bims-polgdi 2025-12-07 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–12–07
23 papers selected by
Luca Bolliger, lxBio

Mitochondria-targeted gene delivery using fluorinated lipid nanoparticles to alleviate Leber's hereditary optic neuropathy.
Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
Intercellular Mitochondrial Transfer: A Novel Neuroprotective Strategy in Stroke Management.
Mitochondrial Genetics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association.
Examining saliva proteomic dynamics in mitochondrial diseases from a perspective of intrinsic health.
Targeting multiple genetic defects of mitochondrial diseases with a single bacterial lipoate protein ligase.
Engineering exosomes for targeted neurodegenerative therapy: innovations in biogenesis, drug loading, and clinical translation.
Evaluation of mitochondrial DNA copy number alterations and their clinical correlates in methamphetamine use disorder.
Molecular mechanisms of mitochondrial function in neurodegenerative diseases.
Cardiac magnetic resonance findings in mitochondrial disease: a guide for clinicians.
Receptor-mediated mitophagy: a new target of neurodegenerative diseases.
[Rare Disease Day].
Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.
The Role of Mitochondrial DNA Copy Number in Neurodevelopmental Disorders: A Bidirectional Two-Sample Mendelian Randomization Study.
Elamipretide: First Approval.
[Key Findings from 2020 Annual Report on Rare Disease (2) Patients in Korea: Incidence, Mortality and Medical Service Utilization].
Neuroimmune dynamics and brain aging: mechanisms and consequences.
Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.
Slirp2 modulates oogenesis via regulating mitochondrial protein translation.
AI-driven enhancements in rare disease diagnosis and support system optimization.
Adaptation of mtDNA content to endurance training, a cross-sectional study and an endurance training intervention.
NeuroMoE: A Transformer-Based Mixture-of-Experts Framework for Multi-Modal Neurological Disorder Classification.
Factors associated with diagnostic delays in Peruvian patients with rare diseases.

Nat Commun. 2025 Dec 04. 16(1): 10891

Mitochondria-targeted gene delivery using fluorinated lipid nanoparticles to alleviate Leber's hereditary optic neuropathy.

Yi Wang, Min Zhao, Hai-Xin Xie, Hao-Yuan Yu, Jing-Song Yang, Lu-Xin Qie, Na-Hui Liu, Jia-Qi Chen, Zi-Juan Yi, Tian-Jiao Zhou, Lei Xing, Xian Wu Cheng, Hu-Lin Jiang.

Mutations in mitochondrial DNA (mtDNA) lead to various mitochondrial diseases for which no cure is currently available. Despite the promising potential of mtDNA correction to treat these disorders, the double mitochondrial membranes have proven to be a tough barrier to overcome. Here, we develop fluorinated lipid nanoparticles with a mitochondrial targeting sequence (F-M-LNP) to overcome the mitochondrial barrier by virtue of their high affinity for mitochondrial membranes, thereby effectively introducing gene into mitochondria. Through the rational design of ionizable lipid structures, we synthesize 16 lipid nanoparticles (LNPs) with varying degrees of fluorination and investigate the key structural features required for efficient mitochondria-targeted gene delivery. As fluorinated ionizable lipid-mediated mitochondrial transport is independent of mitochondrial membrane potential (MMP), F-M-LNPs deliver gene to mitochondria under pathological conditions where MMP is impaired, resulting in a 3.8-fold increase in functional protein expression compared to non-fluorinated LNPs. In a male mouse model of genetically induced mitochondrial disease, F-M-LNP demonstrate functional complementation of mutant mtDNA, alleviating disease symptoms. Together, our results show that modifying vectors with fluorinated groups offers valuable tools for correcting mitochondrial genome defects.

DOI: https://doi.org/10.1038/s41467-025-65874-x
Mol Cell Biochem. 2025 Dec 01.

Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.

Chuanlong Zhang, Xiaoxia Zheng, Lijuan Xiang, Zhanguo Su.

  The deterioration of mitochondrial function is a hallmark of aging muscle and markedly accelerates the onset and progression of a range of mitochondrial diseases. Symptoms including limited mobility, persistent fatigue, and muscle weakness are often attributed to impaired mitochondrial dynamics, involving key mechanisms such as mitophagy, fusion, and fission. Exercise has been shown to positively influence mitochondrial health by regulating mitochondrial biogenesis, dynamics, and turnover. This review examines the exercise-induced modulation of mitochondrial processes in aging muscle and delineates its prospects as an intervention for managing mitochondrial diseases. We highlight the molecular mechanisms by which exercise orchestrates mitochondrial dynamics, augments organelle function, and triggers mitophagy-all of which are crucial for the preservation of muscle cell homeostasis. Furthermore, we explore how pivotal molecular pathways such as AMPK, PGC-1α, and SIRT1 regulate mitochondrial adaptations to exercise. This review also underscores the therapeutic promise of exercise in attenuating mitochondrial disease progression via enhanced mitochondrial quality control and improved muscle function. By integrating findings from mitochondrial science, gerontology, and exercise physiology, this review positions exercise as a crucial regulator of mitochondrial dynamics and a viable non-pharmacological strategy for maintaining muscle integrity in the contexts of aging and mitochondrial disease.

