bims-polgdi 2025-05-11 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–05–11
24 papers selected by
Luca Bolliger, lxBio

The Role of N6-Methyladenosine in Mitochondrial Dysfunction and Pathology.
The role of mitochondrial mRNA translation in cellular communication.
[The regulatory effect and mechanism of PGC-1α on mitochondrial function].
Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.
Impaired Mitochondrial Biogenesis Inhibits Epithelial-Mesenchymal Transition in Villi of PCOS Patients.
The involvement of mitochondria in erythrocyte pathology and diseases: from mechanisms to therapeutic strategies.
Agent-based modeling of neuronal mitochondrial dynamics using intrinsic variables of individual mitochondria.
Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.
Tracing mitochondrial marks of neuronal aging in iPSCs-derived neurons and directly converted neurons.
R-loop control and mitochondrial genome stability require the 5'-3' exonuclease/flap endonuclease OEX1.
Perspectives on the interpretation of mitochondrial responses during skeletal muscle disuse-induced atrophy.
Phase separation in mitochondrial fate and mitochondrial diseases.
Effect of aging, endurance training, and denervation on innate immune signaling in skeletal muscle.
Synthetic DNA and mitochondrial donation: no need for donor eggs?
Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.
Isolated and Syndromic Genetic Optic Neuropathies: A Review of Genetic and Phenotypic Heterogeneity.
The Power Struggle: Kynurenine Pathway Enzyme Knockouts and Brain Mitochondrial Respiration.
Holistic Exome-Based Genetic Testing in Adults With Epilepsy.
A Review of the Neuroprotective Properties of Exosomes Derived from Stem Cells and Exosome-Coated Nanoparticles for Treating Neurodegenerative Diseases and Stroke.
Current Development of iPSC-Based Modeling in Neurodegenerative Diseases.
Exosome-powered neuropharmaceutics: unlocking the blood-brain barrier for next-gen therapies.
Say hello to my little friend… micronutraceuticals in neuroenergetics, neuronal health, and neurodegenerative diseases.
[Recent advances on the role of exosomes in neurodegenerative diseases].
Metformin aggravates pancreatitis by regulating the release of oxidised mitochondrial DNA via the frataxin (FXN)/ninjurin 1 (NINJ1) signalling pathway.

Int J Mol Sci. 2025 Apr 11. pii: 3624. [Epub ahead of print]26(8):

The Role of N6-Methyladenosine in Mitochondrial Dysfunction and Pathology.

Wenxin Yan, Saqirile, Ke Li, Kexin Li, Changshan Wang.

  Mitochondria are indispensable in cells and play crucial roles in maintaining cellular homeostasis, energy production, and regulating cell death. Mitochondrial dysfunction has various manifestations, causing different diseases by affecting the diverse functions of mitochondria in the body. Previous studies have mainly focused on mitochondrial-related diseases caused by nuclear gene mutations or mitochondrial gene mutations, or mitochondrial dysfunction resulting from epigenetic regulation, such as DNA and histone modification. In recent years, as a popular research area, m6A has been involved in a variety of important processes under physiological and pathological conditions. However, there are few summaries on how RNA methylation, especially m6A RNA methylation, affects mitochondrial function. Additionally, the role of m6A in pathology through influencing mitochondrial function may provide us with a new perspective on disease treatment. In this review, we summarize several manifestations of mitochondrial dysfunction and compile examples from recent years of how m6A affects mitochondrial function and its role in some diseases.

Keywords:  N6-methydenosine; cancer; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/ijms26083624
J Cell Sci. 2025 May 01. pii: jcs263753. [Epub ahead of print]138(9):

The role of mitochondrial mRNA translation in cellular communication.

Eleonora Zilio, Tim Schlegel, Marta Zaninello, Elena I Rugarli.

  Mitochondria are dynamic and heterogeneous organelles that rewire their network and metabolic functions in response to changing cellular needs. To this end, mitochondria integrate a plethora of incoming signals to influence cell fate and survival. A crucial and highly regulated node of cell-mitochondria communication is the translation of nuclear-encoded mitochondrial mRNAs. By controlling and monitoring the spatio-temporal translation of these mRNAs, cells can rapidly adjust mitochondrial function to meet metabolic demands, optimise ATP production and regulate organelle biogenesis and turnover. In this Review, we focus on how RNA-binding proteins that recognise nuclear-encoded mitochondrial mRNAs acutely modulate the rate of translation in response to nutrient availability. We further discuss the relevance of localised translation of these mRNAs for subsets of mitochondria in polarised cells. Finally, we highlight quality control mechanisms that monitor the translation process at the mitochondrial surface and their connections to mitophagy and stress responses. We propose that these processes collectively contribute to mitochondrial specialisation and signalling function.

Keywords:  Cell signalling; Mitochondria; RNA-binding proteins; Ribosome quality control; Translation; mRNA

DOI:  https://doi.org/10.1242/jcs.263753
Sheng Li Xue Bao. 2025 Apr 25. 77(2): 300-308

[The regulatory effect and mechanism of PGC-1α on mitochondrial function].

