bims-polgdi 2025-08-10 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–08–10
23 papers selected by
Luca Bolliger, lxBio

Mitochondrial disease management through phytochemical interventions.
Exosomes as a Nanotheranostic Platform in Brain Diseases.
A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations.
The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.
Retrospective observational study of the magnetic resonance imaging features of MPV17-related mitochondrial DNA depletion syndrome.
Strategies to rescue mitochondria in Parkinson's disease: The significance of mitochondrial transfer.
Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
Updates on Mitochondrial Myopathies.
Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease.
[Mitochondrial damage and male reproductive dysfunction: Progress in research].
Mitochondrial metabolism and cancer therapeutic innovation.
Blood and Neuronal Extracellular Vesicle Mitochondrial Disruptions in Schizophrenia.
Mitochondrial Response to Psychological Stress and Its Medial Prefrontal Biomarker Correlates.
The complex web of membrane contact sites in brain aging and neurodegeneration.
Metabolic dysfunction promoted by mitochondrial DNA mutation burden drives retinal degeneration.
Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
Modeling rare genetic disease with patient-derived induced pluripotent stem cells: reassessment of the minimum numbers of lines needed.
Advancements in Liposomal Drug Delivery Systems for Paediatric Neurological Disorders: A Comprehensive Review.
Noninvasive Assessments of Mitochondrial Capacity in People with Mitochondrial Myopathies.
Impacts of aging on brain metabolism.
Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.
Genetic mapping of lifespan and mitochondrial stress response in C. elegans.

Mol Cell Biochem. 2025 Aug 03.

Mitochondrial disease management through phytochemical interventions.

R Prabhu Ramya, K B Megha, S Reshma, M J Ajai Krishnan, S Amir, Rashmi Sharma, P V Mohanan.

  Mitochondrial diseases are a diverse group of disorders caused by dysfunction in mitochondria, the energy-generating organelles of cells. These disorders result from mutations in either nuclear or mitochondrial DNA and can be classified as primary (genetic origin) or secondary (environmentally induced). Due to their systemic impact, mitochondrial dysfunction leads to a wide range of clinical symptoms varying from tissue type and patient age. This review aims to provide a comprehensive overview of mitochondrial diseases, focusing on their classification, pathophysiology, diagnostic challenges and emerging therapeutic strategies. Current diagnostic approaches face limitations due to the complexity and heterogeneity of mitochondrial disorders. Recent evidence highlights the potential of phytochemicals such as polyphenols, flavonoids, alkaloids and terpenoids in modulating mitochondrial function. These natural compounds can enhance mitochondrial biogenesis, reduce oxidative stress and improve cellular energy metabolism. Phytochemicals represent a promising therapeutic avenue for mitigating mitochondrial dysfunction. However, further research is needed to validate their efficacy and develop standardized treatment protocols. An improved understanding of the molecular mechanisms involved in mitochondrial pathology will aid in developing more targeted diagnostic and therapeutic strategies.

Keywords:  Mitochondrial biogenesis; Mitochondrial diseases; Oxidative stress; Phytochemicals; Therapeutic strategies

DOI:  https://doi.org/10.1007/s11010-025-05360-6
Eur J Neurosci. 2025 Aug;62(3): e70215

Exosomes as a Nanotheranostic Platform in Brain Diseases.

Megha Kudpaje, Suresh Joghee, Ram Mohan Ram Kumar.

  Exosomes, nanoscale extracellular vesicles (30-150 nm), play a critical role in intercellular communication by transporting bioactive molecules, including proteins, lipids, and nucleic acids. These vesicles have emerged as a transformative tool for drug delivery in brain diseases, particularly due to their ability to cross the blood-brain barrier (BBB), a major challenge in treating central nervous system (CNS) disorders. Recent studies have highlighted the potential of exosome-based therapies in treating neurodegenerative diseases such as Alzheimer's and Parkinson's, neuroinflammatory conditions, and brain tumors like glioblastoma. Exosomes can be engineered to enhance their targeting precision by modifying their surface to selectively deliver therapeutic agents to specific brain cells, including neurons, glial cells, and endothelial cells. This review explores the latest advancements in optimizing exosome-mediated drug delivery, focusing on surface modifications and other strategies to improve targeting efficiency and therapeutic outcomes. Additionally, exosomes are being investigated as diagnostic biomarkers for early disease detection and monitoring, offering a noninvasive alternative to traditional methods. Despite their promise, challenges such as large-scale production, cargo loading, safety concerns, and regulatory barriers remain. This review provides an overview of the current state of exosome-based therapies, critically evaluates the ongoing challenges, and explores future directions for optimizing their use in brain disease treatment, emphasizing enhancing targeted delivery and therapeutic efficacy.

