bims-polgdi 2025-07-20 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–07–20
eleven papers selected by
Luca Bolliger, lxBio

Mitochondrial DNA: how does it leave mitochondria?
Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease.
(ID-ICPMB05) Running on Empty: Mitochondria Without DNA Exhibit Differential Motility and Connectivity.
Why and how paternal mitochondrial DNA gets cut out of the inheritance.
Megakaryocytes as mitochondria factories: potential donors for mitochondria transplantation.
Mitochondria-Targeting Abasic Site-Reactive Probe (mTAP) Enables the Manipulation of Mitochondrial DNA Levels.
TWNK gene pathogenic variant and Perrault syndrome.
Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases.
Mitochondrial unfolded protein response in regulatory T cell function: a protective mechanism in immune aging.
A Tunisian POLG mutation expands the clinical spectrum of POLG-related disorders.
Hypoxia-Induced Activation of Calpain and Oxidative Stress in Mitochondria Leads to RGC Death in Human iPSC-derived Retinal Organoids.

Trends Cell Biol. 2025 Jul 10. pii: S0962-8924(25)00146-1. [Epub ahead of print]

Mitochondrial DNA: how does it leave mitochondria?

Vladimir Gogvadze, Boris Zhivotovsky.

  In recent years, studies have reported the presence of mitochondrial DNA (mtDNA) in the cytosol. However, a certain number of publications on the mechanisms of mtDNA release contain uncertainties. mtDNA is located in the mitochondrial matrix and cannot be released through the same pathways as intermembrane space proteins. This forum article aims to examine the assumptions and elucidate the processes underlying this phenomenon.

Keywords:  Bcl-2 family proteins; inner mitochondrial membrane; mitochondria; mtDNA; outer mitochondrial membrane

DOI:  https://doi.org/10.1016/j.tcb.2025.06.005
N Engl J Med. 2025 Jul 16.

Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease.

Louise A Hyslop, Emma L Blakely, Magomet Aushev, Jordan Marley, Yuko Takeda, Angela Pyle, Eilis Moody, Catherine Feeney, Jan Dutton, Carol Shaw, Sarah J Smith, Kate Craig, Charlotte L Alston, Lisa Lister, Karina Endacott, Samantha Byerley, Helen McDermott, Kathryn Wilson, Lynne Botham, Beth Matthew, Nilendran Prathalingam, Matthew Prior, Alison Murdoch, Douglass M Turnbull, Gavin Hudson, Meenakshi Choudhary, Robert W Taylor, Rekha N Pillai, Jane A Stewart, Robert McFarland, Mary Herbert.

BACKGROUND: Children born to women who carry pathogenic variants in mitochondrial DNA (mtDNA) are at risk for a range of clinical syndromes collectively known as mtDNA disease. Mitochondrial donation by pronuclear transfer involves transplantation of nuclear genome from a fertilized egg from the affected woman to an enucleated fertilized egg donated by an unaffected woman. Thus, pronuclear transfer offers affected women the potential to have a genetically related child with a reduced risk of mtDNA disease.
METHODS: We offered mitochondrial donation (by pronuclear transfer) or preimplantation genetic testing (PGT) to a series of women with pathogenic mtDNA variants who sought to reduce the transmission of these variants to their children. Patients with heteroplasmy (variants present in a proportion of copies of mtDNA) were offered PGT, and patients with homoplasmy (variants present in all copies of mtDNA) or elevated heteroplasmy were offered pronuclear transfer.
RESULTS: Clinical pregnancies were confirmed in 8 of 22 patients (36%) and 16 of 39 patients (41%) who underwent an intracytoplasmic sperm injection procedure for pronuclear transfer or for PGT, respectively. Pronuclear transfer resulted in 8 live births and 1 ongoing pregnancy. PGT resulted in 18 live births. Heteroplasmy levels in the blood of the 8 infants whose mothers underwent pronuclear transfer ranged from undetectable to 16%. Levels of the maternal pathogenic mtDNA variant were 95 to 100% lower in 6 newborns and 77 to 88% lower in 2 newborns than in the corresponding enucleated zygotes. Heteroplasmy levels were known for 10 of the 18 infants whose mothers underwent PGT and ranged from undetectable to 7%.
CONCLUSIONS: We found that mitochondrial donation through pronuclear transfer was compatible with human embryo viability. An integrated program involving pronuclear transfer and PGT was effective in reducing the transmission of homoplasmic and heteroplasmic pathogenic mtDNA variants. (Funded by NHS England and others.).