Song-Hua Nan, Chao-Jie Peng, Ying-Lin Cui.

Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) is a core member of the PGC-1 family and serves as a transcriptional coactivator, playing a crucial regulatory role in various diseases. Mitochondria, the main site of cellular energy metabolism, are essential for maintaining cell growth and function. Their function is regulated by various transcription factors and coactivators. PGC-1α regulates the biogenesis, dynamics, energy metabolism, calcium homeostasis, and autophagy processes of mitochondria by interacting with multiple nuclear transcription factors, thereby exerting significant effects on mitochondrial function. This review explores the biological functions of PGC-1α and its regulatory effects and related mechanisms on mitochondria, providing important information for our in-depth understanding of the role of PGC-1α in cellular metabolism. The potential role of PGC-1α in metabolic diseases, cardiovascular diseases, and neurodegenerative diseases was also discussed, providing a theoretical basis for the development of new treatment strategies.

DOI: https://doi.org/10.13294/j.aps.2025.0036
Aging Cell. 2025 May 02. e70085

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.

Hiroaki Tamashiro, Kaori Ishikawa, Koichi Sadotomo, Emi Ogasawara, Kazuto Nakada.

  mtDNA mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear. Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced. To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal. These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.

Keywords:  aging; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.1111/acel.70085
Endocrinology. 2025 Apr 22. pii: bqaf076. [Epub ahead of print]166(6):

Impaired Mitochondrial Biogenesis Inhibits Epithelial-Mesenchymal Transition in Villi of PCOS Patients.

Hui-Ying Jie, Lu Luo, Bing Cai, Yan Xu, Yuan Yuan, Yang-Xing Wen, Si-Min Liu, Ji-Fan Tan, Ming-Hui Chen, Can-Quan Zhou, Qing-Yun Mai.

   CONTEXT: Polycystic ovary syndrome (PCOS) is accompanied by impaired mitochondrial biogenesis in the ovary and uterus. Whether impaired mitochondrial biogenesis exhibits in villi of PCOS, and its effect and underlying mechanism remain unclear.
OBJECTIVE: This work aimed to investigate mitochondrial biogenesis status and effect on villi of PCOS patients.
METHODS: Placenta RNA-sequencing data of PCOS downloaded from the GEO database was analyzed with Gene Set Enrichment Analysis (GSEA). GSEA results were validated in first-trimester villi of 8 PCOS patients with euploid miscarriage and 22 matched controls. The function and impact of mitochondrial biogenesis on trophoblast cells were investigated using human trophoblast cell lines HTR-8/SVneo and BeWo.
RESULTS: Mitochondria-related and epithelial-mesenchymal transition (EMT) pathways were enriched in placentas of PCOS. In villi of PCOS patients with euploid miscarriage, reduced mitochondrial DNA copy number (mtDNA CN) and N-cadherin protein level, and an elevated E-cadherin protein level were detected, indicating mitochondrial biogenesis dysfunction and impaired EMT. 5 α-Dihydrotestosterone (DHT) exposure downregulated mtDNA CN via reducing mitochondrial transcription factor A (TFAM) level, a critical transcription factor of mtDNA, in HTR-8/SVneo cells. Decreased expression level of TFAM was observed in villi of PCOS. Knockdown of TFAM significantly impeded EMT, characterized by decreased levels of N-cadherin and vimentin in HTR-8/SVneo cells, and increased level of E-cadherin in BeWo cells. Reduction of reactive oxygen species (ROS) mitigated TFAM knockdown-induced impairment of EMT via increasing nuclear Yes-associated protein level in trophoblast cells.
CONCLUSION: The villi of PCOS patients with euploid miscarriage exhibited impaired mitochondrial biogenesis. Androgen-induced downregulation of TFAM impeded EMT via ROS/YAP axis in trophoblast cell.

Keywords:  TFAM; epithelial-mesenchymal transition (EMT); hyperandrogenism; miscarriage; mitochondrial biogenesis; polycystic ovary syndrome (PCOS)

DOI:  https://doi.org/10.1210/endocr/bqaf076
Clin Exp Med. 2025 May 09. 25(1): 144

The involvement of mitochondria in erythrocyte pathology and diseases: from mechanisms to therapeutic strategies.

Dier Lin, Hongjun Yang, Xiaoxue Liang, Mengjiao Yang, Yangyang Zhao.

  Erythrocytes, as the predominant cellular components within the bloodstream, are crucial for the maintenance of physiological health. Mitochondria, known as cellular powerhouses and metabolic regulators, play a critical role in the maturation of the erythroid lineage. The absence of mitochondria in red blood cells upon completing their maturation process is a defining characteristic of their development. Dysregulation of mitochondrial metabolism has been associated with the onset and progression of various diseases. Mitochondrial metabolic disorders, along with the involvement of mitochondria in the induction of oxidative stress and the activation of immune responses, significantly contribute to the pathogenesis of diverse hematologic disorders, particularly in sickle cell disease. This review offers a comprehensive overview of the role of mitochondria in disorders related to abnormal erythropoiesis, immune responses, and hemolysis, as well as evaluating potential therapeutic strategies that target mitochondria. Ultimately, we emphasize the necessity for future research to elucidate the involvement of mitochondria in red blood cell disorders, which may inform the development of novel diagnostic and therapeutic approaches.