Keywords:  blood–brain barriers; brain targeting; drug delivery; exosomes; extracellular vesicles; neurological disorders

DOI:  https://doi.org/10.1111/ejn.70215
BMJ Case Rep. 2025 Aug 08. pii: bcr0720080504. [Epub ahead of print]2009

A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.

An I Jonckheere, Marije Hogeveen, Leo Nijtmans, Mariel van den Brand, Antoon Janssen, Heleen Diepstra, Frans van den Brandt, Bert van den Heuvel, Frans Hol, Tom Hofste, Livia Kapusta, U Dillmann, M Shamdeen, J Smeitink, J Smeitink, Richard Rodenburg.

To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing.A homoplasmic nonsense mutation m.8529G→A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNAWe describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.

DOI: https://doi.org/10.1136/bcr.07.2008.0504
Sci Adv. 2025 Aug 08. 11(32): eadw4954

Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations.

Barbara Arbeithuber, Kate Anthony, Bonnie Higgins, Peter Oppelt, Omar Shebl, Irene Tiemann-Boege, Francesca Chiaromonte, Thomas Ebner, Kateryna D Makova.

Mitochondria, cellular powerhouses, harbor DNA [mitochondrial DNA (mtDNA)] inherited from the mothers. mtDNA mutations can cause diseases, yet whether they increase with age in human oocytes remains understudied. Here, using highly accurate duplex sequencing, we detected de novo mutations in single oocytes, blood, and saliva in women 20 to 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies were less prevalent in coding than noncoding regions, whereas mutations with low allele frequencies were more uniformly distributed along the mtDNA, suggesting frequency-dependent purifying selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations with aging and having functional consequences. These findings are particularly timely as humans tend to reproduce later in life.

DOI: https://doi.org/10.1126/sciadv.adw4954
Annu Rev Cell Dev Biol. 2025 Aug 06.

The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.

Nazma Malik, Reuben J Shaw.

Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.

DOI: https://doi.org/10.1146/annurev-cellbio-120420-094431
Pediatr Radiol. 2025 Aug 07.

Retrospective observational study of the magnetic resonance imaging features of MPV17-related mitochondrial DNA depletion syndrome.

Suzanne O'Hagan, Surita Meldau, Penelope Rose, Magriet Van Niekerk, Christelle Ackermann, Gillian Riordan, Ronald Van Toorn.

   BACKGROUND: MPV17-related mitochondrial deoxyribonucleic acid (DNA) maintenance defects present in most affected individuals as an early-onset encephalohepatopathic disease. Diagnosis requires comprehensive molecular genetic testing, which is often not available in resource-limited settings. Therefore, the role of imaging as a diagnostic tool necessitates further exploration. Herein, we present the largest known cohort of patients with genetically confirmed MPV17-related mitochondrial DNA depletion syndrome, highlighting in detail the neuroimaging findings.
OBJECTIVE: To establish novel features on magnetic resonance imaging (MRI) that characterise MPV17-related mitochondrial DNA depletion syndrome, in order to provide a non-invasive, accessible, and reproducible biomarker inquiry.
MATERIALS AND METHODS: Retrospective, descriptive study based at a large tertiary level hospital. Eight patients with MPV17-related mitochondrial DNA depletion syndrome who had undergone brain MRI were identified between 2015 and 2023. Neuroimaging findings were captured and described in detail. Two board-certified radiologists with experience in paediatric neuroradiology reviewed all images by consensus.
RESULTS: All patients were homozygous for the MPV17: c.106C>T variant. Age at brain MRI ranged from 11 days to 8 months. Seven out of the eight patients showed signal abnormalities in the reticulospinal tracts and/or reticular formation. Other neuroimaging findings included leukoencephalopathy, injury to extra-reticular white matter tracts and frequent basal ganglia involvement. Newly identified areas of involvement include the perirolandic cortices, hippocampi, optic pathways and olfactory nerves.
CONCLUSION: Lesions in the reticular formation and reticulospinal tracts on brain MRI in a neonate or infant with hepatic dysfunction may represent a distinctive, albeit not specific, feature of MPV17-related mitochondrial DNA depletion syndrome.

Keywords:  MPV17 mitochondrial DNA depletion syndrome; Mitochondrial DNA; Mitochondrial disease; Neuroimaging; Pediatric; Resource-limited settings; Reticular formation

DOI:  https://doi.org/10.1007/s00247-025-06341-z
Ageing Res Rev. 2025 Aug 05. pii: S1568-1637(25)00202-8. [Epub ahead of print]112 102856

Strategies to rescue mitochondria in Parkinson's disease: The significance of mitochondrial transfer.

