bims-polgdi 2025-04-20 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–04–20
27 papers selected by
Luca Bolliger, lxBio

The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.
Optimization of mtDNA-targeted platinum TALENs for bi-directionally modifying heteroplasmy levels in patient-derived m.3243A>G-iPSCs.
Assessing reliability and accuracy of qPCR, dPCR and ddPCR for estimating mitochondrial DNA copy number in songbird blood and sperm cells.
Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.
Relative mtDNA copy number in embryo spent culture medium is not a reliable biomarker of human embryo aneuploidy.
Transcriptome analysis of atad3-null zebrafish embryos elucidates possible disease mechanisms.
In vivo composition of the mitochondrial nucleoid in mice.
L-Carnitine and Mildronate Demonstrate Divergent Protective Effects on Mitochondrial DNA Quality Control and Inflammation Following Traumatic Brain Injury.
Yeast models of mutations in NFU1 gene for biochemical characterization and drug screening.
Mitochondria in focus: From structure and function to their role in human diseases. A review.
Cellular senescence as a source of chronic microinflammation that promotes the aging process.
Interleukin-13-mediated alterations in esophageal epithelial mitochondria contribute to tissue remodeling in eosinophilic esophagitis.
Testing for differences in polygenic scores in the presence of confounding.
MtDNA 3243 A>G mutation and recurrent cholangitis after Kasai procedure in biliary atresia: a case report.
Calcium acts as a critical determinant of mitochondria-nuclear networking driven retrograde signaling.
Diverse Clinical manifestations of Cobalamin C Metabolism Disorders.
Mitochondrial DNA in Exercise-Mediated Innate Immune Responses.
Investigating the genetic association of mitochondrial DNA copy number with neurodegenerative diseases.
Stress-related neurodegenerative diseases: Molecular mechanisms implicated in neurodegeneration and therapeutic strategies.
Impact of Serum Circulating Factors and PDE5 Inhibitor Therapy on Cardiomyocyte Metabolism in Single Ventricle Heart Disease.
Mitochondrial DNA haplogroups and circulating cell-free mitochondrial DNA as biomarkers of bronchopulmonary dysplasia.
A population-based cohort study of mitochondrial disease and mental health conditions in Ontario, Canada.
Pharmacological modulation of mitochondrial function as novel strategies for treating intestinal inflammatory diseases and colorectal cancer.
RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis.
Mitochondrial classic metabolism and its often-underappreciated facets.
Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
Investigating the Therapeutic Potential of the Ketogenic Diet in Modulating Neurodegenerative Pathophysiology: An Interdisciplinary Approach.

Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2417477122

The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.

Josefin M E Forslund, Tran V H Nguyen, Vimal Parkash, Andreas Berner, Steffi Goffart, Jaakko L O Pohjoismäki, Paulina H Wanrooij, Erik Johansson, Sjoerd Wanrooij.

  Mitochondrial DNA (mtDNA) stability, essential for cellular energy production, relies on DNA polymerase gamma (POLγ). Here, we show that the POLγ Y951N disease-causing mutation induces replication stalling and severe mtDNA depletion. However, unlike other POLγ disease-causing mutations, Y951N does not directly impair exonuclease activity and only mildly affects polymerase activity. Instead, we found that Y951N compromises the enzyme's ability to efficiently toggle between DNA synthesis and degradation, and is thus a patient-derived mutation with impaired polymerase-exonuclease switching. These findings provide insights into the intramolecular switch when POLγ proofreads the newly synthesized DNA strand and reveal a new mechanism for causing mitochondrial DNA instability.

Keywords:  DNA polymerases; mitochondria; mitochondrial disease; mtDNA; mtDNA replication

DOI:  https://doi.org/10.1073/pnas.2417477122
Mol Ther Nucleic Acids. 2025 Jun 10. 36(2): 102521

Optimization of mtDNA-targeted platinum TALENs for bi-directionally modifying heteroplasmy levels in patient-derived m.3243A>G-iPSCs.

Naoki Yahata, Yu-Ichi Goto, Ryuji Hata.

  Patient-derived induced pluripotent stem cells (iPSCs) are a useful pathological model for debilitating diseases caused by mitochondrial DNA (mtDNA) mutations. We established iPSCs derived from mitochondrial disease patients, heteroplasmic for the m.3243A>G mutation. The proportion of a selected mtDNA can be reduced by delivering a programmable nuclease into the mitochondria, and we developed various mtDNA-targeted Platinum TALENs (mpTALENs) to modify m.3243A>G-iPSC heteroplasmy levels in either wild-type or mutant direction. For TALEN optimization, the use of non-conventional repeat-variable di-residues (ncRVD)-LK/WK or NM-enhanced cleavage activity and specificity, and the replacement of conventional with obligate heterodimeric FokI nuclease domains increased target specificity and protected mtDNA from copy number depletion. In vitro, depending on whether wild-type or mutant mtDNA was targeted, we could obtain m.3243A>G-iPSCs with a higher or lower mutation load, while the cells retained their ability to differentiate into three germ layers. These results demonstrate that our mpTALEN optimization created a useful tool for altering heteroplasmy levels in m.3243A>G-iPSCs, improving the potential for studying mutation pathology. The enhanced efficiency also holds promise for using m.3243G(MUT)-mpTALEN as a therapeutic strategy for treating patients suffering from m.3243A>G mitochondrial diseases.

Keywords:  MELAS; MT: RNA/DNA Editing; diabetes mellitus; induced pluripotent stem cells, iPSCs; mitochondria; mitochondrial DNA, mtDNA; transcription activator-like effector nuclease, TALEN

DOI:  https://doi.org/10.1016/j.omtn.2025.102521
PeerJ. 2025 ;13 e19278

Assessing reliability and accuracy of qPCR, dPCR and ddPCR for estimating mitochondrial DNA copy number in songbird blood and sperm cells.

Laima Bagdonaitė, Erica H Leder, Jan T Lifjeld, Arild Johnsen, Quentin Mauvisseau.