Keywords:  Anemia; Immune responses; Mitochondria; Oxidative stress; Red blood cell

DOI:  https://doi.org/10.1007/s10238-024-01555-1
iScience. 2025 May 16. 28(5): 112390

Agent-based modeling of neuronal mitochondrial dynamics using intrinsic variables of individual mitochondria.

Garrett M Fogo, Francisco J Torres Torres, Reagan L Speas, Anthony R Anzell, Thomas H Sanderson.

  Mitochondrial networks undergo remodeling to regulate form and function. The dynamic nature of mitochondria is maintained by the dueling processes of mitochondrial fission and fusion. Dysfunctional mitochondrial dynamics have been linked to debilitating diseases and injuries, suggesting mitochondrial dynamics as a promising therapeutic target. Increasing our understanding of the factors influencing mitochondrial dynamics will help inform therapeutic development. Utilizing live imaging of primary neurons, we analyzed how intrinsic properties of individual mitochondria influence their behavior. We found that size, shape, mitochondrial membrane potential, and protein oxidation predict mitochondrial fission and fusion. We constructed an agent-based model of mitochondrial dynamics, the mitochondrial dynamics simulation (MiDyS). In silico experiments of neuronal ischemia/reperfusion injury and antioxidant treatment illustrate the utility of MiDyS for testing hypothesized mechanisms of injury progression and evaluating therapeutic strategies. We present MiDyS as a framework for leveraging in silico experimentation to inform and improve the design of therapeutic trials.

Keywords:  Cell biology; Molecular biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.112390
Ageing Res Rev. 2025 May 02. pii: S1568-1637(25)00108-4. [Epub ahead of print]109 102762

Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.

Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.

  Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.

Keywords:  Aging; Liver; Mitochondria; Mitohormesis; Muscle; Sestrin2

DOI:  https://doi.org/10.1016/j.arr.2025.102762
Commun Biol. 2025 May 10. 8(1): 723

Tracing mitochondrial marks of neuronal aging in iPSCs-derived neurons and directly converted neurons.

Nimmy Varghese, Leonora Szabo, M Zameel Cader, Imane Lejri, Amandine Grimm, Anne Eckert.

This study aims to determine if neurons derived from induced pluripotent stem cells (iPSCsNs) and directly converted neurons (iNs) from the same source cells exhibit changes in mitochondrial properties related to aging. This research addresses the uncertainty around whether aged iPSCsNs retain aging-associated mitochondrial impairments upon transitioning through pluripotency while direct conversion maintains these impairments. We observe that both aged models exhibit characteristics of aging, such as decreased ATP, mitochondrial membrane potential, respiration, NAD+/NADH ratio, and increased radicals and mitochondrial mass. In addition, both neuronal models show a fragmented mitochondrial network. However, aged iPSCsNs do not exhibit a metabolic shift towards glycolysis, unlike aged iNs. Furthermore, mRNA expression differed significantly between aged iPSCsNs and aged iNs. The study concludes that aged iPSCsNs may differ in transcriptomics and the aging-associated glycolytic shift but can be a valuable tool for studying specific feature of mitochondrial neuronal aging in vitro alongside aged iNs.

DOI: https://doi.org/10.1038/s42003-025-08152-2
Plant Cell. 2025 May 05. pii: koaf104. [Epub ahead of print]

R-loop control and mitochondrial genome stability require the 5'-3' exonuclease/flap endonuclease OEX1.

Déborah Schatz, Anaïs Le Blevenec, Fabio G Moratti, Kin Pan Chung, Pierre Mercier, Rana Khalid Iqbal, Elody Vallet, André Dietrich, Ralph Bock, Frédérique Weber-Lotfi, José M Gualberto.

Maintenance of the plant organelle genomes involves factors mostly inherited from their symbiotic ancestors. In bacteria, DNA Polymerase I (Pol I) performs multiple replication and repair functions through its 5'-3'-exonuclease/flap-endonuclease domain. Plant organelles possess two DNA polymerases that are evolutionarily derived from Pol I but lack this key domain. ORGANELLAR EXONUCLEASES 1 and 2 (OEX1 and OEX2) compensate for this missing function and are targeted to mitochondria and chloroplasts, respectively, in Arabidopsis (Arabidopsis thaliana). Loss of OEX1 causes developmental and fertility defects that increase with increasing differential segregation of mitochondrial DNA (mtDNA) subgenomes generated by recombination. OEX1 activity is modulated by alternative splicing, which generates two isoforms that variably affect mtDNA stability and repair. OEX1 has 5'-3'-exonuclease and flap endonuclease activities, with a high affinity for RNA-DNA hybrids. It rapidly degrades RNA in Okazaki-like structures and R-loops. Consistent with a role in suppressing R-loops, oex1 mutant plants accumulate RNA-DNA hybrids in highly transcribed mtDNA regions. Taken together, our results identify OEX1 as an important factor that compensates for the missing activity of plant organellar polymerases, playing multiple important roles in the processing of replication and recombination intermediates, such as replication primers and R-loops, whose accumulation can lead to genome instability.