Junhan Liang, Zhaoqin Su, Gongmeiyue Su, Madiha Rasheed, Shiyi Tang, Hafsa Sunniya, Mohamed Maazouzi, Yaoyuan Cui, Junxiao Wang, Xuezhe Wang, Jing Yang, Mingchao Ding, Zhao Li, Yulin Deng.

  Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuronal degeneration and pathological α-synuclein accumulation. Mitochondrial dysfunction is a central feature in PD pathogenesis, contributing to impaired bioenergetics, oxidative stress, neuroinflammation, and defective organelle communication. This review synthesizes the current understanding of mitochondrial quality control mechanisms, including fission, fusion, mitophagy, and biogenesis, and their disruption in PD. Particular emphasis is placed on the role of intercellular mitochondrial transfer as a compensatory mechanism. Emerging evidence suggests that mitochondria can be transferred between neurons and glial cells through tunneling nanotubes, extracellular vesicles, and gap junctions, offering protective effects by restoring metabolic function and attenuating cellular stress. We examine the molecular mediators of these transfer pathways, the influence of PD-associated mutations, and the bidirectional dynamics between donor and recipient cells. Additionally, we explore translational strategies, including mitochondrial transplantation, bioengineered mitochondria, and stem cell-based delivery systems. While preclinical models demonstrate promising therapeutic outcomes, clinical translation faces challenges, including targeting specificity, mitochondrial viability, and immune compatibility. By integrating mechanistic insights with therapeutic developments, this review highlights mitochondrial transfer as a novel and promising approach in the future treatment of PD, potentially addressing longstanding limitations in conventional neuroprotective strategies.

Keywords:  Future therapies; Mitochondria transfer; Mitochondrial dysfunction; Parkinson’s disease; Quality control

DOI:  https://doi.org/10.1016/j.arr.2025.102856
bioRxiv. 2025 Jul 21. pii: 2025.07.17.665416. [Epub ahead of print]

Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.

Leena Kadam, Kaylee Chan, Ethan Tawater, Leslie Myatt.

Introduction: The placenta is exposed to an altered metabolic environment in obesity and gestational diabetes (GDM) leading to disruption in placental function. Mitochondria are critical for energy production and cellular adaptation to stress. We previously reported reduced trophoblast mitochondrial respiration in GDM. Here we examine changes in mitochondrial structure dynamics, quality and protein homeostasis as well as clearance in both obese and GDM placentas of male and female fetuses. As obesity significantly increases the risk for GDM, our goal is to determine the distinct effects of each on placental mitochondria.
Methods: We collected placental villous tissue following elective cesarean section at term from lean (LN, pre-pregnancy BMI 18.5-24.9), obese (OB, BMI>30) or obese with type A2 GDM women. Expression of proteins involved in mitochondrial biogenesis, structure dynamics, quality control and clearance were assessed by Western blotting. Significant changes between groups were determined in fetal sex-dependent and independent manner.
Results: Only placentas from obese women showed increase in proteins regulating mitochondrial biogenesis (PGC-1α and SIRT1). We report fetal sex-specific changes in mitochondrial fusion but an overall decline in fission in OB and GDM placentas. Both maternal obesity and GDM affected proteins involved in maintaining mitochondrial protein quality and genome stability. This was accompanied by a reduction in mitochondrial complexes, suggesting impaired mitochondrial function. Obesity led to partial activation of mitophagy pathways (e.g., increased PINK1 without PARKIN activation), GDM placentas failed to mount this response.
Discussion: Obesity and GDM affect placental mitochondria through distinct complex sex-specific mechanisms that may contribute to altered mitochondrial function.

DOI: https://doi.org/10.1101/2025.07.17.665416
Curr Neurol Neurosci Rep. 2025 Aug 04. 25(1): 55

Updates on Mitochondrial Myopathies.

Emanuele Barca, Valentina Emmanuele.

   PURPOSE OF REVIEW: Mitochondrial myopathies (MM) are a genetically and clinically heterogeneous group of disorders that remain underrecognized in adult and pediatric neurology. This review aims to provide a clinically useful tool for guiding diagnosis and management of MM. We also highlight the rapidly evolving diagnostic and therapeutic landscape, including novel diagnostic approaches and disease-modifying interventions.
RECENT FINDINGS: Large cohort data highlight key clinical subtypes - fixed myopathies, syndromic forms, and metabolic myopathies- with distinct diagnostic implications. Novel tools such as GDF-15, long-read mtDNA sequencing, and multi-omic approaches are enhancing diagnostic sensitivity. Emerging therapies for TK2 deficiency and precision mitochondrial gene editing are progressing rapidly, with several nearing regulatory decisions. Numerous preclinical therapeutic strategies are currently under development, offering promise for improving outcomes in these otherwise devastating disorders. Recognizing MM in clinical settings is essential for timely diagnosis, to guide prognosis and family planning as well as provide access to emerging treatment. A tiered diagnostic approach and integration of new genomic technologies can improve outcomes.
HUMAN AND ANIMAL RIGHTS: This article does not contain any studies with human or animal subjects performed by any of the authors.

