoisomerase 1 protect against ribonucleotide-dependent deletions.
Role of mitochondrial quality control in neurodegenerative disease progression.
Type-Specific Single-Neuron Analysis Reveals Mitochondrial DNA Maintenance Failure Affecting Atrophying Pontine Neurons Differentially in Lewy Body Dementia Syndromes.
Apoptosis-inducing factor (AIF) at the crossroad of cell survival and cell death: implications for cancer and mitochondrial diseases.
Cross-comparison of strains used for mitochondrial imaging in Caenorhabditis elegans during aging.
Engineered extracellular vesicles derived from pluripotent stem cells: a cell-free approach to regenerative medicine.
Association of mitochondrial DNA content and embryo morphology in fully expanded euploid blastocysts.
Base editors model mitochondrial disease.
Ndufs4-/- mice: a testing ground for longevity interventions.
A mitochondrial disease model is generated and corrected using engineered base editors in rat zygotes.
DJ-1 deficiency and aging: dual drivers of retinal mitochondrial dysfunction.
Functionalized exosomes for targeted therapy in cancer and regenerative medicine: genetic, chemical, and physical modifications.
Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity.
Qualitative study of fatigue in adults with primary mitochondrial disease: Development of the PROMIS Fatigue Mitochondrial Disease Short Form.
Oocyte mitochondria link maternal environment to offspring phenotype.
The rare-to-common disease journey: a winding road to new therapies.

Nucleic Acids Res. 2025 Jun 06. pii: gkaf475. [Epub ahead of print]53(11):

The low endoribonuclease activity and lack of rNMP preference of human mitochondrial topoisomerase 1 protect against ribonucleotide-dependent deletions.

Cyrielle P J Bader, Erika Miyazaki-Kasho, Josefin M E Forslund, Aiswarya Dash, Malgorzata Wessels, Paulina H Wanrooij.

The incorporation of ribonucleotides (rNMPs) into the nuclear genome leads to severe genomic instability, including strand breaks and short 2-5 bp deletions at repetitive sequences. Curiously, the detrimental effects of rNMPs are not observed for the human mitochondrial genome (mtDNA) that typically contains several rNMPs per molecule. Given that the nuclear genome instability phenotype is dependent on the activity of the nuclear topoisomerase 1 enzyme (hTOP1), and mammalian mitochondria contain a distinct topoisomerase 1 paralog (hTOP1MT), we hypothesized that the differential effects of rNMPs on the two genomes may reflect divergent properties of the two cellular topoisomerase 1 enzymes. Here, we characterized the endoribonuclease activity of hTOP1MT and found it to be less efficient than that of its nuclear counterpart, a finding that was partly explained by its weaker affinity for its DNA substrate. Moreover, while hTOP1 and yeast TOP1 were able to cleave at an rNMP located even outside of the consensus cleavage site, hTOP1MT showed no such preference for rNMPs. As a consequence, hTOP1MT was inefficient at producing the short rNMP-dependent deletions that are characteristic of TOP1-driven genome instability. These findings help explain the tolerance of rNMPs in the mitochondrial genome.

DOI: https://doi.org/10.1093/nar/gkaf475
Front Cell Neurosci. 2025 ;19 1588645

Role of mitochondrial quality control in neurodegenerative disease progression.

Tingting Liu, Weibo Sun, Shuhao Guo, Zhiying Yuan, Minghang Zhu, Jing Lu, Tao Chen, Yuanyuan Qu, Chuwen Feng, Tiansong Yang.

  Neurodegenerative diseases are a diverse group of neurological disorders, in which abnormal mitochondrial function is closely associated with their development and progression. This has generated significant research interest in the field. The proper functioning of mitochondria relies on the dynamic regulation of the mitochondrial quality control system. Key processes such as mitochondrial biogenesis, mitophagy, and mitochondrial dynamics (division/fusion) are essential for maintaining this balance. These processes collectively govern mitochondrial function and homeostasis. Therefore, the mitochondrial quality control system plays a critical role in the onset and progression of neurodegenerative diseases. This article provides a concise overview of the molecular mechanisms involved in mitochondrial biogenesis, mitophagy, and mitochondrial dynamics, explores their interactions, and summarizes current research progress in understanding the mitochondrial quality control system in the context of neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; mitochondrial quality control

DOI:  https://doi.org/10.3389/fncel.2025.1588645
Aging Cell. 2025 Jun 06. e70125

Type-Specific Single-Neuron Analysis Reveals Mitochondrial DNA Maintenance Failure Affecting Atrophying Pontine Neurons Differentially in Lewy Body Dementia Syndromes.