DOI: https://doi.org/10.1093/plcell/koaf104
J Physiol. 2025 May 05.

Perspectives on the interpretation of mitochondrial responses during skeletal muscle disuse-induced atrophy.

Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Christopher G R Perry.

  Reductions in skeletal muscle mitochondrial respiration or increases in mitochondrial reactive oxygen species (ROS) are often interpreted as 'mitochondrial dysfunctions'. However, such changes can also occur as intentional programmed responses to stressors. The term 'mitochondrial dysfunction' could therefore consider the net impact of such responses on other cellular functions. In the case of disuse-induced skeletal muscle atrophy, lower mitochondrial respiration, increased ROS and increased mitochondrial-linked apoptosis have been associated with muscle loss. Such observations support hypotheses that mitochondria contribute to atrophy. If true, there are exciting opportunities for exploring therapeutic strategies that prevent such changes in mitochondrial metabolism. These observations might also support alternative hypotheses where mitochondria are intentionally reprogrammed to serve specific purposes, such as a recalibration of ATP supply to reduced ATP demand during disuse. The goal of this review is to describe what is known regarding skeletal muscle mitochondrial functional responses to muscle disuse, as well as to discuss how these foundational discoveries might lead to new directions that determine whether mitochondrial responses to disuse are causal of atrophy or are adaptive in nature. Three critical questions for consideration include: (1) when is a change in mitochondrial function 'dysfunctional'; (2) how might changes in mitochondrial function represent intentional reprogramming to serve specific purposes; and (3) what factors should be considered when constructing experimental designs to determine the role of mitochondrial functional responses to disuse? Understanding when mitochondrial functional remodelling are dysfunctions or adaptive responses could inform new therapeutic approaches to maintain muscle mass during periods of disuse.

Keywords:  mitochondrial energetics; muscle disuse; skeletal muscle

DOI:  https://doi.org/10.1113/JP284160
Proc Natl Acad Sci U S A. 2025 May 27. 122(21): e2422255122

Phase separation in mitochondrial fate and mitochondrial diseases.

Qingyi Chen, Sanqi An, Chuanlong Wang, Yanshuang Zhou, Xingguo Liu, Wenkai Ren.

  Mitochondria are central metabolic organelles that control cell fate and the development of mitochondrial diseases. Traditionally, phase separation directly regulates cell functions by driving RNA, proteins, or other molecules to concentrate into lipid droplets. Recent studies show that phase separation regulates cell functions and diseases through the regulation of subcellular organelles, particularly mitochondria. In fact, phase separation is involved in various mitochondrial activities including nucleoid assembly, autophagy, and mitochondria-related inflammation. Here, we outline the key mechanisms through which phase separation influences mitochondrial activities and the development of mitochondrial diseases. Insights into how phase separation regulates mitochondrial activities and diseases will help us develop interventions for related diseases.

Keywords:  mitochondrial disease; mitochondrial dynamics; mitophagy; nucleoid assembly; phase separation

DOI:  https://doi.org/10.1073/pnas.2422255122
J Appl Physiol (1985). 2025 May 08.

Effect of aging, endurance training, and denervation on innate immune signaling in skeletal muscle.

Priyanka Khemraj, Anastasiya Kuznyetsova, David A Hood.

  Skeletal muscle function relies on mitochondria for energy and for mediating its unique adaptive plasticity. The NLRP3 inflammasome complex is an innate immune mechanism that responds to mitochondrial damage-associated molecular patterns (DAMPS), however its activity relative to mitochondrial dysfunction in muscle requires exploration. The purpose of this study was to characterize immune signaling and mitochondrial function in muscle during aging, endurance training, and disuse induced by denervation. Denervation led to decreases in muscle mass, mitochondrial content, and impaired respiration. Protein analyses revealed increases in NF-κB p65 and downstream inflammatory markers including NLRP3, caspase-1, GSDMD-N, STING and IL-1β, along with pro-apoptotic BAX and AIF. When assessing potential DAMPS, denervation led to increased ROS production but no changes in cytosolic mtDNA levels, relative to total mtDNA. Since we hypothesized that inflammasome activation would be increased with age, we studied young (6-8 months) and aged (21-22 months) mice that remained sedentary or underwent a 6-week voluntary running protocol. Aging resulted in marked increases in the expression of multiple pro-inflammatory and pro-apoptotic proteins. Remarkably, training uniformly attenuated age-related increases in BAX, NLRP3, caspase-1, STING, and GSDMD protein expression, and tended to reduce the elevated level of cytosolic mtDNA evident in aged muscle. Training adaptations were evident also in the aged animals by the preservation of muscle mass and improvements in oxygen consumption and endurance performance and were achieved despite a lower training distance than in young animals. Our results strongly implicate endurance training as a promising therapeutic for combatting disuse and age-related inflammation in skeletal muscle.