Keywords:  Exercise intolerance; Mitochondrial myopathy; Muscle biopsy; Next-generation sequencing; Rhabdomyolysis; TK2 deficiency

DOI:  https://doi.org/10.1007/s11910-025-01444-4
bioRxiv. 2025 Jul 24. pii: 2025.07.24.666629. [Epub ahead of print]

Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease.

Subrata Pradhan, Sagar Gaikwad, Chi-Lin Tsai, Charlene Smith, Nan Zhang, Keegan Bush, Anirban Chakraborty, Subo Yuan, Sanjeev Choudhary, C Dirk Keene, Lisa M Ellerby, Tapas K Hazra, Albert R La Spada, Yogesh P Wairkar, Tatsuo Ashizawa, John A Tainer, Tej K Pandita, Leslie M Thompson, Partha S Sarkar.

Huntingtin (HTT) function is enigmatic, as the native protein plays critical roles in neuronal health, while mutant HTT (mHTT), carrying an expanded polyglutamine stretch, triggers neurotoxicity and contributes to the pathogenesis of Huntington's disease (HD). We recently found that HTT is part of a nuclear transcription-coupled DNA repair (TCR) complex with DNA repair enzymes including polynucleotide-kinase-3'-phosphatase (PNKP). This complex resolves DNA lesions during transcription to maintain genome integrity, while in HD, mHTT impairs the activity of this complex, resulting in accumulation of DNA lesions. Using molecular, cellular biology and computational methods, we find that HTT has a role in assembling a functional DNA repair complex in mitochondria. Together with mitochondrial RNA polymerase and transcription factors, HTT resolves mitochondrial DNA lesions to preserve mitochondrial genome integrity and function. Pathogenic mHTT impairs this activity, resulting in persistent DNA lesions and reduced mitochondrial function in HD. Importantly, restoring activity of this complex in a Drosophila HD model through ectopic HTT or PNKP expression significantly improves mitochondrial genome integrity and ameliorates motor deficits.
HIGHLIGHTS: HTT organizes a functional, multifactorial mitochondrial DNA repair complexMutant HTT impairs the mitochondrial DNA repair complex causing DNA damage accumulationHTT-associated repair complex resolves mitochondrial DNA lesions and DNA integrityRestoring repair activity in HD flies rescues mitochondrial DNA integrity and motor defects.

DOI: https://doi.org/10.1101/2025.07.24.666629
Zhonghua Nan Ke Xue. 2024 Aug;30(8): 744-749

[Mitochondrial damage and male reproductive dysfunction: Progress in research].

Jin-Dong Li, Zhen-Xiang Liu, Xue-Jun Shang.

Mitochondria are the center of sperm metabolism and essential for all aspects of flagellar motility, capacitation, acrosome reaction and gametic fusion of sperm. Abnormalities in the mitochondrial ultrastructure, membrane potential, reactive oxygen species, Ca2+ homoeostasis, sperm apoptosis, mitochondrial DNA, mitochondrial enzymes and proteomic activity can decrease sperm quality and even cause male infertility. This paper elucidates the impact of mitochondrial dysfunction on sperm by reviewing and analyzing relevant literature on mitochondria and male reproductive function, aiming to provide some theoretical evidence for exploring effective interventions for male reproductive dysfunction.

Keywords: mitochondria; sperm; male infertility; reactive oxygen species; apoptosis; mitochondrial DNA; mitochondrial fusion/division
Signal Transduct Target Ther. 2025 Aug 04. 10(1): 245

Mitochondrial metabolism and cancer therapeutic innovation.

Hongxiang Du, Tianhan Xu, Sihui Yu, Sufang Wu, Jiawen Zhang.

Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions.

DOI: https://doi.org/10.1038/s41392-025-02311-x
bioRxiv. 2025 Jul 31. pii: 2025.07.30.667452. [Epub ahead of print]

Blood and Neuronal Extracellular Vesicle Mitochondrial Disruptions in Schizophrenia.