  Mitochondrial DNA (mtDNA) copy number varies across species, individuals, and cell types. In birds, there are two types of cells with a relatively low number of mitochondria: red blood cells and spermatozoa. Previous studies investigating variation of mitochondrial abundance in animal sperm have generally used quantitative PCR (qPCR), but this method shows potential limitations when quantifying targets at low abundance. To mitigate such issues, we investigated and compared the reliability and accuracy of qPCR, digital PCR (dPCR) and droplet digital PCR (ddPCR) to quantify high and low concentration DNA. We used synthetic DNA targets, to calculate the limit of detection and the limit of quantification and found that with both dPCR and ddPCR, these limits were lower than with qPCR. Then, to compare quantification accuracy and repeatability, we used DNA extracted from blood and sperm cells of Eurasian siskin. We found that qPCR, dPCR and ddPCR all reliably quantified mitochondrial DNA in sperm samples but showed significant differences when analyzing the typically lower levels of mtDNA in blood, with ddPCR consistently showing lower variation among replicates. Our study provides critical insights and recommendations for future studies aiming to quantify target mtDNA and indicates that dPCR and ddPCR are the preferred methods when working with samples with low abundance of mtDNA.

Keywords:  Quantification; Songbirds; Spermatozoa; dPCR; ddPCR; mtDNA; qPCR

DOI:  https://doi.org/10.7717/peerj.19278
HGG Adv. 2025 Apr 15. pii: S2666-2477(25)00044-2. [Epub ahead of print] 100441

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.

Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium

Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is not always specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants. Here, we analyzed a cohort of 6,660 rare disease families (5,625 genetically undiagnosed, 84%) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium as well as other rare disease cohorts. Using dedicated pipelines to address the technical challenges posed by the mtDNA-circular genome, variant heteroplasmy, and nuclear misalignment-we called single nucleotide variants, small indels, and large mtDNA deletions from exome and/or genome sequencing data, in addition to RNA-sequencing data when available. Diagnostic mtDNA variants were identified in 10 previously genetically undiagnosed families (one large deletion, eight reported pathogenic variants, one previously unreported likely pathogenic variant), as well as candidate diagnostic variants in a further 11 undiagnosed families. In one additional undiagnosed proband, detection of >900 heteroplasmic variants provided functional evidence of pathogenicity to a de novo variant in the nuclear gene POLG (DNA polymerase gamma), responsible for mtDNA replication and repair. Overall, mtDNA variant calling from data generated by exome and genome sequencing-primarily for nuclear variant analysis-resulted in a genetic diagnosis for 0.2% of undiagnosed families affected by a broad range of rare diseases, as well as identification of additional promising candidates.

DOI: https://doi.org/10.1016/j.xhgg.2025.100441
Reprod Fertil. 2025 Apr 01. pii: RAF-25-0001. [Epub ahead of print]

Relative mtDNA copy number in embryo spent culture medium is not a reliable biomarker of human embryo aneuploidy.

Sasipat Teerawongsuwan, Kodchakorn Wiangwised, Nattapavee Ngampiyakul, Nitid Wanikorn, Panida Boonnithipaisit, Panyada Khiuhok, Phanthitra Aekudompong, Amarin Narkwichean, Sirinun Pongmayteegul, Ruttachuk Rungsiwiwut.

Mitochondrial DNA (mtDNA) from embryonic cells is released into the spent culture medium (SCM) during cellular processes, providing a potential biomarker of embryo health. Analysing mtDNA levels in SCM enables a non-invasive evaluation of embryo quality and potential developmental abnormalities. In this retrospective study, we aimed to investigate the relationship between relative mtDNA copy number in embryo SCM and key factors, including embryo fragmentation, morphological quality, and chromosomal abnormalities. Fertilised embryos produced through intracytoplasmic sperm injection were cultured to the blastocyst stage in an incubator. Embryo fragmentation was assessed on Day 3 using the Istanbul criteria, while morphological grading was evaluated on Day 5 using the Gardner criteria. On Day 5, trophectoderm (TE) biopsies were performed for preimplantation genetic testing for aneuploidy, followed by embryo cryopreservation, and collection of embryo SCM. The mtDNA was quantified using quantitative PCR. Statistical analyses using the Mann-Whitney U and Kruskal-Wallis tests (significance at p<0.05) showed that relative mtDNA copy number did not significantly differ among embryos with fragmentation levels <10%, 10-25%, and >25% (p>0.05). For blastocyst grading, which evaluates the inner cell mass (ICM) and TE, no significant difference was observed in relative mtDNA copy number between grades B and C for ICM (p=0.190) and TE (p=0.289). Furthermore, a trend toward higher relative mtDNA levels was observed in aneuploid than in euploid embryos, though the difference was not statistically significant. Thus, relative mtDNA copy number in SCM may not accurately reflect embryo characteristics, such as fragmentation, morphological grading, or chromosomal abnormalities.

DOI: https://doi.org/10.1530/RAF-25-0001
Orphanet J Rare Dis. 2025 Apr 15. 20(1): 181

Transcriptome analysis of atad3-null zebrafish embryos elucidates possible disease mechanisms.

Shlomit Ezer, Nathan Ronin, Shira Yanovsky-Dagan, Shahar Rotem-Bamberger, Orli Halstuk, Yair Wexler, Zohar Ben-Moshe, Inbar Plaschkes, Hadar Benyamini, Ann Saada, Adi Inbal, Tamar Harel.

   BACKGROUND: ATAD3A, a nuclear gene encoding the ATAD3A protein, has diverse roles in mitochondrial processes, encompassing mitochondrial dynamics, mitochondrial DNA maintenance, metabolic pathways and inter-organellar interactions. Pathogenic variants in this gene cause neurological diseases in humans with recognizable genotype-phenotype correlations. Yet, gaps in knowledge remain regarding the underlying pathogenesis.
METHODS: To further investigate the gene function and its implication in health and disease, we utilized CRISPR/Cas9 genome editing to generate a knockout model of the zebrafish ortholog gene, atad3. We characterized the phenotype of the null model, performed mitochondrial and functional tests, and compared the transcriptome of null embryos to their healthy siblings.
RESULTS: Analysis of atad3-null zebrafish embryos revealed microcephaly, small eyes, pericardial edema and musculature thinning, closely mirroring the human rare disease phenotype. Larvae exhibited delayed hatching and embryonic lethality by 13 days post-fertilization (dpf). Locomotor activity, ATP content, mitochondrial content, and mitochondrial activity were all reduced in the mutant embryos. Transcriptome analysis at 3 dpf via RNA-sequencing indicated decline in most mitochondrial pathways, accompanied by a global upregulation of cytosolic tRNA synthetases, presumably secondary to mitochondrial stress and possibly endoplasmic reticulum (ER)-stress. Differential expression of select genes was corroborated in fibroblasts from an affected individual.
CONCLUSIONS: The atad3-null zebrafish model emerges as a reliable representation of human ATAD3A-associated disorders, with similarities in differentially expressed pathways and processes. Furthermore, our study underscores mitochondrial dysfunction as the primary underlying pathogenic mechanism in ATAD3A-associated disorders and identifies potential readouts for therapeutic studies.