Keywords:  NLRP3 Inflammasome; exercise; mitochondria; mitochondrial biogenesis; muscle disuse

DOI:  https://doi.org/10.1152/japplphysiol.00038.2025
J Med Ethics. 2025 May 07. pii: jme-2024-110122. [Epub ahead of print]

Synthetic DNA and mitochondrial donation: no need for donor eggs?

Adrian Villalba, Iain Brassington, Anna Smajdor, Daniela Cutas.

  Mitochondrial replacement therapy has been developed in order to prevent the transmission of mitochondrial mutations, yet it raises ethical concerns, particularly regarding the involvement of third-party DNA and the risks associated with donor procedures. This paper explores an alternative approach using synthetic DNA (synDNA) to construct mitochondrial organelles, thereby bypassing the need for donor oocytes and bypassing risks to donors. We argue that those who support mitochondrial replacement techniques as an ethically acceptable means of preventing the transmission of mitochondrial disease should consider the use of synthetic mitochondria as a preferable ethical alternative, should it prove technically viable. That this will be viable is more than we can demonstrate here. However, progress in synDNA technology suggests that it is not unreasonable to think that synthetic mitochondria creation is feasible, and perhaps even probable.

Keywords:  Reproductive Medicine

DOI:  https://doi.org/10.1136/jme-2024-110122
Bioessays. 2025 May 04. e70016

Mitochondria and Endoplasmic Reticulum Contact Site as a Regulator of Proteostatic Stress Responses in Neurodegenerative Diseases.

Seiji Watanabe, Koji Yamanaka.

  Recent evidence indicates that the mitochondria-endoplasmic reticulum (ER) contact site is a novel microdomain essential for cellular homeostasis. Various proteins are accumulated at the mitochondria-associated membrane (MAM), an ER subcomponent closely associated with the mitochondria, contributing to Ca2+ transfer to the mitochondria, lipid synthesis, mitochondrial fission/fusion, and autophagy. These functions are disrupted in the diseases, particularly in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this review, we summarize the disruption of protein homeostasis in various neurodegenerative diseases, present recent works on the mechanisms of MAM aberration, including ours mainly focused on ALS, and then discuss challenges and prospects for future MAM-targeted therapies in neurodegenerative diseases.

Keywords:  mitochondria‐associated membranes; neurodegenerative diseases; protein homeostasis

DOI:  https://doi.org/10.1002/bies.70016
Int J Mol Sci. 2025 Apr 20. pii: 3892. [Epub ahead of print]26(8):

Isolated and Syndromic Genetic Optic Neuropathies: A Review of Genetic and Phenotypic Heterogeneity.

Marco Zeppieri, Caterina Gagliano, Marco Di Maita, Alessandro Avitabile, Giuseppe Gagliano, Edoardo Dammino, Daniele Tognetto, Maria Francesca Cordeiro, Fabiana D'Esposito.

  Nonsyndromic and syndromic hereditary optic neuropathies (HONs) encompass a variety of genetic illnesses that cause progressive optic nerve damage, resulting in considerable vision impairment. These disorders result from pathogenic variants in mitochondrial or nuclear DNA, impacting essential cellular processes like oxidative phosphorylation, mitochondrial dynamics, and neuroprotection. Advances in next-generation sequencing (NGS) have significantly improved the identification of genetic variations, enabling precise diagnoses and genotype-phenotype correlations. This review consolidates current knowledge regarding the classification, molecular pathogenesis, clinical manifestations, diagnostic methodologies, and emerging therapeutic strategies for HONs. The critical role of mitochondrial dysfunction in optic nerve degeneration highlights the necessity for multimodal therapeutic approaches. Recent clinical trials evaluating gene therapy for Leber hereditary optic neuropathy (LHON) and neuroprotective strategies in dominant optic atrophy (DOA) are discussed. Additionally, individualized therapeutic interventions, as demonstrated by recent case studies involving tailored gene therapies, are evaluated. The integration of molecular and imaging biomarkers in future personalized treatment strategies aims to enhance prognosis and therapeutic outcomes.

Keywords:  Leber hereditary optic neuropathy (LHON); dominant optic atrophy (DOA); gene therapy; hereditary optic neuropathy; mitochondrial DNA; optic atrophy; wolfram syndrome

DOI:  https://doi.org/10.3390/ijms26083892
J Neurochem. 2025 May;169(5): e70075

The Power Struggle: Kynurenine Pathway Enzyme Knockouts and Brain Mitochondrial Respiration.

László Juhász, Krisztina Spisák, Boglárka Zsuzsa Szolnoki, Anna Nászai, Ágnes Szabó, Attila Rutai, Szabolcs Péter Tallósy, Andrea Szabó, József Toldi, Masaru Tanaka, Keiko Takeda, Kinuyo Ozaki, Hiromi Inoue, Sayo Yamamoto, Etsuro Ono, Mihály Boros, József Kaszaki, László Vécsei.