Eloise J Stephenson, Laura J Bailey, Stephen Gentleman, Helen Tuppen, Istvan Bodi, Claire Troakes, Christopher M Morris, Tony M Carr, Sarah Guthrie, Joanna L Elson, Ilse S Pienaar.

  The age-associated neurodegenerative disorder, Lewy body dementia (LBD), encompasses neuropsychiatric symptom-overlapping Dementia with Lewy bodies (DLB) and Parkinson's Disease with Dementia (PDD). We characterised how differential mitochondrial DNA (mtDNA) profiles contribute to neurotype-specific neurodegeneration and thereby clinicopathological heterogeneity, between LBD's syndromes. We further characterised key nuclear-encoding genes' recalibrations in response to such mtDNA changes. In post-mortem 'single-cell' acetylcholine- and noradrenaline-producing neurons, respectively of the pedunculopontine nucleus (PPN) and locus coeruleus (LC) from DLB, PDD and neurological-control brains, we quantified 'major arc'-locating mtDNA deletions (mtDels) and -copy number (mtCN), and measured mRNA levels of nuclear-encoding genes regulating mtDNA maintenance, -biogenesis and mitophagy. DLB cases' OXPHOS defect instigating mtDel burden was higher in both neurotypes than PDD. In DLB, mtCN was reduced for both neurotypes, but PDD cases revealed mtDNA depletion in LC-noradrenergic neurons only. DLB patients' shorter survival correlated with PPN-cholinergic neurons' mtDel levels, inversely with wild-type mtCN, implying that such neurons' inability to maintain sufficient wild-type mtDNA content drive DLBs' rapid psycho-cognitive manifestations. Contrastingly, PDD's longer disease duration allowed compensation against mtDels' clonal expansion in PPN-cholinergic neurons. Moreover, PDD induced mRNA depletion of a mitochondrial genome maintenance gene in PPN-cholinergic neurons, whilst LC-noradrenergic neurons displayed reduced expression of a mitophagy regulating gene. Here we identify mitochondrial genome maintenance and mitophagy pathway enrichment as therapeutic targets to offset defective mtDNA within pontine cholinergic and noradrenergic neurons of PDD patients. The pronounced LBD subtype-related mitochondria-nuclear genetic differences question the consensus that pathology converges at disease end-stage, calling for LBD subtype and neurotype-specific therapeutics.

Keywords:  Lewy body dementia; brainstem; cholinergic neurons; mitochondrial DNA; noradrenergic neurons; nuclear gene transcriptomic responses

DOI:  https://doi.org/10.1111/acel.70125
Cell Commun Signal. 2025 Jun 04. 23(1): 264

Apoptosis-inducing factor (AIF) at the crossroad of cell survival and cell death: implications for cancer and mitochondrial diseases.

Tran Ngoc Anh Nguyen, Hong-Toan Lai, Romain Fernandes, Filippo G Dall'Olio, Camille Blériot, Tap Ha-Duong, Catherine Brenner.

  Apoptosis-inducing factor (AIF), a mitochondrial NAD(P)H-dependent oxidoreductase, was initially studied as a cell death inducer in a process later named parthanatos. However, it has been revealed that AIF also participates in mitochondrial bioenergetics through interaction with its partner coiled-coil-helix-coiled-coil-helix domain containing 4 (CHCHD4) and involvement in mitochondrial protein import. These dual roles place AIF between pro-survival and pro-death cell fate decisions. In this review, we first describe the structure and the dual functions of AIF, highlighting its structure-function relationships. We then report previously identified AIFM1 mutations and their clinical phenotypes. Finally, we discuss the relevance of AIF in cancer and the potential of targeting this protein for the treatment of cancer.