DOI: https://doi.org/10.1056/NEJMoa2415539
Physiol Plant. 2025 Jul-Aug;177(4):177(4): e70404

(ID-ICPMB05) Running on Empty: Mitochondria Without DNA Exhibit Differential Motility and Connectivity.

Joanna M Chustecki, Alora Q Schneider, Madeleine H Faber, Bara Altartouri, Alan C Christensen.

  Plant mitochondria are in continuous motion. While providing ATP to other cellular processes, they also constantly consume ATP to move rapidly within the cell. This movement is in part related to taking up, converting and delivering metabolites and energy to and from different parts of the cell. Plant mitochondria have varying amounts of DNA, even within a single cell, from none to the full mitochondrial genome. Because mitochondrial dynamics are altered in an Arabidopsis mutant with disrupted DNA maintenance, we hypothesised that exchanging DNA templates for repair is one of the functions of their movement and interactions. Here, we image mitochondrial DNA by two distinct methods while tracking mitochondrial position to investigate differences in the behaviour of mitochondria with and without DNA in Arabidopsis thaliana. In addition to staining mitochondrial DNA with SYBR Green, we have developed and implemented a fluorescent mitochondrial DNA binding protein that will enable future understanding of mitochondrial dynamics, genome maintenance and replication. We demonstrate that mitochondria without mtDNA have altered physical behaviour and lower immediate connectivity to the rest of the population, further supporting a link between the physical and genetic dynamics of these complex organelles.

Keywords:  arabidopsis thaliana; fluorescence; mitochondrial DNA; mitochondrial dynamics; nucleoid binding protein

DOI:  https://doi.org/10.1111/ppl.70404
Curr Opin Genet Dev. 2025 Jul 16. pii: S0959-437X(25)00073-5. [Epub ahead of print]94 102381

Why and how paternal mitochondrial DNA gets cut out of the inheritance.

Mayu Shimomura, Thomas R Hurd.

Mitochondrial DNA (mtDNA) is inherited maternally across animals, yet the evolutionary rationale behind this unusual mode of inheritance remains a longstanding mystery. Understanding the processes that prevent the transmission of paternal mtDNA and thus ensure maternal-only inheritance is crucial to uncovering the evolutionary significance of this widespread phenomenon. Historically, research has focused on mechanisms that act within eggs to destroy sperm mitochondria via autophagy and the ubiquitin-proteasome degradation system. However, recent discoveries across multiple animal species, including humans, reveal a surprising twist: paternal mtDNA is actively degraded within mitochondria independently of and prior to the complete breakdown of the organelle itself, often even prior to fertilization. Only a few studies have begun to illuminate the molecular machinery responsible for this early mtDNA elimination. In this review, we explore the emerging landscape of paternal mtDNA elimination mechanisms across species, highlighting newly discovered pathways, evolutionary implications, and open questions that are furthering our understanding of mitochondrial inheritance.

DOI: https://doi.org/10.1016/j.gde.2025.102381
Curr Opin Hematol. 2025 Jul 15.

Megakaryocytes as mitochondria factories: potential donors for mitochondria transplantation.

Émilie Mercure, Martin Pelletier, Éric Boilard.