Keywords:   ATAD3A ; CRISPR/Cas9; Mitochondria; RNA-seq; Transcriptome; Zebrafish knockout model

DOI:  https://doi.org/10.1186/s13023-025-03709-0
Biochim Biophys Acta Mol Cell Res. 2025 Apr 15. pii: S0167-4889(25)00060-6. [Epub ahead of print] 119955

In vivo composition of the mitochondrial nucleoid in mice.

Rodolfo García-Villegas, Franka Odenthal, Yvonne Giannoula, Nina A Bonekamp, Inge Kühl, Chan Bae Park, Henrik Spåhr, Elisa Motori, Fredrik Levander, Nils-Göran Larsson.

  Mitochondrial DNA (mtDNA) is compacted into dynamic structures called mitochondrial nucleoids (mt-nucleoids), with the mitochondrial transcription factor A (TFAM) as the core packaging protein. We generated bacterial artificial chromosome (BAC) transgenic mice expressing FLAG-tagged TFAM protein (Tfam-FLAGBAC mice) to investigate the mt-nucleoid composition in vivo. Importantly, we show that the TFAM-FLAG protein is functional and complements the absence of the wild-type TFAM protein in homozygous Tfam knockout mice. We performed immunoprecipitation experiments from different mouse tissues and identified 12 proteins as core mt-nucleoid components by proteomics analysis. Among these, eight proteins correspond to mtDNA replication and transcription factors, while the other four are involved in the mitoribosome assembly. In addition, we used the Tfam-FLAGBAC mice to identify ten proteins that may stabilize TFAM-FLAG upon depletion of the mitochondrial RNA polymerase despite the absence of mtDNA and induction of the LONP1 protease. Finally, we evaluated the changes in mt-nucleoids caused by very high levels of TFAM unraveling nine interactors that could counteract the high TFAM levels to maintain active mtDNA transcription. Altogether, we demonstrate that the Tfam-FLAGBAC mice are a valuable tool for investigating the mt-nucleoid composition in vivo.

Keywords:  Mitochondrial nucleoid; Mitochondrial translation; TFAM; Transgenic mice; mtDNA expression

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119955
Int J Mol Sci. 2025 Mar 22. pii: 2902. [Epub ahead of print]26(7):

L-Carnitine and Mildronate Demonstrate Divergent Protective Effects on Mitochondrial DNA Quality Control and Inflammation Following Traumatic Brain Injury.

Artem P Gureev, Veronika V Nesterova, Polina I Babenkova, Mikhail E Ivanov, Egor Y Plotnikov, Denis N Silachev.

  Traumatic brain injuries (TBIs) are a serious problem affecting individuals of all ages. Mitochondrial dysfunctions represent a significant form of secondary injury and may serve as a promising target for therapeutic intervention. Our research demonstrated that craniotomy, which precedes the experimental induction of trauma in mice, can cause considerable damage to mitochondrial DNA (mtDNA), disrupt the regulatory expression of angiogenesis, and increase inflammation. However, the reduction in the mtDNA copy number and glial activation occur only after a direct impact to the brain. We explored two potential therapeutic agents: the dietary supplement L-carnitine-a potential reserve source of ATP for the brain-and the cardiac drug mildronate, which inhibits L-carnitine but activates alternative compensatory pathways for the brain to adapt to metabolic disturbances. We found that L-carnitine injections could protect against mtDNA depletion by promoting mitochondrial biogenesis. However, they also appeared to aggravate inflammatory responses, likely due to changes in the composition of the gut microbiome. On the other hand, mildronate enhanced the expression of genes related to angiogenesis while also reducing local and systemic inflammation. Therefore, both compounds, despite their opposing metabolic effects, have the potential to be used in the treatment of secondary injuries caused by TBI.

Keywords:  L-carnitine; gene expression; gut microbiome; inflammation; mildronate; mitochondrial DNA; traumatic brain injury

DOI:  https://doi.org/10.3390/ijms26072902
Biochem Biophys Res Commun. 2025 Apr 12. pii: S0006-291X(25)00474-7. [Epub ahead of print]763 151760

Yeast models of mutations in NFU1 gene for biochemical characterization and drug screening.

Siru Liu, Yi Liu, Wanyan Fan, Hua Zhou, Heng Cai.

  The mutations in the NFU1 gene result in the autosomal recessive hereditary disorder known as Multiple Mitochondrial Dysfunction Syndrome 1 (MMDS1). Pathogenic mutations cause the intra-mitochondrial target proteins of NFU1 (known as Nfu1 in yeast) to become dysfunctional. There have been reports of 20 NFU1 mutations to date, however the precise pathogenic mechanism of MMDS1 is yet unknown. In this study, we simulated the missense mutations identified in patients and constructed four yeast models to confirm the pathogenic relevance of these mutations in humans. We analyzed the mitochondrial phenotype of yeast cells, including their respiration and oxidative stress. Mutated yeast strains exhibited a higher frequency of small colony formation, suggesting enhanced mutability of mtDNA. There are differences in the effects of mutations at different sites on cells, and their severity may be related to the CxxC motif. Finally, we established an efficient, yeast-based method to select drugs capable of alleviating oxidative stress caused by NFU1 mutations. These yeast models are useful for studying the pathogenic association of novel mutations or rare polymorphisms in NFU1, which will provide theoretical guidance for treating MMDS1 disease or other mitochondrial diseases.

Keywords:  Drug drop test; Mitochondrial dysfunction; NFU1; Saccharomyces cerevisiae; Yeast model

DOI:  https://doi.org/10.1016/j.bbrc.2025.151760
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2025 Apr 14.

Mitochondria in focus: From structure and function to their role in human diseases. A review.

Daniel Follprecht, Jakub Vavricka, Viktorie Johankova, Pavel Broz, Ales Krouzecky.

  Mitochondria, double-membraned organelles within all eukaryotic cells, are essential for the proper functioning of the human organism. The frequently used phrase "powerhouses of the cell" fails to adequately capture their multifaceted roles. In addition to producing energy in the form of adenosine triphosphate through oxidative phosphorylation, mitochondria are also involved in apoptosis (programmed cell death), calcium regulation, and signaling through reactive oxygen species. Recent research suggests that they can communicate with one another and influence cellular processes. Impaired mitochondrial function on the one hand, can have widespread and profound effects on cellular and organismal health, contributing to various diseases and age-related conditions. Regular exercise on the other hand, promotes mitochondrial health by enhancing their volume, density, and functionality. Although research has made significant progress in the last few decades, mainly through the use of modern technologies, there is still a need to intensify research efforts in this field. Exploring new approaches to enhance mitochondrial health could potentially impact longevity. In this review, we focus on mitochondrial research and discoveries, examine the structure and diverse roles of mitochondria in the human body, explore their influence on energy metabolism and cellular signaling and emphasize their importance in maintaining overall health.