Keywords:  Apoptosis-inducing factor (AIF); Cancer; Cell death; Mitochondrial diseases; Mitochondrial protein import

DOI:  https://doi.org/10.1186/s12964-025-02272-2
Life Sci Alliance. 2025 Aug;pii: e202403189. [Epub ahead of print]8(8):

Cross-comparison of strains used for mitochondrial imaging in Caenorhabditis elegans during aging.

Juri Kim, Naibedya Dutta, Matthew Vega, Andrew Bong, Maxim Averbukh, Rebecca Aviles Barahona, Athena Alcala, Jacob T Holmes, Gilberto Garcia, Ryo Higuchi-Sanabria.

Measurements of mitochondrial morphology are a powerful proxy for assessing mitochondrial health, particularly during aging when organelle dynamics are disrupted. Caenorhabditis elegans provides an ideal system for in vivo mitochondrial imaging, but widely used high-copy transgenic strains can induce artifacts that confound interpretation because of their impact on cellular and organismal health and physiology. Here, we present and validate a suite of C. elegans strains expressing single-copy, matrix-localized GFP in the muscle, intestine, and hypodermis using the MosSCI technology. These strains enable robust, tissue-specific visualization of mitochondrial morphology without the caveats associated with multi-copy reporters. We benchmark their performance against existing models and demonstrate that our mitochondrial reporters are similarly capable of assessing age-associated mitochondrial morphology, while avoiding defects in cellular and physiological health associated with the multi-copy reporters. Furthermore, we assess how aging methods, bacterial diets, and inhibition of fusion and fission machinery impact mitochondrial morphology during aging. Our findings provide a standardized and physiologically relevant platform for studying mitochondrial dynamics during aging in C. elegans.

DOI: https://doi.org/10.26508/lsa.202403189
Burns Trauma. 2025 ;13 tkaf013

Engineered extracellular vesicles derived from pluripotent stem cells: a cell-free approach to regenerative medicine.

Aline Yen Ling Wang, Huang-Kai Kao, Yen-Yu Liu, Charles Yuen Yung Loh.

  The engineered extracellular vesicles (EVs) derived from pluripotent stem cells (PSCs) are a new concept in regenerative medicine. These vesicles are secreted from the embryonic stem cells as well as the induced PSCs (iPSCs) and are involved in the transfer of bioactive molecules required for cell signaling. This review describes the possibilities for their use in the modification of therapeutic approaches in regenerative medicine and targeted therapies. PSCs can differentiate into various cell types that can be useful for tissue engineering or to generate models of diseases in a dish. Compared to cell therapies, engineered EVs are characterized by lower immunogenicity, higher targetability, and improved stability. Some of the applications are angiogenic, tissue restorative, immunomodulatory, and gene therapies for the treatment of certain diseases. iPSC-derived engineered EVs find application in regenerative medicine, drug delivery systems, diagnostics of diseases, and hydrogel systems. In regenerative medicine, they can promote the restoration of cardiac, bone, cartilage, and corneal tissues. Engineered EVs are also employed in drug targeting to particular sites as well as in the diagnosis of diseases based on biomarkers and improving image contrast. Hydrogels that contain EVs provide a depot-based delivery system to slowly release drugs in a controlled manner that enhances tissue repair. Thus, the results described above demonstrate the potential of engineered PSC-EVs for various biomedical applications. Future work will be directed toward expanding the knowledge of engineered PSC-EVs and their possibilities to create new therapeutic approaches based on the functions of these vesicles.

Keywords:  Cell-free medicine; Engineered EVs; Extracellular vesicles; Pluripotent stem cells; Regenerative medicine

DOI:  https://doi.org/10.1093/burnst/tkaf013
Hum Fertil (Camb). 2025 Dec;28(1): 2501547

Association of mitochondrial DNA content and embryo morphology in fully expanded euploid blastocysts.

Ivo Karač, Gary G Ramsey, Romana Gračan, Sanja Vujisić Živković, Kristian Bodulić.