Keywords:  Aging muscle; Exercise; Mitochondrial diseases; Mitochondrial dynamics

DOI:  https://doi.org/10.1007/s11010-025-05441-6
Eur J Pharmacol. 2025 Dec 03. pii: S0014-2999(25)01187-2. [Epub ahead of print] 178433

Intercellular Mitochondrial Transfer: A Novel Neuroprotective Strategy in Stroke Management.

Xihang Piao, Xiaolei Tang, Li Li, Ying Zhang, Haiyan Li.

  Stroke remains a leading cause of death and long-term disability worldwide. Although revascularization therapies have transformed acute care, effective neuroprotective strategies are still lacking. Intercellular mitochondrial transfer has recently gained attention as a promising endogenous repair mechanism. Through tunneling nanotubes, extracellular vesicles, or cell fusion, healthy mitochondria can be transferred from donor to recipient cells, helping restore bioenergetic homeostasis in injured neurons. This phenomenon, functionally comparable to organelle-level metabolic rescue, offers several advantages. It avoids the ethical concerns associated with genetic manipulation, leverages intrinsic intercellular communication for targeted delivery, and provides mitochondrial DNA complementation to correct metabolic defects. Here, we integrate current evidence on the cellular sources, transfer routes, and regulatory mechanisms underlying poststroke mitochondrial exchange; delineate the coordinated contributions of astrocytes, mesenchymal stem cells, microglia, and endothelial cells to this process; and critically evaluate its translational promise alongside the key barriers that must be addressed for successful clinical application.

Keywords:  Mitochondrial transfer; multicellular cooperation; stroke; therapeutic strategies; tunneling nanotubes

DOI:  https://doi.org/10.1016/j.ejphar.2025.178433
Circulation. 2025 Dec 02.

Mitochondrial Genetics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association.

American Heart Association Council on Genomic and Precision Medicine Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation Council on Cardiovascular and Stroke Nursing Council on Peripheral Vascular Disease

  Metabolic and genetic abnormalities have long been noted in cardiovascular diseases, but the contribution of mitochondrial genetic (mitochondrial DNA [mtDNA]) variation is understudied. Mitochondrial genetics is complex in that each mitochondrion contains multiple mtDNA copies that may carry different variants, which is called heteroplasmy. Heteroplasmic variation is dynamic, increases with advancing age, and may contribute to aging-related cardiovascular diseases. Pathogenic variants in mitochondrial genes of the mtDNA or nuclear genome cause mitochondrial diseases, often with cardiac involvement, particularly in patients with adult-onset disease. Population-level studies have identified mtDNA variants associated with cardiovascular risk factors and disease, but evaluation of mtDNA genetic variation is often limited to only a handful of variants and small sample sizes. Studies in animal models have linked several mtDNA variants to cardiac remodeling and dysfunction and suggest a role for mitochondrial-nuclear genetic interactions in disease penetrance. The objective of this scientific statement is to outline the current state of understanding of the role of mitochondrial genetics in cardiovascular pathobiology and highlight important gaps in knowledge. The intended audience of this scientific statement is meant to be broad, spanning clinical, translational, and basic researchers and health care professionals. Despite remaining limitations and barriers, recent advances in genomic sequencing, mtDNA gene editing modalities, and the directed differentiation of stem cells to cardiovascular cell types are creating new opportunities to advance understanding of mitochondrial genetics in cardiovascular pathophysiology.

Keywords:  AHA Scientific Statements; DNA, mitochondrial; cardiovascular diseases; genes, mitochondrial; mitochondria

DOI:  https://doi.org/10.1161/CIR.0000000000001393
Sci Rep. 2025 Dec 02. 15(1): 43031

Examining saliva proteomic dynamics in mitochondrial diseases from a perspective of intrinsic health.

Jiaying Zhao, Bowen Xu, Tianhui Huang, Sewanou Hermann Honfo, Caroline Trumpff, Martin Picard, Alan A Cohen, Molei Liu.