   PURPOSE OF REVIEW: There is an increasing recognition that mitochondria are dynamic regulators of cell fate. Mitochondria transplantation has emerged as a promising therapeutic strategy for conditions ranging from metabolic disorders to neurodegenerative diseases. Thus, there is a growing need for scalable mitochondrial sources for transplantation. We highlight megakaryocytes, best known for their role in platelet production, as a novel and versatile candidate source for mitochondria transplantation.
RECENT FINDINGS: Megakaryocytes are naturally equipped to package and deliver functional mitochondria when producing platelets. Furthermore, MKs can share their mitochondria with neighboring cells in the bone marrow. Given the abundance of mitochondria in megakaryocytes, they may represent an ideal source of mitochondria for transplantation. A better understanding of the role of mitochondria in megakaryocyte heterogeneity and metabolic functions may help harness megakaryocytes for therapeutic transplantation applications.
SUMMARY: Megakaryocyte-derived mitochondria transplantation offers a promising avenue for treating metabolic disorders, leveraging existing mechanisms. Future research should address limitations in megakaryocyte biogenesis and heterogeneity, and optimize delivery systems to maximize therapeutic efficacy.

Keywords:  cell therapy; megakaryocytes; mitochondria transplantation

DOI:  https://doi.org/10.1097/MOH.0000000000000889
Angew Chem Int Ed Engl. 2025 Jul 15. e202502470

Mitochondria-Targeting Abasic Site-Reactive Probe (mTAP) Enables the Manipulation of Mitochondrial DNA Levels.

Anal Jana, Yu-Hsuan Chen, Linlin Zhao.

  Mitochondrial DNA (mtDNA) encodes essential genes for mitochondrial and cellular functions and acts as a cell signaling molecule in innate immune and inflammatory responses. Defects in mtDNA are implicated in a range of mitochondrial disorders and human diseases. Currently, no chemical strategy exists to prevent mtDNA loss under genotoxic stress. To address this, we developed a mitochondria-targeting probe (mTAP) that selectively reacts with key mtDNA repair intermediates-abasic (AP) sites. We confirmed that mTAP forms oxime conjugates exclusively with mitochondrial AP sites without conjugation with nuclear AP sites. Upon mTAP conjugation, DNA substrates containing AP sites were resistant to cleavage by AP endonuclease (APE1) and mitochondrial extracts. This conjugation significantly reduced the DNA-binding affinity of APE1 without affecting the DNA-binding activity of a mtDNA-packaging factor, mitochondrial transcription factor A (TFAM). Importantly, cellular experiments demonstrated that mTAP treatment alleviated the decrease in mtDNA and transcription product levels induced by mitochondrial AP site damage. Functional assays also demonstrated that mTAP treatment did not compromise mtDNA replication activity or increase the overall mtDNA damage level. These findings highlight the potential of mTAP as a valuable chemical tool to modulate mtDNA levels under genotoxic stress.

Keywords:  Abasic sites; DNA Repair; DNA damage; Mitochondrial DNA; Nucleic acid modifications

DOI:  https://doi.org/10.1002/anie.202502470
Gene. 2025 Jul 14. pii: S0378-1119(25)00456-1. [Epub ahead of print] 149667

TWNK gene pathogenic variant and Perrault syndrome.

Hongbo Li, Chunyu Cao, Yafeng Lv.

  Perrault syndrome is a rare autosomal recessive genetic disorder characterized primarily by sensorineural hearing loss and ovarian dysfunction in females, often accompanied by neurological and other systemic abnormalities. The disease exhibits significant clinical heterogeneity, and its pathogenesis involves pathogenic variants in multiple genes, among which pathogenic variants in the TWNK gene represent an important cause. The TWNK gene encodes the Twinkle, a mitochondrial DNA (mtDNA) helicase that plays a crucial role in the replication and maintenance of mtDNA stability. Due to the variability in mtDNA copy numbers across different tissues, TWNK gene pathogenic variants result in a wide spectrum of clinical manifestations with notable heterogeneity. In particular, the high sensitivity of the nervous system to energy metabolism disturbances may exacerbate the associated symptoms. The complex genetic background of Perrault syndrome poses challenges for clinical treatment, making it essential to further investigate its molecular and genetic basis to enhance diagnosis, treatment, and genetic counseling. This review summarizes the clinical features, molecular pathogenesis, diagnostic techniques, therapeutic approaches, and genetic counseling strategies related to Perrault syndrome caused by TWNK pathogenic variants, providing a scientific basis for its clinical management.