  Over the past two decades, mitochondrial DNA (mtDNA) content has been studied as a potential biomarker for embryo viability and implantation success during in vitro fertilization (IVF) procedures. However, its reliability for embryo selection remains uncertain. Therefore, our study aimed to examine the relationship between blastocyst mtDNA content and blastocyst quality, timing of fully expanded blastocyst formation, and cleavage-stage embryo quality in blastocysts biopsied at the uniform expansion stage. We analyzed bioinformatics data from 125 day-5 and day-6 blastocysts from women aged 18 to 35 years. Each blastocyst was biopsied at expansion stage 4 and classified as euploid through preimplantation genetic testing for aneuploidy using next-generation sequencing. Blastocysts were categorized into four groups based on quality and the day of biopsy. Poor-quality day-6 blastocysts exhibited lower mtDNA levels compared to good-quality day-5 blastocysts (p = 0.006), poor-quality day-5 blastocysts (p = 0.008), and good-quality day-6 blastocysts (p = 0.003). Embryos with day-3 grades lower than 2.5 displayed lower blastocyst mtDNA levels compared to those graded 1 (p < 0.001), 1.5 (p < 0.001), and 2 (p < 0.001). These findings suggest further insights into the interplay between blastocyst mtDNA content and preimplantation embryo morphology. Nonetheless, mtDNA remains an unreliable biomarker for assessing embryo viability, warranting further investigation to determine its clinical relevance.

Keywords:  Blastocyst; euploid; mitochondrial DNA; morphology; next-generation sequencing: embryo; preimplantation diagnosis

DOI:  https://doi.org/10.1080/14647273.2025.2501547
Nat Biotechnol. 2025 Jun 03.

Base editors model mitochondrial disease.

Patrick Buchholz, Jens Boch.

DOI: https://doi.org/10.1038/s41587-025-02706-9
Geroscience. 2025 Jun 05.

Ndufs4-/- mice: a testing ground for longevity interventions.

Jackson Nuss, Matt Kaeberlein, Alessandro Bitto, Anthony S Grillo.

  Mice missing the complex I subunit Ndufs4 of the electron transport chain are widely used as a leading animal model of Leigh syndrome, a pediatric neurodegenerative disorder that leads to premature death. More broadly, this animal model has enabled a better understanding of the pathophysiology of mitochondrial disease and mitochondrial dysfunction in sporadic disorders. Intriguingly, longevity interventions are very effective at treating symptoms of disease in this model. Herein, we introduce the model and its notable features that may help provide insights in longevity research. We performed a retrospective analysis of historical data from our laboratories over the past 10 years regarding the use of this animal model in aging studies, the manifestation and progression of mitochondrial disease, and factors that influence their premature death. We observed a correlation between weight and lifespan in female animals and a sex-independent correlation between the onset of clasping, a typical neurodegenerative symptom, and overall survival. We observed a sexual dimorphism in lifespan with female mice being more resilient despite a similar age of onset of disease symptoms. Lastly, we report increased lifespan and delayed onset of disease symptoms following treatment with 17-alpha-estradiol, a non-feminizing estrogen which can extend lifespan in genetically heterogeneous mice. This analysis serves as a useful guide for researchers utilizing this animal in the discovery of effective interventions for longevity and to prevent the onset of disease. It suggests there may be unprecedented underlying sex-specific differences in patients with Leigh syndrome and further strengthens the connection between normative aging and mitochondrial dysfunction.

Keywords:  Interventions; Longevity; Mitochondrial dysfunction; Vertebrate models

DOI:  https://doi.org/10.1007/s11357-025-01704-8
Nat Biotechnol. 2025 Jun 03.

A mitochondrial disease model is generated and corrected using engineered base editors in rat zygotes.

Liang Chen, Changming Luan, Mengjia Hong, Meng Yuan, Hao Huang, Debo Gao, Xinyuan Guo, Zhengxin Chen, Yongmei Li, Lei Yang, Zongyi Yi, Wensheng Wei, Mingyao Liu, Liangcai Gao, Honghui Han, Dali Li.