Mitochondrial disease (MitoD), a clinical condition caused by genetic mitochondrial defects, affects cellular energy transformation and alters multiple dimensions of health. Recently, we collected a longitudinal saliva proteomics data set consisting of six healthy controls and six MitoD subjects throughout the awakening response process. We undertook three independent unsupervised or inferential approaches to characterize proteome dynamics and assessed their ability to separate MitoD individuals from controls. First, we designed a permutation test to detect the global difference in the proteomic co-regulation structure between healthy and unhealthy subjects. Second, we performed non-linear embedding and cluster analysis on elasticity to capture a more complicated relationship between health and the proteome. Third, we developed a machine learning algorithm to extract low-dimensional representations of the proteome dynamic and use them to cluster subjects into healthy and unhealthy groups without any knowledge of their true status. All three methods showed clear differences between MitoD individuals and controls. Our results revealed a significant and consistent association between MitoD status and the saliva proteome at multiple levels during the awakening response, including its dynamic change, co-regulation structure, and elasticity. Pipelines such as those shown here are the first step toward establishing interpretable and accurate framework for detecting signals related to mitochondrial disease progression from proteome dynamics.

DOI: https://doi.org/10.1038/s41598-025-23879-y
Sci Adv. 2025 Dec 05. 11(49): eaea8481

Targeting multiple genetic defects of mitochondrial diseases with a single bacterial lipoate protein ligase.

Zhijuan Hu, Junru Yu, Ziwei Liu, Min Jiang, An-Ping Zeng.

Metabolic disorders caused by defects in energy metabolism can lead to many life-threatening diseases; their therapy remains elusive in most cases. Conventional gene therapy relies on the "one gene for one genetic defect" strategy. Here, we demonstrate a more efficient strategy to target multiple genetic defects with a single gene intervention. Specifically, we used a bacterial lipoate protein ligase involved in protein lipoylation to rescue mitochondrial dysfunctions in human lipoylation pathway (LIPT2, LIAS, and LIPT1), lipoyl precursor supply (MECR), and sulfur insertion accessary partner (FDX1). The efficacy and safety of Escherichia coli-derived LplA or Bacillus subtilis-derived LplJ were validated in human cells and mouse models. LplA knock-in mice exhibited normal health with enhanced energy expenditure. Overexpressing LplA through a mating strategy rescued embryonic lethality in Lipt1-/- mutants, yielding viable offspring with normal body weight, energy expenditure, tissue morphology, and biochemical profile. Our work highlights how evolutionary differences in biosynthetic pathways between humans and bacteria can be leveraged for cross-species therapeutic innovations.

DOI: https://doi.org/10.1126/sciadv.aea8481
Theranostics. 2026 ;16(1): 545-579

Engineering exosomes for targeted neurodegenerative therapy: innovations in biogenesis, drug loading, and clinical translation.

Qinqin Huang, Shile Wang, Zeming Liu, Lang Rao, Ke Cheng, Xiaobo Mao.

  Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS), are characterized by progressive neuronal dysfunction and limited therapeutic options, largely due to the restrictive nature of the blood-brain barrier (BBB). Exosomes, naturally occurring extracellular vesicles (EVs), have gained attention as innovative drug delivery vehicles owing to their intrinsic ability to cross the BBB, minimal immunogenicity, high biocompatibility, and capability to carry diverse therapeutic cargos such as proteins, nucleic acids, and small molecules. Furthermore, exosomes can be bioengineered to enhance drug-loading efficiency and targeting specificity, positioning them as a versatile and effective platform for treating NDDs. In this review, we summarize recent advances in exosome biogenesis, secretion, and engineering, with an emphasis on innovative strategies for exosome isolation, drug loading, and surface modification. We further explore their roles in modulating neuroinflammation, promoting neural regeneration, and enabling precise therapeutic delivery. Critical challenges associated with large-scale production, quality control, and regulatory compliance under Good Manufacturing Practices (GMP) are also discussed. Collectively, these developments underscore the transformative potential of engineered exosomes in advancing precision therapies for neurodegenerative disorders and offer strategic insights into their clinical translation.

Keywords:  blood-brain barrier (BBB); clinical trials; drug delivery; exosomes; neurodegenerative diseases (NDDs); targeted therapy

DOI:  https://doi.org/10.7150/thno.117143
J Psychiatr Res. 2025 Nov 27. pii: S0022-3956(25)00734-4. [Epub ahead of print]193 309-315

Evaluation of mitochondrial DNA copy number alterations and their clinical correlates in methamphetamine use disorder.

Hasan Mervan Aytac, Yasemin Oyaci, Mustafa Pehlivan, Sena Inal Azizoglu, Vuslat Ozer, Eren Aytac, Oya Guclu, Sacide Pehlivan.