A Ankeeta, Ashutosh Tripathi, Bindu Pillai, Yizhou Ma, Joshua J Chiappelli, Jessica N Jernberg, Keiko Kunitoki, Xiaoming Du, Si Gao, Bhim M Adhikari, Consuelo Walss-Bass, Giselli Scaini, Peter Kochunov, Anilkumar Pillai, L Elliot Hong.

The high energy demand of the human brain obligates robust mitochondrial energy metabolism, while mitochondrial dysfunctions have been linked to neuropsychiatric disorders including schizophrenia spectrum disorders (SSD). However, in vivo assessments that can directly inform brain mitochondrial functioning and its etiopathophysiological path to SSD remain difficult to obtain. We hypothesized that system and brain mitochondrial dysfunctions in SSD may be indexed by elevated cell-free mitochondrial DNA (cf-mtDNA) levels in the blood and in neuronal extracellular vesicles (nEVs). We also explored if these mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS). We examined blood cf-mtDNA in 58 SSD patients and 33 healthy controls, followed by assessing nEV mtDNA and metabolite levels using MRS in a subgroup of patients and controls. We found that people with SSD had significantly elevated cf-mtDNA levels in both the blood (p=0.0002) and neuronal EVs (p=0.003) compared to controls. These mtDNA abnormalities can be linked back to brain lactate+ levels such that higher blood and nEV mtDNA levels were significantly associated with higher lactate+ levels measured at the anterior cingulate cortex (r=0.53, 0.53; p=0.008, 0.03, respectively) in SSD patients. Furthermore, higher developmental stress and trauma were significantly associated with higher cf-mtDNA levels in both the blood and neuronal EVs in SSD patients (r=0.29, 0.49; p=0.01, 0.03, respectively). In conclusion, if replicated and fully developed, blood and neuronal EV-based cell free mtDNA may provide a clinically accessible biomarker to more directly evaluate the mitochondrial hypothesis and the abnormal bioenergetics pathways in schizophrenia.

DOI: https://doi.org/10.1101/2025.07.30.667452
bioRxiv. 2025 Aug 01. pii: 2025.07.30.667787. [Epub ahead of print]

Mitochondrial Response to Psychological Stress and Its Medial Prefrontal Biomarker Correlates.

Ankeeta Ankeeta, Ashutosh Tripathi, Yizhou Ma, Bindu Pillai, Joshua J Chiappelli, Jennifer N Jernberg, Keiko Kunitoki, Bhim M Adhikari, Si Gao, Xiaoming Du, Loise Kabui, Francisco Pallares Solano, Oluwabunmi Akindona, Zhenyao Ye, Shuo Chen, Mohammad Milad, Peter Kochunov, Anilkumar R Pillai, Elliot L Hong.

BACKGROUND: Stress response obligates increased mitochondrial activities to meet stress induced high energy requirement. This stress mitochondrial response process involves glucocorticoid but also multiple alternative pathways that are top down regulated by the medial prefrontal cortex (mPFC). These pathways are important for many neuropsychiatric conditions that are sensitive to stress. However, the field lacks a reliable, clinically accessible stress mitochondrial response paradigm to study the process in humans.
METHOD: We used an established psychological stress challenge combined with assaying salivary cell-free mitochondrial DNA (cf mtDNA), thought to reflect heightened mitochondrial changes or disruptions, in 35 healthy individuals (21 males). We also explored if these stress induced cf mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS), as well as high resolution brain imaging based cortical thickness focusing on the mPFC.
RESULTS: We found that salivary cf mtDNA was significant elevated immediately after the stress challenge (p=2.0x10-7) and gradually declined after. Exploratory causal analysis showed that this cf mtDNA response was not primarily driven by cortisol response. Instead, individuals with higher baseline dACC lactate+ levels, thought to in part reflect mitochondrial dysfunctions, was significantly associated with the cf mtDNA response (r=0.80, p<0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r=-0.52, p=0.01). Age had a U-shape effect such that cf mtDNA response trended lower in earlier adulthood but higher in older people, explaining 33.8% of the ct mtDNA response variance (p=0.003).
CONCLUSION: This stress challenge-salivary cf mtDNA assay paradigm may offer a new, noninvasive approach to evaluate the stress-mitochondrial pathway functioning in aging, psychopharmacology, and neuropsychiatric conditions where psychological stress plays a role.

DOI: https://doi.org/10.1101/2025.07.30.667787
Cell Mol Life Sci. 2025 Aug 08. 82(1): 301

The complex web of membrane contact sites in brain aging and neurodegeneration.

Domenico Azarnia Tehran, Paola Pizzo.