Efficient generation and correction of mutations in mitochondrial DNA (mtDNA) is challenging. Here, through embryonic injection of an mtDNA adenine base editor (eTd-mtABE), Leigh syndrome rat models were generated efficiently (up to 74%) in the F0 generation, exhibiting severe defects. To correct this mutation, a precise mtDNA C-to-T base editor was engineered and injected into mutated embryos. It achieved restoration of wild-type alleles to an average of 53%, leading to amelioration of disease symptoms.

DOI: https://doi.org/10.1038/s41587-025-02684-y
bioRxiv. 2025 May 21. pii: 2025.05.19.654941. [Epub ahead of print]

DJ-1 deficiency and aging: dual drivers of retinal mitochondrial dysfunction.

Mala Upadhyay, Johnathon Sturgis, Sanghamitra Bhattacharyya, Ke Jiang, Stephanie A Hagstrom, Vera L Bonilha.

We have previously extensively characterized the role of DJ-1 in oxidative stress regulation in the retina and RPE during aging. However, the DJ-1 protein also plays a role in regulating mitochondria's response to oxidative stress by translocating to the mitochondria where it helps clear generated reactive oxygen species (ROS). To study the effects of aging and oxidative stress in the retina, the DJ-1 KO mouse was analyzed. Freshly dissected ex vivo retinal punches were analyzed for real-time live cell metabolism. Total DNA and protein were isolated from RPE, and retina of 3- and 15-month-old DJ-1 WT and DJ-1 KO mice. The mitochondrial DNA (mtDNA) genome was divided into four discrete regions (RI-RIV), and lesions/10kb were quantified using long-extension PCR. mtDNA content was analyzed using RT-qPCR. Protein levels of OXPHOS complexes, POLG, OGG1, SOD2, and PGC1α were measured by western blotting. Seahorse analysis detected significantly decreased basal and maximal OCR in 3- and 15-month-old DJ-1 KO compared to age-matched DJ-1 WT. In the RPE, a significant decrease in the protein levels of the NDUFB8 subunit of CI, the SDHB subunit of CII, and MTCO1 of CIV in 15-month-old DJ-1 KO mice compared to 15-month-old DJ-1 WT, while the ATP5A subunit of CV was significantly decreased in 3-month-old DJ-1 KO mice compared to 3-month-old DJ-1 WT. In the retina, significantly decreased levels of NDUFB8 subunit of CI and MTCO1 of CIV were detected in the in 3-month-old DJ-1 KO mice compared to 3-month-old DJ-1 WT. We observed a significant increase in mtDNA gene content in 15-month-old DJ-1 KO RPE and retina compared to age-matched DJ-1 WT. The PGC1α levels significantly decreased in 3- and 15-month-old RPE lysates compared to their age group DJ-1 WT. However, in the retina, there was only a decrease in DJ-1 WT with aging. The POLG levels increased when 15-month-old DJ-1 KO lysates were compared to 15-month-old DJ-1 WT. The mtDNA lesions in the RPE detected a trend of increase in 15-month-old DJ-1 WT and DJ-1 KO RPE in all regions compared to 3-month-old mice. In the retina, a significant increase in mtDNA lesions/10kb accumulation in the 15-month-old DJ-1 WT RIV was detected compared to 3-month-old DJ-1 WT. The OGG1 levels significantly increased in 3-month-old retinal lysates compared to the 3-month-old DJ-1 WT. Our findings suggest that DJ-1 is critical for mitochondrial regulation and function in RPE and retina. The observed changes reflect mitochondrial dysfunction related to absence of DJ-1.

DOI: https://doi.org/10.1101/2025.05.19.654941
Cell Commun Signal. 2025 Jun 04. 23(1): 265

Functionalized exosomes for targeted therapy in cancer and regenerative medicine: genetic, chemical, and physical modifications.

Salar Ghaffari Gabaran, Navid Ghasemzadeh, Maryam Rahnama, Erkan Karatas, Ali Akbari, Jafar Rezaie.