Keywords:  mitochondria; mitochondrial disease; mitochondrial function; oxidative phosphorylation; reactive oxygen species

DOI:  https://doi.org/10.5507/bp.2025.009
Proc Jpn Acad Ser B Phys Biol Sci. 2025 ;101(4): 224-237

Cellular senescence as a source of chronic microinflammation that promotes the aging process.

Makoto Nakanishi.

  Why and how do we age? This physiological phenomenon that we all experience remains a great mystery, largely unexplained even in this age of scientific and technological progress. Aging is a significant risk factor for numerous diseases, including cancer. However, underlying mechanisms responsible for this association remain to be elucidated. Recent findings have elucidated the significance of the accumulation of senescent cells and other inflammatory cells in organs and tissues with age, and their deleterious effects, such as the induction of inflammation in the microenvironment, as underlying factors contributing to organ dysfunction and disease development. Cellular senescence is a cellular phenomenon characterized by a permanent cessation of cell proliferation and secretion of several proinflammatory cytokines (senescence associated secretory phenotypes). Notably, the elimination of senescent cells from aging individuals has been demonstrated to alleviate age-related organ and tissue dysfunction, as well as various geriatric diseases. This review summarizes the molecular mechanisms by which senescent cells are induced and contribute to age-related diseases, as well as the technologies that ameliorate them.

Keywords:  DNA methylation; aging; cancer; neurodegenerative diseases; senescence; senolysis

DOI:  https://doi.org/10.2183/pjab.101.014
bioRxiv. 2025 Apr 02. pii: 2025.04.02.646853. [Epub ahead of print]

Interleukin-13-mediated alterations in esophageal epithelial mitochondria contribute to tissue remodeling in eosinophilic esophagitis.

Jazmyne L Jackson, Reshu Saxena, Mary Grace Murray, Abigail J Staub, Alena Klochkova, Travis H Bordner, Courtney Worrell, Annie D Fuller, John M Crespo, Andres J Klein-Szanto, John Elrod, Tatiana A Karakasheva, Melanie Ruffner, Amanda B Muir, Kelly A Whelan.

Background: The significance of mitochondria in EoE pathobiology remains elusive.
Objective: To determine the impact of EoE inflammatory mediators upon mitochondrial biology in esophageal epithelium, the mechanisms mediating these effects, and their functional significance to EoE pathobiology.
Methods: Mitochondria were evaluated in human biopsies, MC903/Ovalbumin-induced murine EoE, and human esophageal keratinocytes. Esophageal keratinocytes were treated with EoE-relevant cytokines and JAK/STAT inhibitor ruxolitinib. To deplete mitochondria, 3D organoids generated from TFAM loxp/loxp mice were subjected ex vivo to Cre or siRNA against Transcription factor A, mitochondria (TFAM) was transfected into esophageal keratinocytes. Mitochondrial respiration, membrane potential, and superoxide levels were measured.
Results: We find evidence of increased mitochondria in esophageal epithelium of patients with EoE and mice with EoE-like inflammation. In esophageal keratinocytes, IL-4 and IL-13 increase mitochondrial mass. IL-13 increases mitochondrial biogenesis in a JAK/STAT-dependent manner. In 3D organoids, IL-13 limits squamous cell differentiation (SCD), and this is blunted upon TFAM depletion. IL-13 decreases mitochondrial respiration and superoxide level, although mitochondria remain intact. IL-13-mediated suppression of superoxide was abrogated upon TFAM depletion in esophageal keratinocytes.
Conclusions: We report that increased mitochondrial mass is a feature of EoE. Among EoE-relevant cytokines, IL-13 is the primary driver of increased mitochondrial mass in esophageal keratinocytes by promoting mitochondrial biogenesis in a JAK/STAT-dependent manner. IL-13-mediated accumulation of mitochondria impairs SCD in esophageal keratinocytes and also suppresses oxidative stress, a factor that is known to induce SCD. These findings identify a novel mechanism through which IL-13 promotes EoE-associated epithelial remodeling.
Clinical Implication: These findings further lay a foundation for exploration of level of esophageal epithelial mitochondria as a predictive biomarker for response to dupilumab.
Capsule summary: IL-13 promotes mitochondrial biogenesis in esophageal epithelium, contributing to impaired squamous cell differentiation.

DOI: https://doi.org/10.1101/2025.04.02.646853
Genetics. 2025 Apr 15. pii: iyaf071. [Epub ahead of print]

Testing for differences in polygenic scores in the presence of confounding.

Jennifer Blanc, Jeremy J Berg.

  Polygenic scores have become an important tool in human genetics, enabling the prediction of individuals' phenotypes from their genotypes. Understanding how the pattern of differences in polygenic score predictions across individuals intersects with variation in ancestry can provide insights into the evolutionary forces acting on the trait in question and is important for understanding health disparities. However, because most polygenic scores are computed using effect estimates from population samples, they are susceptible to confounding by both genetic and environmental effects that are correlated with ancestry. The extent to which this confounding drives patterns in the distribution of polygenic scores depends on the patterns of population structure in both the original estimation panel and in the prediction/test panel. Here, we use theory from population and statistical genetics, together with simulations, to study the procedure of testing for an association between polygenic scores and axes of ancestry variation in the presence of confounding. We use a general model of genetic relatedness to describe how confounding in the estimation panel biases the distribution of polygenic scores in ways that depends on the degree of overlap in population structure between panels. We then show how this confounding can bias tests for associations between polygenic scores and important axes of ancestry variation in the test panel. Specifically, for any given test, there exists a single axis of population structure in the GWAS panel that needs to be controlled for in order to protect the test. In the context of this result, we study the behavior of multiple approaches to control for stratification along this axis, including standard methods such using principal components as fixed covariates in the GWAS, linear mixed models, and a novel approach for directly estimating the axis using the test panel genotypes. Our analyses highlight the role of estimation noise in the models of population structure as a plausible source of residual confounding in polygenic score analyses.