  To sustain the essential biological functions required for life, eukaryotic cells rely on complex interactions between different intracellular compartments. Membrane contact sites (MCS), regions where organelles come into close proximity, have recently emerged as major hubs for cellular communication, mediating a broad range of physiological processes, including calcium signalling, lipid synthesis and bioenergetics. MCS are particularly abundant and indispensable in polarized and long-lived cells, such as neurons, where they support both structural and functional integrity. In this review, we explore the functional diversity, molecular composition, and dynamic regulation of key mammalian MCS: endoplasmic reticulum (ER)-plasma membrane, ER-mitochondria and contact sites involving lipid droplets. We highlight their central role in neuronal health and discuss how MCS dysfunction has increasingly been recognized as a hallmark of brain aging and various neurodegenerative diseases, most notably Alzheimer's disease, where altered MCS dynamics contribute to pathogenesis. Finally, we emphasize the therapeutic potential of targeting MCS and outline key unanswered questions to guide future research.

Keywords:  Inter-organelle crosstalk; Neuronal homeostasis; Organelle contacts; Synaptic dysfunction; Therapeutic targets

DOI:  https://doi.org/10.1007/s00018-025-05830-6
bioRxiv. 2025 Jul 31. pii: 2025.07.30.667736. [Epub ahead of print]

Metabolic dysfunction promoted by mitochondrial DNA mutation burden drives retinal degeneration.

Johnathon Sturgis, Ke Jiang, Stephanie A Hagstrom, Maya Moorthy, Vera L Bonilha.

Retinal degenerative diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and glaucoma, have been linked to mitochondrial dysfunction. However, the impact of mitochondrial DNA (mtDNA) mutation accumulation in the context of these retinopathies has yet to be thoroughly explored. Our previous studies focused on the retinal phenotype observed in the PolgD257A mutator mice (D257A), revealing the effects of aging and mtDNA mutation accumulation in the retina. We have reported that this model exhibited significant morphological and functional deficits in the retina by 6 months of age, with notable alterations in the retinal pigment epithelium (RPE) occurring as early as 3 months, including changes in the cristae density and reduction in length of mitochondria. This study investigated how mtDNA mutations affect the metabolic interaction between the retina and RPE in young (3 months) and old (12 months) wild-type (WT) and D257A mice. We assessed cellular energy production using freshly dissected retina samples from both groups through Seahorse analysis, immunofluorescence, and Western blot experiments. The analysis of aged D257A retina punches revealed significantly reduced basal and maximal mitochondrial respiration, along with increased mitochondrial reserve capacity compared to WT. However, glycolytic flux, measured as a function of extracellular acidification rate (ECAR), did not differ between WT and D257A mice. Both D257A retina and RPE exhibited decreased expression of essential electron transport proteins involved in oxidative phosphorylation. Additionally, we observed a reduction in the expression of glucose transporter 1 (GLUT-1) and lactate transporter (MCT1) at the apical surface of the RPE. Enzymes associated with glycolysis, including hexokinase II and lactate dehydrogenase A, were significantly lower in the aged D257A retina, while hexokinase I and pyruvate kinase 2 were upregulated in the RPE. These findings indicate that the accumulation of mtDNA mutations leads to impaired metabolism in both the retina and RPE. Furthermore, it suggests that glucose from the choroidal blood supply is being utilized by the RPE rather than being transported to the neural retina. Mitochondrial dysfunction in RPE promotes a glycolytic state in these cells, leading to reduced availability of metabolites and, consequently, diminished overall retinal function. These results are essential for advancing our understanding of the mechanisms underlying retinal degeneration and provide a new perspective on the role of mtDNA mutations in these diseases.

DOI: https://doi.org/10.1101/2025.07.30.667736
Nat Commun. 2025 Aug 04. 16(1): 7174

Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.

Ioannis Segos, Jens Van Eeckhoven, Simon Berger, Nikhil Mishra, Eric J Lambie, Barbara Conradt.

The unequal segregation of organelles has been proposed to be an intrinsic mechanism that contributes to cell fate divergence during asymmetric cell division; however, in vivo evidence is sparse. Using super-resolution microscopy, we analysed the segregation of organelles during the division of the neuroblast QL.p in C. elegans larvae. QL.p divides to generate a daughter that survives, QL.pa, and a daughter that dies, QL.pp. We found that mitochondria segregate unequally by density and morphology and that this is dependent on mitochondrial dynamics. Furthermore, we found that mitochondrial density in QL.pp correlates with the time it takes QL.pp to die. We propose that low mitochondrial density in QL.pp promotes the cell death fate and ensures that QL.pp dies in a highly reproducible and timely manner. Our results provide in vivo evidence that the unequal segregation of mitochondria can contribute to cell fate divergence during asymmetric cell division in a developing animal.