  This study aimed to compare peripheral blood mitochondrial DNA (mtDNA) copy number between patients with methamphetamine use disorder (MUD) and healthy controls, and to examine its associations with clinical characteristics and symptom severity. Fifty-two patients with MUD, diagnosed according to DSM-5 using the SCID-5-CV, and 52 age- and sex-matched healthy controls were included. Clinical features were assessed with validated psychiatric scales, including the Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-I) scales, the Positive and Negative Syndrome Scale (PANSS), and the Hamilton Depression (HAM-D) and Anxiety (HAM-A) Rating Scales. Peripheral mtDNA copy number was quantified by quantitative polymerase chain reaction (qPCR). mtDNA copy number was significantly lower in MUD patients compared to controls (p < .001). After adjusting for age and sex, a significant inverse correlation was observed between mtDNA copy number and illness duration (r = -0.312, p = .037). No significant associations were found between mtDNA copy number and psychometric scale scores or clinical characteristics, including history of suicide attempts, self-mutilation, violent behavior, hospitalization, withdrawal symptoms, or drug-induced psychosis (p > .05). In summary, our results indicate a marked decrease in peripheral blood mtDNA copy number among individuals with MUD, along with a significant inverse relationship between mtDNA copy number and the duration of substance use, suggesting cumulative mitochondrial stress associated with chronic methamphetamine exposure.

Keywords:  Addiction; Clinical parameters; Methamphetamine; Mitochondria; mtDNA copy number

DOI:  https://doi.org/10.1016/j.jpsychires.2025.11.028
Mol Biol Rep. 2025 Dec 01. 53(1): 143

Molecular mechanisms of mitochondrial function in neurodegenerative diseases.

Heather M Wilkins, Simone Patergnani.

Mitochondria regulate cellular homeostasis and function in both neurons and glial cells, but molecular mechanisms are not fully understood. Recent advances have expanded our understanding of how mitochondrial dynamics, quality control, bioenergetics, redox regulation, and proteostasis contribute to neurodegenerative processes. The collection "Neuroscience: Mitochondrial Function in Neurons and Glia" highlights the pivotal role of mitochondria in energy production, redox signaling, calcium buffering, and apoptosis. Articles within this collection discuss the effects of mitochondria in neurodegeneration. Together, these studies emphasize ongoing challenges in defining cell type specific mitochondrial responses and point to the need for improved strategies to target mitochondrial dysfunction in neurological disease.

DOI: https://doi.org/10.1007/s11033-025-11303-7
Eur Heart J Imaging Methods Pract. 2025 Oct;3(4): qyaf134

Cardiac magnetic resonance findings in mitochondrial disease: a guide for clinicians.

Rhys Gray, Vasiliki Kantartzı, Luis R Lopes, Konstantinos Savvatis, Mark Westwood.

  Mitochondrial myopathies are heritable conditions caused by genetic variations in mitochondrial DNA or nuclear DNA. These result in dysfunctional cellular oxidative phosphorylation and ATP production, affecting organs with high-energy requirements such as the heart, brain and skeletal muscle. Cardiac involvement is common affecting one third of patients and includes left ventricular hypertrophy, conduction disease, Wolff-Parkinson-White syndrome, and dilated cardiomyopathy. Due to the variability in the clinical presentation, a multiparametric approach incorporating clinical, biochemical, histological/histochemical and genetic criteria is required to make the diagnosis. Cardiologists should be aware of the clinical red flags and imaging findings and how to differentiate mitochondrial cardiomyopathy from other causes of left ventricular hypertrophy. Cardiovascular magnetic resonance imaging is a highly sensitive tool for depicting myocardial abnormalities to aid in both the diagnosis of patients presenting with left ventricular hypertrophy, and in the assessment of cardiac involvement in patients with a known diagnosis of mitochondrial myopathy, as this is an independent predictor of morbidity and early mortality. The most common CMRI findings include increased maximal LV wall thickness and mass and non-ischaemic subepicardial and midwall LGE, most commonly affecting the basal inferolateral or lateral wall. Future studies should consider integrating late gadolinium enhancement imaging into risk prediction models to enhance stratification of major adverse cardiac events such as heart failure and arrhythmia. As our understanding of mitochondrial disease evolves, integrating advanced imaging with molecular diagnostics will be essential for early detection of disease, improved risk prediction and outcomes.

Keywords:  cardiac MRI; mitochondria myopathy; mitochondrial cardiomyopathy; mitochondrial disease

DOI:  https://doi.org/10.1093/ehjimp/qyaf134
Front Neurol. 2025 ;16 1665315

Receptor-mediated mitophagy: a new target of neurodegenerative diseases.

Junlan Yang, Fuquan Yang, Guiyan Chen, Ming Liu, Shiqing Yuan, Tian-E Zhang.

  Neurodegenerative diseases are a category of neurological conditions with high prevalence that pose major treatment challenges. Common pathologies involve protein accumulation and mitochondrial damage. Mitophagy maintains cellular homeostasis by removing defective mitochondria, which are associated with the pathogenesis of neurodegenerative diseases. Although the ubiquitin-dependent mitophagy mediated by the PINK1-Parkin pathway has been extensively studied, growing evidence indicates that receptor-mediated mitophagy plays a crucial compensatory role in neurons, particularly when the PINK1-Parkin pathway is impaired. This review focuses on the emerging field of receptor-mediated mitophagy, systematically elaborating its role as a key homeostatic mechanism operating independently of the canonical PINK1/Parkin pathway. It provides a focused analysis of the specific functions and activation mechanisms of key receptors-including BNIP3, NIX, FUNDC1, and AMBRA1-in models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review explores the clinical potential of targeting these specific receptors for precise intervention, aiming to provide a new theoretical foundation and direction for developing therapeutic strategies against neurodegenerative diseases.