Keywords:  Confounding; Polygenic Scores; Population Structure

DOI:  https://doi.org/10.1093/genetics/iyaf071
Transl Pediatr. 2025 Mar 31. 14(3): 522-528

MtDNA 3243 A>G mutation and recurrent cholangitis after Kasai procedure in biliary atresia: a case report.

Jie Sun, Yanan Zhang, Dayan Sun, Jinshi Huang.

   Background: Cholangitis following the Kasai procedure contributes to a poor prognosis in biliary atresia (BA). We report a case of a pediatric patient with BA who developed recurrent cholangitis after undergoing a Kasai procedure and was subsequently found to carry the mitochondrial DNA (mtDNA) 3243 A>G mutation.
Case Description: This case involves a 7-month-old female infant who, at 2 months of age, exhibited symptoms including jaundice, stool discoloration, and dark urine, prompting a diagnosis of hyperbilirubinemia. Hepatobiliary dynamic imaging suggested BA, a diagnosis confirmed by abdominal ultrasound and laparoscopic exploration at our hospital. She underwent a Kasai procedure and was discharged on day 19. However, recurrent, treatment-resistant cholangitis subsequently led to her readmission. Given the patient's complex clinical course, genetic testing, conducted with informed consent, revealed a pathogenic mtDNA variant at position 3243 (A>G). Due to the severity of her condition, she underwent liver transplantation 5 months after the Kasai procedure.
Conclusions: This article reports a rare case of the mtDNA 3243 A>G mutation presenting as recurrent cholangitis, suggesting that mitochondrial dysfunction may consistently induce inflammation. This case highlights the importance of recognizing mitochondrial mutations in BA due to their critical impact on the patient's prognosis. A comprehensive genetic evaluation may benefit patients with BA accompanied by recurrent cholangitis.

Keywords:  Biliary atresia (BA); case report; cholangitis; genetic analysis; mitochondrial DNA mutation (mtDNA mutation)

DOI:  https://doi.org/10.21037/tp-2024-592
Cell Calcium. 2025 Apr 08. pii: S0143-4160(25)00026-0. [Epub ahead of print]127 103017

Calcium acts as a critical determinant of mitochondria-nuclear networking driven retrograde signaling.

Kriti Ahuja, Rajender K Motiani.

  Mitochondria are robust signaling organelle that regulate a variety of cellular functions. One of the key mechanisms that drive mitochondrial signaling is inter-organelle crosstalk. Mitochondria communicates with other organelles primarily via exchange of calcium (Ca2+), reactive oxygen species (ROS) and lipids across organelle membranes. Mitochondria has its own genome but a majority of mitochondrial proteins are encoded by nuclear genome. Therefore, several mitochondrial functions are controlled by nucleus via anterograde signaling. However, the role of mitochondria in driving expression of genes encoded by nuclear genome has recently gained attention. Recent studies from independent groups have demonstrated a critical role for mitochondrial Ca2+signaling in stimulating nuclear gene expression. These studies report that inhibition of mitochondrial Ca2+uptake through silencing of Mitochondrial Ca2+Uniporter (MCU) leads to Ca2+oscillations in the cytosol. The rise in cytosolic Ca2+ results in activation of Ca2+ sensitive transcription factors such as NFATs and NF-κB. These transcription factors consequently induce expression of their target genes in the nuclear genome. It is important to highlight that these groups used different cell types and elegantly presented a phenomenon that is conserved across various systems. Notably, mitochondrial Ca2+ signaling mediated transcriptional regulation controls diverse cellular functions ranging from B-cell activation, melanogenesis and aging associated inflammation. Future studies on this signaling module would result in better understanding of this axis in human pathophysiology and could lead to development of novel therapeutic strategies.

Keywords:  Calcium sensitive transcription factors; Mitochondrial calcium signaling; Nuclear transcription; Retrograde signaling

DOI:  https://doi.org/10.1016/j.ceca.2025.103017
Iran J Child Neurol. 2025 ;19(2): 131-141

Diverse Clinical manifestations of Cobalamin C Metabolism Disorders.

Hosein Eslamiyeh.

  Cobalamin, commonly known as vitamin B12, is a crucial micronutrient synthesized predominantly by a few microorganisms. In the human body, Vitamin B12 (Cobalamin) is essential for DNA synthesis and is required as a cofactor for functioning two crucial enzymes, methylmalonyl-CoA mutase and methionine synthase. The deficiency in these cobalamin-derivated coenzymes leads to enzyme activity dysfunction and an accumulation of their respective substrates, methylmalonic acid, and homocysteine,harming the brain and many other organs. Furthermore, deficiency in this micronutrient can lead to a wide spectrum of hematologic and neuropsychiatric disorders. In addition to vitamin B12 deficiency, some genetic disorders block the intracellular processing of Cobalamin to its cofactors and lead to symptoms somewhat similar to vitamin B12 deficiency. These disorders are called Cobalamin metabolism disorders. Many of them are reversible when diagnosed early and treated promptly. This group's most common and well-understood disease is Cobalamin C (CblC) metabolism disorder. This case series report aimed to provide a comprehensive overview of diverse clinical presentations within the spectrum of CblC metabolism disorder and the introduction of two cases of late-onset presentation with ataxia and repeated seizures as the first manifestation of the disorder. Few case reports are available, specifically in children, describing cerebellar ataxia and seizure as the first manifestations of late-onset CblC metabolism disorder. Additionally, this report sought to contribute to the existing literature by highlighting potential areas for timely recognition and targeted clinical and therapeutic interventions, thereby enhancing the comprehensive care and support for individuals affected by CblC metabolism disorder.

Keywords:  Cobalamin C deficiency; Epilepsies; Hydroxycobalamin; Methylmalonic acidemia and homocystinuriam Cerebellar Ataxias

DOI:  https://doi.org/10.22037/ijcn.v19i2.45047
Int J Mol Sci. 2025 Mar 27. pii: 3069. [Epub ahead of print]26(7):

Mitochondrial DNA in Exercise-Mediated Innate Immune Responses.

Xin Wen, Jingcheng Fan, Xuemei Duan, Xinyi Zhu, Jianzheng Bai, Tan Zhang.