DOI: https://doi.org/10.1038/s41467-025-62484-5
Stem Cells Transl Med. 2025 Jul 24. pii: szaf032. [Epub ahead of print]14(8):

Modeling rare genetic disease with patient-derived induced pluripotent stem cells: reassessment of the minimum numbers of lines needed.

Ashok R Dinasarapu, Diane J Sutcliffe, Lauren Grychowski, Erkin Ozel, Anika Thite, Jasper E Visser, Ellen J Hess, Sharon M Kolk, H A Jinnah.

  Induced pluripotent stem cells (iPSCs) are widely used to model human genetic diseases. The most common strategy involves collecting cells from relevant individuals and then reprogramming them into iPSCs. This strategy is very powerful, but finding enough individuals with a specific genetic disease can be challenging, especially since most are rare. In addition, making numerous iPSC lines is time-consuming and expensive. As a result, most studies have included relatively small numbers of iPSC lines, sometimes from the same individual. Considering the experimental variability obtained using different iPSC lines, there has been great interest in delineating the most efficient number of lines needed to achieve a robust and reproducible result. Several recommendations have been published, although most conclusions have been based on methods where experimental variance from individual cases is difficult to separate from technical issues related to the preparation of iPSCs. The current study used gene expression profiles determined by RNA sequencing (RNAseq) to empirically evaluate the impact of the number of unique individuals and the number of replicate iPSC lines from each individual for modeling Lesch-Nyhan disease (LND). This disease is caused by mutations in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyltransferase. Results for detecting disease-relevant changes in gene expression depended on the analytical method employed, and whether or not statistical procedures were used to address multiple iPSC lines from the same individual. In keeping with prior studies, the best results were obtained with iPSC lines from 3-4 unique individuals per group. In contrast to prior studies, results were improved with 2 lines per individual, without statistical corrections for duplicate lines from the same individual. In the current study where all lines were produced in parallel using the same methods, most variance in gene expression came from technical factors unrelated to the individual from whom the iPSC lines were prepared.

Keywords:   HPRT1 ; Lesch–Nyhan disease; disease modeling; human; induced pluripotent stem cell; transcriptome

DOI:  https://doi.org/10.1093/stcltm/szaf032
AAPS PharmSciTech. 2025 Aug 04. 26(7): 206

Advancements in Liposomal Drug Delivery Systems for Paediatric Neurological Disorders: A Comprehensive Review.

Parvathy Hari, Safa A Vahab, Vrinda S Kumar.

  Paediatric neurological conditions pose many challenges for treatment because of the dynamic properties of the developing nervous system. Special therapeutic interventions are necessary to cope with these alterations because they are frequently impaired by the blood-brain barrier, which denies drugs access to the brain. Liposomes, a lipid carrier, present a promising option, making it possible to deliver a broad variety of drugs to desired locations within the central nervous system. One of the main benefits of liposomes is that they can cross the blood-brain barrier by mechanisms like endocytosis, facilitating controlled drug delivery, minimising toxicity, and enhancing bioavailability. This can be achieved by surface modification of liposomes, enhancing the bioavailability of drugs via oral, nasal, and intravenous routes. In paediatric neurological disorders, liposomes have a great potential in developing treatment approaches, which is discussed in this review. They provide potential therapeutic advantages for ailments like epilepsy, migraine, autism, ADHD, and brain tumours, highlighting their significance in aiding the management of these intricate conditions.

Keywords:  Blood–brain barrier; Clinical translation; Liposomal nanocarriers; Paediatric neurological disorders; Targeted delivery

DOI:  https://doi.org/10.1208/s12249-025-03198-1
Muscles. 2024 Nov 26. 3(4): 393-403

Noninvasive Assessments of Mitochondrial Capacity in People with Mitochondrial Myopathies.

Kevin K McCully, Hannah M Bossie, Fran D Kendall.