Keywords:  PINK1/Parkin-independent mitophagy; autophagy receptors; mitochondria; mitochondrial dysfunction; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fneur.2025.1665315
Jugan Geongang Gwa Jilbyeong. 2024 Feb 29. 17(8): 345-350

[Rare Disease Day].

Jimin Kim, Jiwon M.

  Rare diseases require long-term treatment and management because disease-related information is limited. Furthermore, their causes and symptoms are very complex, which make full recovery and cure very challenging. Accordingly, annual celebrations are held to strengthen patients' and families' will to overcome and improve awareness of rare diseases among the public and policymakers. In 2008, the European Organization for Rare Diseases established the last day of February as "World Rare Disease Day" and has been conducting an annual campaign. The Republic of Korea also changed the Rare Disease Day to the same day as World Rare Disease Day through a law amendment in 2023. The year 2024 is significant. It will be the first time we celebrate the "Rare Disease Day" anniversary on the last day of February. A commemorative event and symposium will be held on this day to reflect its meaning.

Keywords:  Awareness; Rare disease day; World rare disease day

DOI:  https://doi.org/10.56786/PHWR.2024.17.8.4
Nat Commun. 2025 Dec 03.

Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.

Geoffray Monteuuis, Ryan Awadhpersad, Daan van der Kolk, Sachin K Singh, Tuula A Nyman, Alina Malyutina, Nicola Zamboni, Kari Moisio, Juhana Juutila, Ville Hietakangas, Sara Seneca, Christopher J Carroll, Christopher B Jackson.

Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects - besides a compendium of known mitochondrial translation quality control factors - is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.

DOI: https://doi.org/10.1038/s41467-025-66656-1
Psychol Res Behav Manag. 2025 ;18 2323-2332

The Role of Mitochondrial DNA Copy Number in Neurodevelopmental Disorders: A Bidirectional Two-Sample Mendelian Randomization Study.

Xinhui Qiu, Huilu Song, Chenyang Wu, Chaojun Chen, Haimei Zhi, Chengyuan Zhang, Xiaobo Zhu.

   Background: Recent studies have indicated a possible connection between impaired mitochondrial bioenergetics and neurodevelopmental disorders (NDDs) such autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Tourette's syndrome (TS). The precise causal relationship between them is yet uncertain. This study utilized bidirectional dual-sample Mendelian randomization (MR) analysis to investigate the causal relationship between Mitochondrial DNA (mtDNA) copy quantity, an indicator of mitochondrial malfunction, and NDDs.
Methods: The study utilized data from the Psychiatric Genomics Consortium (PGC) and IEU OpenGWAS Project database to investigate the relationship between mtDNA copy number and NDDs using MR method. The accuracy and confidence of our results were evaluated using the inverse-variance weighted (IVW) method along with sensitivity analyses such as weighted median, MR-Egger, and MR-PRESSO. Additionally, we conducted the same procedure in the reverse manner with instruments for NDDs.
Results: A notable correlation was discovered between mtDNA copy number and ASD (OR=0.78, 95% CI: 0.65-0.94, P=0.0077). Furthermore, confirmatory GWAS data analysis yielded similar results, which were even more significant (OR=0.80, 95% CI: 0.68-0.93, P=0.0047). However, bidirectional two-sample MR analysis did not reveal significant correlations between mtDNA copy number and ADHD or TS.
Conclusion: This study has uncovered a significant genetic causal relationship between mtDNA copy number and ASD. No associations were discovered between ADHD and TS during the investigation. Due to the inherent constraints of MR investigations, additional study is needed to definitively clarify these genetic causal links.

Keywords:  Tourette syndrome; attention-deficit/hyperactivity disorder; autism spectrum disorder; mendelian randomization; mitochondrial DNA copy number; neurodevelopmental disorders

DOI:  https://doi.org/10.2147/PRBM.S533506
Drugs. 2025 Dec 03.

Elamipretide: First Approval.

Matt Shirley.

Elamipretide (Forzinity™) is a mitochondrial cardiolipin binder being developed by Stealth BioTherapeutics for the treatment of a range of disorders featuring mitochondrial dysfunction. In September 2025, elamipretide was granted accelerated approval in the USA for use to improve muscle strength in adult and pediatric patients with Barth syndrome weighing ≥ 30 kg. With this accelerated approval, elamipretide became the first disease-specific treatment approved for Barth syndrome, an ultra-rare X-linked recessive genetic disorder. Elamipretide is also under phase III clinical development for use in the treatment of dry age-related macular degeneration and mitochondrial myopathies. This article summarizes the milestones in the development of elamipretide leading to this first approval for Barth syndrome.