  Mitochondria are considered as "the plant of power" with cells for a long time. However, recent researches suggest that mitochondria also take part in innate immune response to a great extent. Remarkably, mtDNA was reported to have immunnostimulatory potential in 2004. Since then, there has been rapid growth in understanding the role of mtDNA in innate immune. The mtDNA is released into cytosol, extracellular environment, or circulating blood through BAK/BAX pore, mPTP, and GSDMD pore upon mitochondrial damage, where it is recognized by PRRs including TLR9, cGAS, and NLRP3, thereby triggering innate immune response. On the other hand, regular exercise has been recognized as an effective intervention strategy for innate immune response. Some studies show that chronic moderate-intensity endurance exercise, resistance training, HIIT, and moderate-intensity acute exercise enhance mitochondrial function by promoting mtDNA transcription and replication, thus blunting the abnormal release of mtDNA and excessive innate immune response. On the contrary, high-intensity acute exercise elicits the opposite effect. Nevertheless, only a very small body of research by far has been performed to illustrate the impact of exercise on mtDNA-driven innate immune response, and an overall review is lacking. In light of these, we summarize the current knowledge on the mechanism mediating the release of mtDNA, the role of mtDNA in innate immune response and the influence of exercise on mtDNA leakage, hoping to pave the way to investigate new diagnostic and therapeutic approaches for immunopathies.

Keywords:  exercise; inflammation; innate immune; mtDNA

DOI:  https://doi.org/10.3390/ijms26073069
BMC Neurol. 2025 Apr 16. 25(1): 160

Investigating the genetic association of mitochondrial DNA copy number with neurodegenerative diseases.

Huan Xia, Zi-Hao Wang, Xiao-Bei Wang, Mei-Rong Gao, Sen Jiang, Xin-Yu Du, Xin-Ling Yang.

   OBJECTIVE: This study aims to investigate the causal relationship between Mitochondrial DNA (mtDNA) copy number and several common neurodegenerative diseases (NDs).
METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS) as instrumental variables (IVs). After screening for relevance and potential confounders, we estimated the association between mtDNA copy number and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS). Additionally, we validated our findings using GWAS data on mtDNA copy number from Longchamps et al., sourced from the Genetics Epidemiology Consortium and the UK Biobank (UKB) aging study cohort.
RESULTS: A GWAS analysis of 395,718 UKB participants found no significant association between mtDNA copy number and the risk of NDs, including AD (OR = 0.956, P = 0.708), PD (OR = 1.223, P = 0.179), ALS (OR = 0.972, P = 0.374), and MS (OR = 0.932, P = 0.789). Similarly, reverse MR analysis revealed no significant relationship between genetic predictions of NDs and mtDNA copy number: AD (OR = 0.987, P = 0.062), PD (OR = 0.997, P = 0.514), ALS (OR = 0.974, P = 0.706), and MS (OR = 1.003, P = 0.181).
CONCLUSION: Although mitochondrial dysfunction is implicated in the pathogenesis of NDs, no clear evidence supports a causal role for mtDNA copy number. The relationship between mtDNA copy number and NDs is likely mediated by more complex molecular regulatory mechanisms. Further research is required to elucidate these intricate interactions.

Keywords:  Genome-wide association studies; Mendelian randomization analysis; Mitochondrial DNA copy number; Neurodegenerative diseases

DOI:  https://doi.org/10.1186/s12883-025-04176-7
Prog Brain Res. 2025 ;pii: S0079-6123(25)00011-1. [Epub ahead of print]291 253-288

Stress-related neurodegenerative diseases: Molecular mechanisms implicated in neurodegeneration and therapeutic strategies.

Maryam Azarfarin, Nasrollah Moradikor, Sara Salatin, Mehdi Sarailoo, Masoomeh Dadkhah.

  Chronic stress is a striking cause of major neurodegenerative diseases disorders (NDDs). These diseases share several common mechanisms regarding to disease pathology, in spite of they have various properties and clinical manifestations. NDDs are defined by progressive cognitive decline, and stress contribute to the promotion and progression of disease. In addition, various pathways such as production of reactive oxygen species (ROS), mitochondrial dysfunction, and neurodegeneration are the main crucial hallmarks to develop common NDDs, resulting in neuronal cell death. Although the exact mechanisms of NDDs are underexplored, the potential neuroprotective critical role of such therapies in neuronal loss the treatment of NDDs are not clear. In this regard, researchers investigate the neuroprotective effects of targeting underlying cascade to introduce a promising therapeutic option to NDDs. Herein, we provide an overview of the role of non-pharmacological treatments against oxidative stress, mitochondrial symbiosis, and neuroinflammation in NDDs, mainly discussing the music, diet, and exercise effects of targeting pathways.

Keywords:  Mitochondrial dysfunction; Neurodegenerative diseases; Oxidative stress; Therapeutic strategies

DOI:  https://doi.org/10.1016/bs.pbr.2025.01.011
bioRxiv. 2025 Apr 01. pii: 2025.03.31.646497. [Epub ahead of print]

Impact of Serum Circulating Factors and PDE5 Inhibitor Therapy on Cardiomyocyte Metabolism in Single Ventricle Heart Disease.

Anastacia M Garcia, Ashley E Pietra, Mary E Turner, Julie Pires Da Silva, Angela N Baybayon-Grandgeorge, Genevieve C Sparagna, Danielle A Jeffrey, Brian L Stauffer, Carmen C Sucharov, Shelley D Miyamoto.

Background: While operative and perioperative care continues to improve for single ventricle congenital heart disease (SV), long-term morbidities and mortality remain high. Importantly, phosphodiesterase-5 inhibitor therapies (PDE5i) are increasingly used, however, little is known regarding the direct myocardial effects of PDE5i therapy in the SV population.
Objectives: Our group has previously demonstrated that the failing SV myocardium is characterized by increased PDE5 activity and impaired mitochondrial bioenergetics. Here we sought to determine whether serum circulating factors contribute to pathological metabolic remodeling in SV, and whether PDE5i therapy abrogates these changes.
Methods: Using an established in vitro model whereby primary cardiomyocytes are treated with patient sera +/- PDE5i, we assessed the impact of circulating factors on cardiomyocyte metabolism. Mass spectrometry-based lipidomics and metabolomics were performed to identify phospholipid and metabolite changes. Mitochondrial bioenergetics were assessed using the Seahorse Bioanalyzer and a stable isotope based mitochondrial enzyme activity assay. Relative mitochondrial copy number was quantified using RT-qPCR.
Results: Our data suggest that serum circulating factors contribute to fundamental changes in cardiomyocyte bioenergetics, including impaired mitochondrial function associated with decreased cardiolipin and other phospholipid species, increased reactive oxygen species (ROS) generation, and altered metabolite milieu. Treatment with PDE5i therapy was sufficient to abrogate a number of these metabolic changes, including a rescue of phosphatidylglycerol levels, a reduction in ROS, improved energy production, and normalization of several key metabolic intermediates.
Conclusions: Together, these data suggest PDE5i therapy has direct cardiomyocyte effects and contributes to beneficial cardiomyocyte metabolic remodeling in SV failure.