  People affected by mitochondrial myopathies (MITOs) are thought to have impaired skeletal muscle oxygenation. The aims of this study were to measure skeletal muscle mitochondrial capacity in MITO participants and able-bodied (AB) participants and evaluate the influence of muscle-specific endurance training in one MITO participant. Participants (n = 7) with mitochondrial disease and controls (n = 9) were tested (ages 18-54 years). Mitochondrial capacity (mVO2max) was measured using the rate constant of recovery of oxygen consumption (mVO2) after exercise in the forearm flexor muscles with near-infrared spectroscopy (NIRS). One MITO participant was tested before and after performing 18 forearm exercise sessions in 30 days. There were no differences between MITO and AB participants in mVO2max (MITO: 1.4 ± 0.1 min-1; AB: 1.5 ± 0.3 min-1; p = 0.29), resting mVO2 (MITO: -0.4 ± 0.2%/min; AB: -0.3 ± 0.1%/min; p = 0.23), or initial post exercise oxygen consumption rates (MITO: 4.3 ± 1.2%/min; AB: 4.4 ± 1.4%/min; p = 0.9). Exercise oxygen desaturation was greater in MITO (39.8 ± 9.7% range) than in AB (28 ± 8.8% range) participants, p = 0.02. The MITO participant who trained increased her mitochondrial capacity (58%) and muscle-specific endurance (24%) and had reduced symptoms of muscle fatigue. We found no evidence supporting in vivo impairment of forearm muscle mVO2max in genetically confirmed MITO participants. This is consistent with studies that report increased mitochondrial content, which offsets the decrease in mitochondrial function. Positive muscle adaptations to endurance training appear to be possible in people with MITOs. Characterization of study populations will be important when interpreting the relationship between in vivo mitochondrial capacity and mitochondrial disease.

Keywords:  Kearns–Sayre syndrome; MELAS; NIRS; near-infrared spectroscopy; skeletal muscle

DOI:  https://doi.org/10.3390/muscles3040033
Prog Brain Res. 2025 ;pii: S0079-6123(25)00067-6. [Epub ahead of print]295 9-38

Impacts of aging on brain metabolism.

Bianca Andrade Rodrigues, Thays Calista Santiago Pretes, Josiane do Nascimento Silva.

  Changes in energy homeostasis in aging have significant implications for brain health. Decreased glucose utilization efficiency, mitochondrial dysfunction, loss of metabolic flexibility, and increased oxidative stress can compromise cognitive functions and increase vulnerability to neurodegenerative diseases. Understanding these changes provides valuable insights for prevention and treatment strategies, such as dietary interventions, physical exercise, and pharmacological therapies, aimed at restoring or preserving energy homeostasis in the brain and thus improving cognitive health throughout life. This chapter explores the metabolic changes in the brain associated with aging, examining the underlying biochemical and molecular mechanisms, as well as therapeutic strategies that may alleviate the detrimental effects of brain aging.

Keywords:  Brain aging; Brain metabolism; Energy homeostasis; Glucose; Ketone bodies; Metabolic flexibility; Mitochondrial dysfunction; Oxidative stress

DOI:  https://doi.org/10.1016/bs.pbr.2025.05.009
Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00321-0. [Epub ahead of print]86 103808

Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.

Jose Adan Arevalo, Dianna Xing, Roberto Garcia Leija, Max A Thorwald, Diana Daniela Moreno-Santillán, Kaitlin N Allen, Giovanna Selleghin-Veiga, Heidi C Avalos, Eva Utke, Justin L Conner, George A Brooks, José Pablo Vázquez-Medina.

An age-related decline in mitochondrial function is a multi-factorial hallmark of aging, driven partly by increased lipid hydroperoxide levels that impair mitochondrial respiration in skeletal muscle, leading to atrophy. Although pharmacological and genetic manipulations to counteract increased lipid hydroperoxide levels represent a promising strategy to treat sarcopenia, the mechanisms driving such phenotypes remain understudied. Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme that contributes to peroxidized membrane repair via its phospholipid hydroperoxidase and phospholipase A2 activities. Here, we show decreased mitochondrial Prdx6 levels, increased mitochondrial lipid peroxidation, and dysregulated muscle bioenergetics in aged mice and muscle cells derived from older humans. Mechanistically, we found that Prdx6 supports optimal mitochondrial function and prevents mitochondrial fragmentation by limiting mitochondrial lipid peroxidation via its membrane remodeling activities. Our results suggest that age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics, thereby opening the door to therapeutic modulation of Prdx6 to counteract diminished mitochondrial function in aging.

DOI: https://doi.org/10.1016/j.redox.2025.103808
Res Sq. 2025 Jul 31. pii: rs.3.rs-7093535. [Epub ahead of print]

Genetic mapping of lifespan and mitochondrial stress response in C. elegans.

Johan Auwerx, Xiaoxu Li, Weisha Li, Arwen Gao, YunYun Zhu, Elena Katsyuba, Katherine Overmyer, Terytty Yang Li, Ziwen Wang, Luc Legon, Lucie Plantade, Laurent Mouchiroud, Matteo Cornaglia, Hao Li, Riekelt Houtkooper, Joshua Coon.

The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, highlighting its translational relevance. Overall, our dataset (https://lisp-lms.shinyapps.io/RIAILs_Dox/) serves as a unique resource to dissect lifespan and mitochondrial stress response modulators in a large genetic reference population.

DOI: https://doi.org/10.21203/rs.3.rs-7093535/v1