DOI: https://doi.org/10.1007/s40265-025-02269-8
Jugan Geongang Gwa Jilbyeong. 2024 Feb 15. 17(6): 199-217

[Key Findings from 2020 Annual Report on Rare Disease (2) Patients in Korea: Incidence, Mortality and Medical Service Utilization].

Kyoung-Hwa Choi, Woo-Mi Cho, Ji-Hwan Sung, JiWon M.

  The Korea Disease Control and Prevention Agency approved the "Rare Diseases Statistics in Korea" as national statistics in 2019. It published the "2019 Annual Report on Rare Disease Patients in Korea" for the first time in December 2020. It systematically collects, refines, and analyzes data related to the occurrence and treatment of rare diseases every year and provides results. Accordingly, in the "2020 Annual Report on Rare Disease Patients in Korea (2)", detailed statistics of the year which were different from the "2020 Annual Report on Rare Disease Patients in Korea" announced in 2021 were included in the 2020 report. Therefore, the incidence, mortality, and medical service utilization of patients with rare diseases were included in the same annual report. In this report, we present the main results to promote the use of the "2020 Annual Report on Rare Disease Patients in Korea (2)," published in 2022. A total of 52,310 rare disease cases occurred among 694 diseases between January 1 and December 31, 2020, including 25,353 male (48.5%) and 26,957 female (51.5%). The death statistics referred to those who died in the same year among the cases in 2020. A total of 1,662 of 52,310 cases in 2020 died. The medical use of patients with rare diseases was calculated based on current benefit status and treatment details for the last 3 months after the registration of rare diseases in 2020. In the three months, 48,115 people were treated, and the average total cost per person was 3.1 million won. Among the treatment details, the injection, hospitalization, examination, and consultation fees were the largest in the order of payment. Since the "Annual Report on Rare Disease Patients" is written only for new patients registered for differential copayments, there are limitations, such as no information on unregistered patients. We will continue to strive to improve the "Annual Report on Rare Disease Patients" to provide more useful and accurate information.

Keywords:  Official statistics; Rare disease statistics; Rare diseases

DOI:  https://doi.org/10.56786/PHWR.2024.17.6.1
Front Aging Neurosci. 2025 ;17 1715045

Neuroimmune dynamics and brain aging: mechanisms and consequences.

Ludmila Müller, Svetlana Di Benedetto, Viktor Müller.

  Brain aging is accompanied by profound changes in neuroimmune interactions that shape the balance between resilience and vulnerability. Under healthy conditions, glial cells, neurons, vascular elements, and peripheral immune inputs cooperate to sustain homeostasis. With advancing age, however, immune remodeling and systemic inflammaging drive shifts in microglial surveillance, astrocytic reactivity, and neuronal susceptibility, creating conditions that compromise synaptic function and cognitive performance. These processes unfold along a continuum, from subtle impairments in normal aging to maladaptive dynamics that accelerate neurodegenerative disease. Sex differences, epigenetic regulation, and systemic influences-including the gut microbiome, metabolic state, and lifestyle factors-further modulate these trajectories. Here, we synthesize current knowledge on the cellular, systemic, and molecular mechanisms that govern neuroimmune aging, emphasizing how their dysregulation contributes to cognitive decline and disease vulnerability. We also highlight emerging conceptual frameworks, such as multilayer network modeling and resilience biomarkers, that provide a foundation for integrative approaches to brain aging. Understanding these interconnected systems underscores the necessity of viewing brain aging not solely through a CNS-centric lens, but as a networked process influenced by distal organs, circulating immune cells, microbial communities, and lifestyle factors-setting the stage for integrative models of neuroimmune dynamics in aging. Clarifying how these dynamic interactions unfold and what their consequences are is essential for developing strategies to preserve cognitive health and mitigate the burden of neurodegeneration in an aging society.

Keywords:  aging brain; glial cells; immune cells; immunosenescence; multilayered networks; neurodegenerative diseases; neuroinflammation; neurons

DOI:  https://doi.org/10.3389/fnagi.2025.1715045
Cell Metab. 2025 Dec 02. pii: S1550-4131(25)00489-9. [Epub ahead of print]37(12): 2298-2300

Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.

Sébastien Ibanez, Olivier Feron.

Cancer cells experience multiple stresses within tumors, stemming from elevated metabolic activity, including nutrient shortage, waste buildup, hypoxia, and acidosis. According to Groessl et al.,1 acidosis is the dominant environmental factor offering metabolic flexibility to support tumor fitness and resilience to the other stresses by promoting mitochondria fusion and enhancing respiration capacity.