  Numerous illnesses, including neurological and mental disorders, have been associated with mitochondrial dysfunction. Disruptions in mitochondrial respiration and energy production have been linked to dysmetabolism of the tryptophan (Trp)-kynurenine (KYN) pathway, which produces a diverse array of bioactive metabolites. Kynurenic acid (KYNA) is a putative neuroprotectant. The exact mechanisms through which Trp-KYN metabolic dysregulation affects mitochondrial function remain largely unclear. This study investigates the impact of the genetic deletion of kynurenine aminotransferase (KAT) enzymes, which are responsible for KYNA synthesis, on mitochondrial function, specifically mitochondrial respiration and ATP synthesis, and its potential role in neuropsychiatric pathology. CRISPR/Cas9-induced knockout mouse strains kat1-/-, kat2-/-, and kat3-/- were generated. Eight-to-ten-week-old male mice were used, and cerebral and hepatic respiration, complex I- and II-linked oxidative phosphorylation (CI and CII OXPHOS), and complex IV (CIV) activity were measured using high-resolution respirometry. Mitochondrial membrane potential changes were measured with Fluorescence-Sensor Blue and safranin dye. KAT knockout mice exhibited significantly lower cerebellar respiration (CI OXPHOS, CII OXPHOS, and CIV activity) compared to wild-type mice. Lower baseline respiration and attenuated OXPHOS activities were observed in the hippocampus and striatum, particularly in kat2-/- and kat3-/- mice. Non-neuronal tissues showed reduced CIV activity, while ADP-stimulated CI and CII OXPHOS remained unchanged. The deletion of the KAT genes significantly impairs mitochondrial respiration and ATP synthesis, potentially contributing to pathogenesis. This study highlights the importance of KYNA in mitochondrial function, offering new insights into potential therapeutic targets for various disorders. Targeting the KYN pathway could mitigate mitochondrial dysfunction in a variety of diseased conditions.

Keywords:  kynurenic acid; kynurenine aminotransferase; mitochondrial dysfunction; neurodegenerative diseases; psychiatric diseases; transgenic mice; tryptophan

DOI:  https://doi.org/10.1111/jnc.70075
Neurol Genet. 2025 Jun;11(3): e200260

Holistic Exome-Based Genetic Testing in Adults With Epilepsy.

Martin Krenn, Matias Wagner, Karin Trimmel, Silvia Bonelli, Jakob Rath, Judith Jud, Michelle Schwarz, Ivan Milenkovic, Rosa Weng, Johannes Koren, Christoph Baumgartner, Melanie Brugger, Theresa Brunet, Elisabeth Graf, Juliane Winkelmann, Susanne Aull-Watschinger, Fritz Zimprich, Ekaterina Pataraia.

Background and Objectives: Exome sequencing (ES) is increasingly used in the diagnostic workup of epilepsies. While its utility has been extensively demonstrated in children, its role in adults remains to be defined. In this study, we evaluate the outcomes of a holistic exome-based approach in adults with epilepsy.
Methods: We included 106 adults with epilepsy and a presumed genetic etiology between January 2015 and December 2023 at the Medical University of Vienna, Austria. Diagnostic ES, including copy number variation (CNV) and mitochondrial analyses, was performed. We report on diagnostic outcomes, phenotype expansions, and research findings. Furthermore, we compared the diagnostic outcomes with 3 comprehensive gene panels.
Results: In our cohort, the diagnostic yield was 30.2%, outperforming all 3 simulated gene panels. A developmental and epileptic encephalopathy phenotype was associated with receiving a genetic diagnosis. Overall, 27 distinct molecular etiologies were identified. Eight patients had pathogenic CNVs, and 2 had mitochondrial DNA variants. Molecular diagnoses had potential clinical implications in 8 of 32 solved cases (25%), which were eventually exerted in 5 patients (15.6%). Tailored treatment changes were successfully applied in SCN1A-related epilepsy (discontinuation of sodium channel blockers) and GLUT1 deficiency (ketogenic diet). Three patients with mitochondrial diseases were referred for preventive screening investigations after the genetic diagnosis. Our findings expand the clinical spectrum of 3 known epilepsy genes. In addition, explorative variant prioritization identified heterozygous truncating variants in CLASP1 in 2 unrelated patients with focal epilepsy, suggesting it as a candidate gene.
Discussion: Our study strongly supports the use of holistic genetic approaches, encompassing CNV and mitochondrial analyses, in adults with epilepsy. Similar to pediatric cohorts, results may inform clinical care. Moreover, we report on phenotype expansions and a candidate gene discovery.

DOI: https://doi.org/10.1212/NXG.0000000000200260
Int J Mol Sci. 2025 Apr 21. pii: 3915. [Epub ahead of print]26(8):

A Review of the Neuroprotective Properties of Exosomes Derived from Stem Cells and Exosome-Coated Nanoparticles for Treating Neurodegenerative Diseases and Stroke.

Yu-Ping Yang, Christopher J B Nicol, Ming-Chang Chiang.