Keywords:  Diagnosis; Gene therapy; Genetic counseling; Perrault syndrome; TWNK gene; mitochondrial DNA

DOI:  https://doi.org/10.1016/j.gene.2025.149667
Foods. 2025 Jun 23. pii: 2193. [Epub ahead of print]14(13):

Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases.

Federica Davì, Antonella Iaconis, Marika Cordaro, Rosanna Di Paola, Roberta Fusco.

  In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis and progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, often involving altered mitochondrial dynamics like fragmentation and functional impairment. Accordingly, mitochondrial targeting represents an alternative therapeutic strategy for the treatment of these disorders. Current standard drug treatments present limitations due to adverse effects associated with their chronic use. Therefore, in recent years, nutraceuticals, natural compounds exhibiting diverse biological activities, have garnered significant attention for their potential to treat these diseases. It has been shown that these compounds represent safe and easily available sources for the development of innovative therapeutics, and by modulating mitochondrial function, nutraceuticals offer a promising approach to address neurodegenerative pathologies. We referred to approximately 200 articles published between 2020 and 2025, identified through a focused search across PubMed, Google Scholar, and Scopus using keywords such as "nutraceutical," "mitochondrial dysfunction," and "neurodegenerative diseases. The purpose of this review is to examine how mitochondrial dysfunction contributes to the genesis and progression of neurodegenerative diseases. Also, we discuss recent advances in mitochondrial targeting using nutraceuticals, focusing on their mechanisms of action related to mitochondrial biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability.

Keywords:  antioxidants; mitochondrial dysfunction; neurodegenerative diseases; nutraceutical; oxidative stress

DOI:  https://doi.org/10.3390/foods14132193
Front Immunol. 2025 ;16 1621759

Mitochondrial unfolded protein response in regulatory T cell function: a protective mechanism in immune aging.

Lillie Lewis, Deepa Valvi, Roberto Gedaly, Francesc Marti.

  Age-related conditions, such as neurodegenerative disease, cancer, and autoimmune disorders, are increasingly recognized as closely linked with the gradual deterioration of the immune system. Regulatory T cells (Tregs) are a small, specialized subset of T lymphocytes that play a critical role in maintaining immune homeostasis and self-tolerance. As individuals age, Treg cells demonstrate reduced capacity to suppress some autoreactive immune responses, although they largely retain their capacity to regulate effector antiviral and antitumor immunity. Unlike conventional effector T cells (Teff), which primarily derive energy from glycolysis, Tregs rely more on mitochondrial oxidative phosphorylation to fulfill their energy requirements. This metabolic profile renders them particularly sensitive to mitochondrial dysfunction, underpinning the critical role of mitochondrial protective pathways in preserving the functional integrity of Treg cells. The mitochondrial unfolded protein response (mitoUPR) is gaining special relevance among these protective mechanisms. In this review, we examine the complex interplay between immune aging and mitochondrial dynamics, with particular emphasis on the essential role of mitoUPR in supporting Treg function. We further discuss how targeting mitochondrial stress responses may offer novel therapeutic avenues for age-related diseases characterized by Treg dysfunction.

Keywords:  aging; cell metabolism; cellular stress; immunosenescence; oxidative stress; regulatory T-cells; unfolded protein response

DOI:  https://doi.org/10.3389/fimmu.2025.1621759
Mitochondrion. 2025 Jul 11. pii: S1567-7249(25)00068-6. [Epub ahead of print]85 102071

A Tunisian POLG mutation expands the clinical spectrum of POLG-related disorders.