DOI: https://doi.org/10.1016/j.cmet.2025.11.005
J Mol Cell Biol. 2025 Dec 02. pii: mjaf047. [Epub ahead of print]

Slirp2 modulates oogenesis via regulating mitochondrial protein translation.

Jinguo Cao, Jiting Zhang, Zhaoqi Wu, Wei Luan, Yue Zhou, Huihui Huang, Lingling Li, Wen Hu.

  Mitochondria are essential organelles responsible for generating ATP through oxidative phosphorylation (OXPHOS). Despite having their own genome, mitochondria rely on a complex interplay with nuclear-encoded proteins to maintain their function, as mutations in these proteins can lead to mitochondrial dysfunction and associated diseases. Mutations in the SLIRP (stem-loop interacting RNA-binding protein) gene are known to cause severe human mitochondrial diseases, and loss of SLIRP function can impair mitochondrial mRNA stability and translation. However, in vivo roles of the SLIRP protein remain inadequately understood. Drosophila melanogaster serves as a powerful model for studying mitochondrial function, particularly in the context of reproductive system development and gametogenesis. In this study, we focus on the role of the fly Slirp2 in oogenesis. Loss of Slirp2 impairs mitochondrial protein synthesis, leading to reduced OXPHOS efficiency, diminished ATP production, and disrupted insulin/mTOR signaling. These defects ultimately promote reactive oxygen species-induced programmed cell death, resulting in infertility. Our findings provide novel insights into the mechanistic role of Slirp2 in mitochondrial function and reproductive biology in vivo. We demonstrate that Slirp2 exhibits species-specific regulation of mitochondrial translation, revealing its complex, context-dependent function. These results have broader implications for understanding mitochondrial diseases, suggesting that the effects of Slirp2 mutations may vary across different organisms and tissue types.

Keywords:  SLIRP; Slirp2; mitochondrial diseases; oogenesis

DOI:  https://doi.org/10.1093/jmcb/mjaf047
Intractable Rare Dis Res. 2025 Nov 30. 14(4): 306-308

AI-driven enhancements in rare disease diagnosis and support system optimization.

Xin Wang, Da He, Chunlin Jin.

  Rare diseases are characterized by an extremely low prevalence, high phenotypic heterogeneity, and complex pathogenesis. This combination of factors presents significant challenges, including prolonged diagnostic delays, lack of standardized care, and difficulties in pathological interpretation. The integration of artificial intelligence (AI) offers a transformative approach to overcoming these barriers. In recent years, researchers worldwide have been actively exploring the use of AI to diagnose and manage rare diseases. Key advances include few-shot learning algorithms designed to tackle data scarcity, clinically validated foundation models that enhance diagnostic consistency across institutions, and multimodal AI frameworks that integrate imaging, genomic, and phenotypic data to improve diagnostic accuracy. In addition, there is growing recognition that AI can enhance diagnostic efficiency and thereby optimize support systems for rare diseases. As challenges such as AI model interpretability and data equity are addressed, AI is expected to make significant strides in the diagnosis and treatment of rare diseases.

Keywords:  artificial intelligence; diagnosis; rare disease; support system

DOI:  https://doi.org/10.5582/irdr.2025.01079
Eur J Appl Physiol. 2025 Dec 05.

Adaptation of mtDNA content to endurance training, a cross-sectional study and an endurance training intervention.

Isabel María Sánchez Lorente, Thomas Yvert, Tamara Iturriaga, Lara Sanchez-Barroso, Mar Larrosa, Margarita Pérez-Ruiz, Catalina Santiago-Dorrego.

   BACKGROUND: Maximal oxygen uptake (VO2max) is the gold standard for assessing cardiopulmonary fitness. However, the link between VO2max and mitochondrial function is complex, with no direct causality proven. Analysing mtDNA copy number offers an innovative way to understand aerobic performance by measuring mitochondrial biogenesis, although its relation to physical performance and fitness is not well studied, especially in trained individuals.
OBJECTIVE: This study aimed to compare VO2max and mtDNA copy number in blood leukocytes between highly trained runners and nontrained men. It also examined how leukocyte mtDNA content adapts to a 6-week HIIT aerobic training programme in nontrained individuals.
METHODS: We conducted a cross-sectional study with 20 highly trained runners and 20 nontrained healthy subjects. Then, we implemented a 6-week HIIT training programme for the nontrained group, comparing their VO2max and mtDNA copy number to a control group. Participants trained 4 min/4 min HIIT treadmill running, three times a week.
RESULTS: The cross-sectional part showed that highly trained runners had significantly higher mtDNA copy numbers than nontrained subjects (p = 0.046; d = 0.652; 95% CI: [0.01, 1.28]; [medium-large effect]); further, we observed a significant positive correlation between mtDNA copy number and VO2max combining both groups (p = 0.013; R2 = 0.153 [small-moderate effect]). After the 6-week HIIT programme, the intervention group showed significant increases in both VO2max (p < 0.001) and mtDNA copy number (p = 0.015), with large and medium effect sizes, respectively. The intervention group's mtDNA copy number increased by 321.6 ± 391.6%; 95% CI: [120.2, 522.9], compared to 12.8 ± 32.8%; 95% CI: [- 5.4, 30.9] in controls, indicating substantial interindividual variability, which could be attributed to a combination of biological factors, but we also observed indications of a potential responder versus non-responder pattern.
CONCLUSION: These findings align with previous research, indicating that mtDNA copy number correlates with VO2max, being higher in highly trained runners than in nontrained subjects, and increasing with training after a 6-week HIIT intervention. This study is novel in showing that a 6-week HIIT programme significantly boosts leukocyte mtDNA content, enhancing our understanding of individual adaptations to endurance training.