DOI: https://doi.org/10.1101/2025.03.31.646497
Pediatr Res. 2025 Apr 17.

Mitochondrial DNA haplogroups and circulating cell-free mitochondrial DNA as biomarkers of bronchopulmonary dysplasia.

Sara María Fernandez-Gonzalez, Andrea Sucasas-Alonso, Vanesa Balboa-Barreiro, Ignacio Rego-Perez, Alejandro Avila-Alvarez.

BACKGROUND: Recognizing which premature infants are at higher risk of developing BPD/death is a challenge in neonatology. The aims of our study are to identify mitochondrial haplogroups and quantify circulating cell-free mitochondrial DNA (ccf-mtDNA) levels in very preterm infants at risk of bronchopulmonary dysplasia (BPD) or death and explore the relationship between these variables and the development of BPD/death.
METHODS: Single-center prospective cohort study including preterm infants of ≤32 weeks gestational age (GA) and birth weight ≤1500 g. Clinical variables, mitochondrial haplogroups, and ccf-mtDNA levels were determined. Subsequently, diagnosis and staging of BPD/death were performed, and groups were compared.
RESULTS: The population consisted of 107 newborns (mean GA 28.73 ± 2 weeks; mean birth weight 1,121 ± 332 g). A total of 44 patients (41.1%) presented the outcome of BPD/death without differences in haplogroup distribution and ccf-mtDNA levels between those who survived without BPD (controls). Variables independently associated with BPD/death included GA (p < 0.001; OR = 0.36 [95%CI 0.23-0.5]), birth weight (p < 0.001; OR = 0.99 [95%CI 0.99-0.99]), maximum FiO2 in the delivery room (p = 0.001; OR = 1.07 [95%CI 1.03-1.12]), hours on mechanical ventilation (p = 0.02; OR 1.02 [95%CI 1.00-1.02]), and postnatal corticosteroids (p < 0.001; OR = 47.12 [95%CI = 5.98-371.1]).
CONCLUSION: This is the first study to characterize mtDNA haplogroups and ccf-mtDNA in very preterm infants at risk of BPD/death. None of the mitochondrial variables studied were associated with BPD/death. Further research is needed to elucidate the role of mtDNA in BPD.
IMPACT STATEMENT: Despite advances in perinatal care, bronchopulmonary dysplasia continues to be the most common chronic pulmonary morbidity associated with prematurity. Prediction of BPD in early stages is crucial to improve BPD rates, but this remains a major challenge in neonatal units. Given that mitochondria play an important role in the inflammatory and oxidative stress responses, we aimed to explore the relationship between mitochondrial haplogroups, circulating cell-free mitochondrial DNA levels, and BPD. This is the first work carried out in very preterm infants where mitochondrial haplogroups and the levels ccf-mtDNA are investigated with the intention of discovering a new biomarker for BPD.

DOI: https://doi.org/10.1038/s41390-025-04052-7
Orphanet J Rare Dis. 2025 Apr 14. 20(1): 177

A population-based cohort study of mitochondrial disease and mental health conditions in Ontario, Canada.

Laura C Rosella, Mackenzie Hurst, Emmalin Buajitti, Thomas Samson, L Trevor Young, Ana C Andreazza.

   BACKGROUND: Mitochondrial disease has been linked to mental health disorder in clinical cohorts and post-mortem studies. However, a lack of population-level studies examining the relationship between mitochondrial disease and mental health has resulted in an evidence gap and creates a challenge for identifying and addressing care needs for the mitochondrial disease population. Using multiple linked population health databases in a single-payer health system that covers the full population, this study aimed to investigate the prevalence of mood disorders and other mental health conditions in patients with mitochondrial disease and to examine the joint impact of mitochondrial disease and mental health conditions on healthcare use and health system costs. To contextualize these findings, a clinical comparator cohort of multiple sclerosis (MS) patients was analyzed.
RESULTS: Overall, co-prevalent mental health conditions are common in the mitochondrial population. Double the proportion of patients in the mitochondrial disease cohort had a co-prevalent mental health illness as compared to the MS population (18% vs 9%). Healthcare utilization was highest among patients with co-prevalent mitochondrial disease and mental illness, with 49% hospitalized within 1 year prior to cohort entry (compared to 12% of MS patients with no mental health condition). Costs were likewise highest among mitochondrial disease patients with mental health conditions.
CONCLUSIONS: This study presents the first comprehensive, population-wide cohort study of mitochondrial disease and co-prevalent mental health conditions. Our findings demonstrate a high burden of mental health conditions among mitochondrial disease patients, with high associated health care needs. We also find that patients with concurrent mental illness and mitochondrial disease represent a high-burden, high-cost population in a single-payer health insurance setting.

Keywords:  Epidemiology; Health care costs; Health care utilization; Mental health; Mitochondrial disease

DOI:  https://doi.org/10.1186/s13023-025-03688-2
J Pharm Anal. 2025 Apr;15(4): 101074

Pharmacological modulation of mitochondrial function as novel strategies for treating intestinal inflammatory diseases and colorectal cancer.

Boya Wang, Xinrui Guo, Lanhui Qin, Liheng He, Jingnan Li, Xudong Jin, Dapeng Chen, Guangbo Ge.

  Inflammatory bowel disease (IBD) is a chronic and recurrent intestinal disease, and has become a major global health issue. Individuals with IBD face an elevated risk of developing colorectal cancer (CRC), and recent studies have indicated that mitochondrial dysfunction plays a pivotal role in the pathogenesis of both IBD and CRC. This review covers the pathogenesis of IBD and CRC, focusing on mitochondrial dysfunction, and explores pharmacological targets and strategies for addressing both conditions by modulating mitochondrial function. Additionally, recent advancements in the pharmacological modulation of mitochondrial dysfunction for treating IBD and CRC, encompassing mitochondrial damage, release of mitochondrial DNA (mtDNA), and impairment of mitophagy, are thoroughly summarized. The review also provides a systematic overview of natural compounds (such as flavonoids, alkaloids, and diterpenoids), Chinese medicines, and intestinal microbiota, which can alleviate IBD and attenuate the progression of CRC by modulating mitochondrial function. In the future, it will be imperative to develop more practical methodologies for real-time monitoring and accurate detection of mitochondrial function, which will greatly aid scientists in identifying more effective agents for treating IBD and CRC through modulation of mitochondrial function.