Abir Zioudi, Ismail Gouiza, Said Galai, Meriem Hechmi, Hedia Klaa, Zouhour Miladi, Thouraya Ben Younes, Hanene Benrhouma, Ilhem Ben Youssef-Turki, Souheil Omar, Guy Lenaers, Rym Kefi, Neziha Gouider-Khouja, Ichraf Kraoua.

  Mitochondrial Neuro-Gastro-Intestinal Encephalopathy (MNGIE) is a rare and fatal mitochondrial disorder caused by biallelic mutations in the TYMP gene. In rare cases, it can be caused by pathogenic variants in the POLG gene, with a clinical presentation similar to that of TYMP-related MNGIE, except for the absence of leukoencephalopathy. Here we report the cases of six Tunisian patients presenting with a homogeneous clinical MNGIE-like phenotype, characterized by an early infantile onset. Key features included psychomotor delay or regression, peripheral neuropathy, gastrointestinal disturbances, hypotrophy or growth retardation, and elevated cerebrospinal fluid protein levels. All patients originated from the same governorate and carried the same homozygous POLG variant c.2391G > T (p.Met797Ile), which may suggest a founder effect.

Keywords:  Hyperproteinorachia; MNGIE-like phenotype; Mitochondrial Neuro-Gastro-Intestinal Encephalopathy (MNGIE); Mitochondrial disorders; POLG

DOI:  https://doi.org/10.1016/j.mito.2025.102071
Exp Eye Res. 2025 Jul 10. pii: S0014-4835(25)00282-9. [Epub ahead of print] 110511

Hypoxia-Induced Activation of Calpain and Oxidative Stress in Mitochondria Leads to RGC Death in Human iPSC-derived Retinal Organoids.

Masayuki Hirata, Yayoi Kishimoto, Thomas R Shearer, Mitsuyoshi Azuma.

  Proteolysis by calpain enzyme contributes to retinal ganglion cell (RGC) death in hypoxic monkey and human retinal explants, although the mechanism is not fully understood yet. The present experiments are to determine if calpain activation in mitochondria and the subsequent oxidative stress were underlying mechanism driving RGC death in a hypoxia/regeneration culture model, using retinal organoids derived from human induced pluripotent stem (iPS) cells. Retinal organoids were differentiated from human iPS cells. RGCs labeled with tdTomato were purified with magnetic-activated cell sorting. Cellular localization of calpain-related proteins was observed by immunohistochemistry. For example, α-spectrin breakdown product 150 (SBDP150) was detected as a marker for cytosolic calpain activation. Retinal organoids and purified RGCs were cultured with or without calcium chelator BAPTA, calpain inhibitor SNJ-1945, or NRF2 activator NK252 under hypoxia/reoxygenation. Truncated apoptosis-inducing factor (tAIF), a marker for mitochondrial calpain activation was determined by immunoblotting. Mitochondrial membrane potential (MMP) was measured with MT-1 dye. Thiol levels were assessed with Thiol Assay Kit. Hypoxia/reoxygenation induced an increase in the cytoplasmic calpain activation marker SBDP150 and the mitochondrial calpain activation marker tAIF, leading to RGC death. Additionally, it led to a decrease in thiol levels and MMP impairment. These changes were inhibited by BAPTA and calpain inhibitor SNJ-1945. NK252 prevented RGC death but did not inhibit calpain-mediated proteolysis. Our findings with human iPS-drived RGC culture model demonstrate that calcium influx in hypoxic RGCs activates mitochondrial calpain, which induced the depletion of thiol levels and the collapse of MMP, ultimately leading to cell death.

Keywords:  calpain; human iPS-derived retinal organoids; hypoxia/reoxygenation; mitochondria; oxidative stress

DOI:  https://doi.org/10.1016/j.exer.2025.110511