   BACKGROUND: Extracellular vesicles (EVs), such as exosomes, have been extensively discovered for their function in various diseases and potential therapeutic properties. In this review, we aimed to describe the therapeutic roles of functionalized exosomes in cancer and regenerative medicine.
METHODS: In this review study, we studied numerous articles over the past two decades published on the application of exosomes in different diseases, as well as on perspectives and challenges in this field.
RESULTS: Recent advancements have shown that exosomes can be used as a drug delivery system. However, this approach faces challenges such as low efficiency and non-targeting effects. Different methods, including genetic, chemical, and physical modifications, are used to functionalize exosome surfaces to address these limitations. In some cases, a combination of modification methods has been used to produce smart exosomes. Different therapeutic agents have been inserted on exosome surfaces by different modification methods. These functionalized exosomes can effectively deliver therapeutic agents to target cells. A growing body of evidence shows that functionalized exosomes are promising for cancer therapy and regenerative medicine. They can not only effectively deliver therapeutic agents to cancer cells, inhibiting tumorigenesis, but also efficiently contribute to tissue repair and regeneration by increasing cell proliferation and angiogenesis. In this review, we discuss different modification methods used to functionalize exosomes and related studies. In addition, we describe the application of functionalized exosomes in cancer and regeneration, along with challenges and perspectives.
CONCLUSIONS: Although functionalized exosomes show promising results, further studies are essential for the clinical translation of these exosomes.

Keywords:  Chemical modification; Exosomes; Extracellular vesicles; Modified exosomes

DOI:  https://doi.org/10.1186/s12964-025-02268-y
Front Aging. 2025 ;6 1605070

Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity.

Fayaz A Mir, Arianna R S Lark, Christa J Nehs.

  The relationship between sleep and metabolism has emerged as a critical factor in aging and age-related diseases, including Alzheimer's disease and dementia. Mitochondrial oxidative phosphorylation, essential for neuronal energy production, also generates reactive oxygen species (ROS), which increase with age and contribute to oxidative stress. Sleep plays a vital role in modulating redox balance, facilitating the clearance of free radicals, and supporting mitochondrial function. Disruptions in sleep are closely linked to redox imbalances, and emerging evidence suggests that pharmacological interventions, such as dual orexin receptor antagonists and antioxidant-based therapies, may help restore redox homeostasis. Furthermore, antioxidant-rich diets and supplements have shown promise in improving both sleep quality and metabolic health in aging populations. Neurons, with their high energy demands, are particularly vulnerable to oxidative damage, making redox regulation crucial in maintaining brain integrity. This review explores the bidirectional relationship between sleep and redox metabolism through five key areas: (1) sleep's role in free radical regulation, (2) ROS as mediators of age-related sleep disturbances, (3) feedback loops between impaired sleep and brain metabolism, (4) sleep, redox, and aging in peripheral systems, and (5) therapeutic strategies to restore redox balance and improve aging outcomes. Understanding these mechanisms may provide new targets for interventions aimed at mitigating age-associated diseases.

Keywords:  antioxidants; ketones; metabolic; mitochondria; oxidative stress; sleep

DOI:  https://doi.org/10.3389/fragi.2025.1605070
Mol Genet Metab. 2025 May 26. pii: S1096-7192(25)00144-1. [Epub ahead of print]145(4): 109153

Qualitative study of fatigue in adults with primary mitochondrial disease: Development of the PROMIS Fatigue Mitochondrial Disease Short Form.

Sarah Clifford, Renae J Stefanetti, Roxana Bahar, Magnus J Hansson, Gráinne S Gorman, Amel Karaa.