  Neurological diseases, including neurodegenerative disorders and stroke, represent significant medical challenges due to their complexity and the limitations of current treatment approaches. This review explores the potential of stem cell (SC)-derived exosomes (Exos) as a transformative therapeutic strategy for these diseases. Exos, especially those derived from SCs, exhibit natural targeting ability, biocompatibility, and the capacity to cross the blood-brain barrier (BBB), making them ideal vehicles for drug delivery. This review provides an in-depth discussion of the properties and advantages of SC-Exos. It highlights their potential synergistic benefits in therapeutic approaches to treat neurological diseases. This article discusses the mechanisms of action of SC-Exos, highlighting their ability to target specific cells, modulate disease pathways, and provide controlled release of therapeutic agents. Applications in specific neurological disorders have been investigated, demonstrating the potential to improve outcomes in conditions such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and stroke. Moreover, Exos-coated nanoparticles (NPs) combine the natural properties of Exos with the multifunctionality of NPs. This integration takes advantage of exosome membrane biocompatibility and targeting capabilities while preserving NPs' beneficial features, such as drug loading and controlled release. As a result, Exos-coated NPs may enhance the precision, efficacy, and safety of therapeutic interventions. In conclusion, SC-Exos represent a promising and innovative approach to treating neurological diseases.

Keywords:  SC-Exos; exosome-coated NPs; neurodegenerative diseases; neuroprotective; stroke

DOI:  https://doi.org/10.3390/ijms26083915
Int J Mol Sci. 2025 Apr 16. pii: 3774. [Epub ahead of print]26(8):

Current Development of iPSC-Based Modeling in Neurodegenerative Diseases.

Xiangge Guo, Xumeng Wang, Jiaxuan Wang, Min Ma, Qian Ren.

  Over the past two decades, significant advancements have been made in the induced pluripotent stem cell (iPSC) technology. These developments have enabled the broader application of iPSCs in neuroscience, improved our understanding of disease pathogenesis, and advanced the investigation of therapeutic targets and methods. Specifically, optimizations in reprogramming protocols, coupled with improved neuronal differentiation and maturation techniques, have greatly facilitated the generation of iPSC-derived neural cells. The integration of the cerebral organoid technology and CRISPR/Cas9 genome editing has further propelled the application of iPSCs in neurodegenerative diseases to a new stage. Patient-derived or CRISPR-edited cerebral neurons and organoids now serve as ideal disease models, contributing to our understanding of disease pathophysiology and identifying novel therapeutic targets and candidates. In this review, we examine the development of iPSC-based models in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Keywords:  astrocyte; brain organoid; iPS cell; microglia; neural stem cell; neurodegenerative disease; neuron; oligodendrocyte; reprogramming factor

DOI:  https://doi.org/10.3390/ijms26083774
J Nanobiotechnology. 2025 May 03. 23(1): 329

Exosome-powered neuropharmaceutics: unlocking the blood-brain barrier for next-gen therapies.

Sepehr Mehdizadeh, Mobin Mamaghani, Somayyeh Hassanikia, Younes Pilehvar, Yavuz Nuri Ertas.

   BACKGROUND: The blood-brain barrier (BBB) presents a formidable challenge in neuropharmacology, limiting the delivery of therapeutic agents to the brain. Exosomes, nature's nanocarriers, have emerged as a promising solution due to their biocompatibility, low immunogenicity, and innate ability to traverse the BBB. A thorough examination of BBB anatomy and physiology reveals the complexities of neurological drug delivery and underscores the limitations of conventional methods.
MAIN BODY: This review explores the potential of exosome-powered neuropharmaceutics, highlighting their structural and functional properties, biogenesis, and mechanisms of release. Their intrinsic advantages in drug delivery, including enhanced stability and efficient cellular uptake, are discussed in detail. Exosomes naturally overcome BBB barriers through specific translocation mechanisms, making them a compelling vehicle for targeted brain therapies. Advances in engineering strategies, such as genetic and biochemical modifications, drug loading techniques, and specificity enhancement, further bolster their therapeutic potential. Exosome-based approaches hold immense promise for treating a spectrum of neurological disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), brain tumors, stroke, and psychiatric conditions.
CONCLUSION: By leveraging their innate properties and engineering innovations, exosomes offer a versatile platform for precision neurotherapeutics. Despite their promise, challenges remain in clinical translation, including large-scale production, standardization, and regulatory considerations. Future research directions in exosome nanobiotechnology aim to refine these therapeutic strategies, unlocking new avenues for treating neurological diseases. This review underscores the transformative impact of exosome-based drug delivery, paving the way for next-generation therapies that can effectively penetrate the BBB and revolutionize neuropharmacology.

Keywords:  Blood-brain barrier; Brain cancer; Exosome-mediated drug delivery; Neurodegenerative diseases; Psychiatric disorders; Stroke; Targeted drug delivery

DOI:  https://doi.org/10.1186/s12951-025-03352-8
Front Neurosci. 2025 ;19 1498655

Say hello to my little friend… micronutraceuticals in neuroenergetics, neuronal health, and neurodegenerative diseases.

Shayne Mason.

  Vitamins and minerals (micronutraceuticals) maintain good health. However, the specific effects of these micronutraceuticals on brain health are often overlooked, or not even known. In this review, an overview of the direct and indirect effects of micronutraceuticals on brain energy metabolism (neuroenergetics) and neuronal health is provided. Thereafter, a holistic summary of the existing studies that have shown the impact of micronutraceuticals on neurodegenerative diseases. Lastly, this review concludes by identifying several research gaps that remain and provides suggestions for future research on these hot topics.