Keywords:  Colorectal cancer; Inflammatory bowel disease; Mitochondria; Mitochondrial DNA; Pharmacology

DOI:  https://doi.org/10.1016/j.jpha.2024.101074
Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2503531122

RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis.

Ololade Folajimi Awoyomi, Choco Michael Gorospe, Biswajit Das, Pradeep Mishra, Sushma Sharma, Olena Diachenko, Anna Karin Nilsson, Phong Tran, Paulina H Wanrooij, Andrei Chabes.

  Mitochondrial DNA (mtDNA) replication requires a steady supply of deoxyribonucleotides (dNTPs), synthesized de novo by ribonucleotide reductase (RNR). In nondividing cells, RNR consists of RRM1 and RRM2B subunits. Mutations in RRM2B cause mtDNA depletion syndrome, linked to muscle weakness, neurological decline, and early mortality. The impact of RRM2B deficiency on dNTP pools in nondividing tissues remains unclear. Using a mouse knockout model, we demonstrate that RRM2B deficiency selectively depletes dATP and dGTP, while dCTP and dTTP levels remain stable or increase. This depletion pattern resembles the effects of hydroxyurea, an inhibitor that reduces overall RNR activity. Mechanistically, we propose that the depletion of dATP and dGTP arises from their preferred degradation by the dNTPase SAMHD1 and the lower production rate of dATP by RNR. Identifying dATP and dGTP depletion as a hallmark of RRM2B deficiency provides insights for developing nucleoside bypass therapies to alleviate the effects of RRM2B mutations.

Keywords:  dNTP metabolism; genome stability; mtDNA stability; ribonucleotide reductase

DOI:  https://doi.org/10.1073/pnas.2503531122
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 10. pii: S0925-4439(25)00184-X. [Epub ahead of print] 167839

Mitochondrial classic metabolism and its often-underappreciated facets.

João P Moura, Paulo J Oliveira, Ana M Urbano.

  For many decades, mitochondria were essentially regarded as the main providers of the adenosine triphosphate (ATP) required to maintain the viability and function of eukaryotic cells, thus the widely popular metaphor "powerhouses of the cell". Besides ATP generation - via intermediary metabolism - these organelles have also traditionally been known, albeit to a lesser degree, for their notable role in biosynthesis, both as generators of biosynthetic intermediates and/or as the sites of biosynthesis. From the 1990s onwards, the concept of mitochondria as passive organelles providing the rest of the cell, from which they were otherwise isolated, with ATP and biomolecules on an on-demand basis has been challenged by a series of paradigm-shifting discoveries. Namely, it was shown that mitochondria act as signaling effectors to upregulate ATP generation in response to growth-promoting stimuli and that they are actively engaged, through signaling and epigenetics, in the regulation of a plethora of cellular processes, ultimately deciding cell function and fate. With the focus of mitochondrial research increasingly placed in these "non-classical" functions, the centrality of mitochondrial intermediary metabolism to biosynthesis and other mitochondrial functions tends to be overlooked. In this article, we revisit mitochondrial intermediary metabolism and illustrate how its intermediates, by-products and molecular machinery underpin other mitochondrial functions. A certain emphasis is given to frequently overlooked functions, namely the biosynthesis of iron‑sulfur (FeS) clusters, the only known function shared by all mitochondria and mitochondrion-related organelles. The generation of reactive oxygen species (ROS) and their putative role in signaling is also discussed in detail.

Keywords:  Educational article; Intermediary metabolism; Iron‑sulfur clusters; Metabolic energy; Mitochondrion-related organelles; ROS signaling

DOI:  https://doi.org/10.1016/j.bbadis.2025.167839
Sci Adv. 2025 Apr 18. 11(16): eads1842

Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.

Kristina Bubb, Julia Etich, Kristina Probst, Tanvi Parashar, Maximilian Schuetter, Frederik Dethloff, Susanna Reincke, Janica L Nolte, Marcus Krüger, Ursula Schlötzer-Schrehard, Julian Nüchel, Constantinos Demetriades, Patrick Giavalisco, Jan Riemer, Bent Brachvogel.

Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.

DOI: https://doi.org/10.1126/sciadv.ads1842
Nutrients. 2025 Apr 04. pii: 1268. [Epub ahead of print]17(7):

Investigating the Therapeutic Potential of the Ketogenic Diet in Modulating Neurodegenerative Pathophysiology: An Interdisciplinary Approach.

Iqra Shabbir, Keying Liu, Bakhtawar Riaz, Muhammad Farhan Rahim, Saiyi Zhong, Jude Juventus Aweya, Kit-Leong Cheong.

  The ketogenic diet (KD) is a dietary intervention comprising a high-fat, low-carbohydrate, and moderate-protein intake designed to induce a metabolic state known as ketosis, whereby ketone bodies are produced as an alternative source of energy. Initially established as a treatment for intractable epilepsy, the KD has subsequently gained significant attention for its potential to manage neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's disease. Ketone bodies, such as beta-hydroxybutyrate (BHB), have been demonstrated to possess neuroprotective properties. The increasing prevalence of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, poses a significant public health challenge worldwide. With neurological disorders being the second-leading cause of death globally, the need for effective therapeutic interventions has never been more urgent. Recent evidence suggests that dietary interventions, particularly the ketogenic diet, offer promising potential in mitigating the progression of these diseases by influencing metabolic processes and providing neuroprotective benefits. The ketogenic diet, characterized by high-fat and low-carbohydrate intake, induces ketosis, leading to the production of ketone bodies like beta-hydroxybutyrate, which enhance mitochondrial efficiency, reduce oxidative stress, and modulate inflammatory pathways-mechanisms critical in neurodegenerative pathophysiology. This review explores the role of the ketogenic diet in managing neurological conditions, examining its mechanisms of action, historical context, and therapeutic efficacy. The paper also discusses emerging evidence linking the ketogenic diet to improved cognitive function, reduced motor symptoms, and enhanced mitochondrial activity in patients with neurodegenerative disorders. Additionally, the review highlights the need for further research to refine the therapeutic applications of the ketogenic diet, investigate its impact on various neurodegenerative diseases, and better understand its potential long-term effects. This study underscores the importance of nutrition as a vital aspect of the treatment strategy for neurological diseases, advocating for continued exploration of dietary interventions to improve brain health and function.

Keywords:  Alzheimer’s disease; Parkinson’s disease; beta-hydroxybutyrate; cognitive function; ketogenic diet; mitochondrial function; neurodegenerative diseases; neuroprotection

DOI:  https://doi.org/10.3390/nu17071268