   BACKGROUND: Fatigue is a debilitating symptom in patients with primary mitochondrial disease nPMD). Developing new treatments that improve fatigue is a patient priority but is hampered by a lack of fit-for-purpose patient-reported outcome measures (PROMs). We aimed to understand the impact of fatigue on the lives of people with PMD and develop a brief PMD-specific PROM to evaluate fatigue in clinical trials.
METHODS: Adults with genetically confirmed PMD and self-reported moderate-to-severe fatigue and myopathy/exercise intolerance participated in a concept elicitation interview to explore their experiences of fatigue. Interview transcripts were coded thematically using MAXQDA™. Characteristics and impacts that emerged from the interviews were mapped to items in the PROMIS® Fatigue item bank. Participants then engaged in a cognitive interview to assess relevance and understandability of PROMIS Fatigue items considered for the PROM.
RESULTS: Twelve adults with PMD (n = 8 women, age 20-75 years) were interviewed. The most frequently reported characteristics of fatigue included tiredness, muscle weakness/fatigue, exhaustion, lack of energy, and mental fatigue. Fatigue affected patients' ability to perform daily life activities, including household chores, leisure activities, physical activity/exercise, and work/school, and negatively affected mood and relationships. Nine items were included in the final PROM based on level of endorsement of underlying concepts elicited by the concept elicitation interviews and relevance, clarity, and ease of answering, as assessed in the cognitive interviews.
CONCLUSION: The nine-item PROMIS Fatigue Mitochondrial Disease Short Form is the first PROM designed specifically to assess fatigue in PMD. This study demonstrates the content validity of the short form, and future longitudinal studies will assess its psychometric properties.

Keywords:  Fatigue; Mitochondrial disease; Patient-reported outcome; Questionnaire validation

DOI:  https://doi.org/10.1016/j.ymgme.2025.109153
bioRxiv. 2025 May 16. pii: 2025.05.13.653493. [Epub ahead of print]

Oocyte mitochondria link maternal environment to offspring phenotype.

Jason F Cooper, Kim Nguyen, Darrick Gates, Emily Wolfrum, Colt Capan, Hyoungjoo Lee, Devia Williams, Chidozie Okoye, Kelsie Nauta, Ximena Sanchez-Avila, Ryan T Kelly, Ryan Sheldon, Andrew P Wojtovich, Nicholas O Burton.

During oogenesis and maturation oocytes undergo a recently discovered mitochondrial electron transport chain (ETC) remodeling in flies 1 , frogs 1 , and humans 2 . This conserved oocyte ETC remodeling is regulated by maternal insulin signaling, but its role in biology remains unclear. In the model animal Caenorhabditis elegans , we previously found that insulin signaling to oocytes regulates offspring's ability to adapt to future osmotic stress by altering offspring metabolism. However, the molecular mechanisms that function in oocytes to mediate this intergenerational stress response are similarly unknown. Here, we developed a low-input oocyte proteomics workflow and combined it with our C. elegans intergenerational stress response model to find that both a mother's environment and maternal insulin signaling regulate the abundance of ETC proteins in oocytes - particularly the abundance of proteins involved in the transfer of electrons from QH 2 to cytochrome C by ETC Complex III. Using genetic perturbations of ETC function we further found that promoting ETC Complex III function in oocytes was both necessary and sufficient to link a mother's environment to adaptive changes in offspring metabolism. Lastly, we found that the effects of Complex III dysfunction in oocytes on offspring were mediated via an AMP-kinase (AAK-2) dependent mechanism and that AAK-2 functions in offspring to promote ATP preservation and glycerol metabolism in response to stress. Collectively, our data suggest that the role of oocyte ETC remodeling in biology includes linking maternal environments to changes in offspring metabolism that promote offspring survival in the environment experienced by their mother.

DOI: https://doi.org/10.1101/2025.05.13.653493
Trends Genet. 2025 Jun 02. pii: S0168-9525(25)00110-6. [Epub ahead of print]

The rare-to-common disease journey: a winding road to new therapies.

Laura Reinholdt, Elissa Chesler, Martin Pera, Nadia Rosenthal.

  The study of genetic variants that cause rare diseases has been a central strategy of genetic research for the last century, but the contribution of rare variants to the multifactorial inheritance of common diseases has only recently emerged as an avenue to accelerate functional mapping of the human genome. This perspective defines rare and common diseases, surveys prospects for integrating their study to decipher pathogenic mechanisms, and cites current clinical hurdles of disease translation. We discuss the premise that research into rare disease etiology can inform our understanding of common illnesses and vice versa, identify impediments to progress in translating rare disease findings into common disease treatments, and offer suggestions for realizing the benefits of global health research in the discovery of rare disease variants.

Keywords:  common disease; genetic variants; rare disease

DOI:  https://doi.org/10.1016/j.tig.2025.05.003