Keywords:  brain; energy metabolism; neurodegenerative disease; neuroenergetics; neurons; vitamins

DOI:  https://doi.org/10.3389/fnins.2025.1498655
Se Pu. 2025 May;43(5): 487-497

[Recent advances on the role of exosomes in neurodegenerative diseases].

Cai-Ting Bu, Xue-Dong Zhu, Qian-Ying Zhang, Wen-Ya Shao.

  Exosomes are nano-sized, lipid bilayer vesicles secreted by cells. They carry essential bioactive molecules, such as proteins, nucleic acids, and lipids, and are widely present in bodily fluids including blood and cerebrospinal fluid. Exosomes transfer bioactive molecules to target cells through various mechanisms, including endocytosis, ligand-receptor interactions, or direct membrane fusion, and play crucial roles in intercellular communication, including facilitating intercellular information exchange, maintaining nerve-cell function, participating in immune responses, and providing nutritional support. Exosomes significantly promote signal transmission and intercellular communication in the central nervous system and are involved in the pathogenesis and development of diseases by participating in the spread of pathological proteins, regulating neuroinflammation, and the deposition of pathological proteins. Therefore, exosomes play key roles in the occurrence and development of neurodegenerative diseases, and their contents, especially proteins and miRNAs, are specific for given pathological and physiological states and are relatively stable during extraction and analysis. Hence, exosomes are ideal tools for diagnosing diseases, staging their courses, and assisting prognosis. This article further explores exosomes derived from blood, saliva, urine, and cerebrospinal fluid as potential diagnostic biomarkers for neurodegenerative diseases. As natural drug-delivery systems, exosomes have the advantages of biocompatibility, ability to cross biological barriers, target specificity, stability, and containing natural therapeutic molecules, which can effectively improve the precision and efficacy of drug delivery and reduce side effects, making them an ideal carrier for delivering drugs to the central nervous system. Therefore, exosomes hold great potential in the diagnosis and treatment of central nervous system diseases. This article systematically reviews the latest advances in exosome research directed toward specific neurodegenerative diseases, focusing on their roles played in disease pathogenesis, progression, diagnosis, and treatment, with the aim of providing theoretical support and a reference for the early diagnosis and treatment of these diseases.

Keywords:  biomarkers; drug microcarrier; exosomes; neurodegenerative diseases

DOI:  https://doi.org/10.3724/SP.J.1123.2024.10035
Br J Pharmacol. 2025 May 09.

Metformin aggravates pancreatitis by regulating the release of oxidised mitochondrial DNA via the frataxin (FXN)/ninjurin 1 (NINJ1) signalling pathway.

Guang Xin, Qilong Zhou, Tao Wang, Chengyu Wan, Xiuxian Yu, Ke Li, Fan Li, Shiyi Li, Yuman Dong, Yilan Wang, Lijuan Feng, Kun Zhang, Ao Wen, Wen Huang.

   BACKGROUND AND PURPOSE: Patients with diabetes are at a higher risk of developing acute pancreatitis compared to those without diabetes. Therefore, it is essential to investigate the effects of metformin, a primary treatment for type 2 diabetes, on the progression of pancreatitis.
EXPERIMENTAL APPROACH: Network pharmacology was employed to investigate the potential effects of metformin on pancreatitis and to predict its underlying molecular mechanisms. Pharmacological and mechanistic studies of metformin were conducted utilising mtDNA depletion (ρ0) of 266-6 acinar cells, knockout mouse models and experimental models of both acute and chronic pancreatitis. The mitochondrial homeostasis and plasma membrane integrity were examined through phase-contrast microscopy and time-lapse video imaging.
KEY RESULTS: Network pharmacology analysis revealed that metformin possesses significant potential to modulate the pathogenesis of pancreatitis, likely through its regulation of mitochondrial function and cell membrane morphology. Further, the results revealed that metformin augmented the release of oxidised mitochondrial DNA (Ox-mtDNA) by enhancing NINJ1-mediated plasma membrane rupture, which subsequently ignited a cascade of acinar cell necrosis. Metformin exacerbated mitochondrial iron imbalance by suppressing Frataxin, thereby worsening mitochondrial homeostasis disruption and Ox-mtDNA generation. NINJ1 knockout eliminated the metformin-induced acinar cell necrosis and elevation of Ox-mtDNA levels, and mtDNA depletion reversed the effect of metformin on acinar cell death.
CONCLUSION AND IMPLICATIONS: Metformin exacerbates both acute and chronic pancreatitis, possibly because of increased release of Ox-mtDNA via modulation of mitochondrial iron homeostasis and NINJ1-mediated plasma membrane rupture, suggesting that extreme caution should be exercised when using metformin in diabetic patients with pancreatitis.

Keywords:  FXN/NINJ1 signalling; Ox‐mtDNA; metformin; mitochondrial homeostasis; pancreatitis

DOI:  https://doi.org/10.1111/bph.70065