Keywords:  Long HIIT; Mitochondrial biogenesis; Running; Treadmill training; mtDNA copy number

DOI:  https://doi.org/10.1007/s00421-025-06016-5
Annu Int Conf IEEE Eng Med Biol Soc. 2025 Jul;2025 1-7

NeuroMoE: A Transformer-Based Mixture-of-Experts Framework for Multi-Modal Neurological Disorder Classification.

Wajih Hassan Raza, Aamir Bader Shah, Yu Wen, Yidan Shen, Juan Diego Martinez Lemus, Mya Caryn Schiess, Timothy Michael Ellmore, Renjie Hu, Xin Fu.

The integration of multi-modal Magnetic Resonance Imaging (MRI) and clinical data holds great promise for enhancing the diagnosis of neurological disorders (NDs) in real-world clinical settings. Deep Learning (DL) has recently emerged as a powerful tool for extracting meaningful patterns from medical data to aid in diagnosis. However, existing DL approaches struggle to effectively leverage multi-modal MRI and clinical data, leading to suboptimal performance.To address this challenge, we utilize a unique, proprietary multi-modal clinical dataset curated for ND research. Based on this dataset, we propose a novel transformer-based Mixture-of-Experts (MoE) framework for ND classification, leveraging multiple MRI modalities-anatomical (aMRI), Diffusion Tensor Imaging (DTI), and functional (fMRI)-alongside clinical assessments. Our framework employs transformer encoders to capture spatial relationships within volumetric MRI data while utilizing modality-specific experts for targeted feature extraction. A gating mechanism with adaptive fusion dynamically integrates expert outputs, ensuring optimal predictive performance. Comprehensive experiments and comparisons with multiple baselines demonstrate that our multi-modal approach significantly enhances diagnostic accuracy, particularly in distinguishing overlapping disease states. Our framework achieves a validation accuracy of 82.47%, outperforming baseline methods by over 10%, highlighting its potential to improve ND diagnosis by applying multi-modal learning to real-world clinical data.Clinical Relevance- In neurological disorder (ND) research, a critical gap remains in mapping the continuum of disease progression, from prodromal conditions such as idiopathic REM Sleep Behavior Disorder (iRBD) to fully developed disorders like Parkinson's Disease (PD). A robust multimodal approach that seamlessly integrates diverse data modalities is essential for accurately predicting and understanding this progression. Advancements in this area would provide the foundation for developing models capable of distinguishing overlapping disease states (e.g., PD, dementia with Lewy bodies, and multiple system atrophy) and predicting the transition from presymptomatic conditions like iRBD to established NDs.

DOI: https://doi.org/10.1109/EMBC58623.2025.11254303
Intractable Rare Dis Res. 2025 Nov 30. 14(4): 288-296

Factors associated with diagnostic delays in Peruvian patients with rare diseases.

Araceli Margot Falen Solís, Hugo Hernán Abarca Barriga.

  Rare diseases affect fewer than 1 in 2,000 individuals. Patients often encounter barriers to specialist care and prompt diagnosis, hindering effective disease management and access to appropriate treatments. This study aimed to identify determinants of diagnostic delay among patients with rare diseases affiliated with Peruvian associations in 2024. A descriptive cross-sectional design was employed in 2024, enrolling patients with rare diseases or their caregivers from Peruvian associations. Data collection utilized an expert-validated survey encompassing sociodemographic characteristics, medical history, and diagnostic challenges. The primary outcome was diagnostic delay, defined as the interval from symptom onset to confirmed diagnosis. Data analysis included descriptive and inferential statistical methods. A total of 236 participants responded, with the majority being women (61.4%). A diagnosis was received within a year of symptom onset for 54.7% of participants, and 46.2% reported difficulties accessing healthcare. Major barriers identified included prolonged wait times for appointments or treatment (52.3%) and geographic limitations impeding access (37.6%). The median diagnostic delay was longer for women (63.1 months) compared to men (26.9 months). Limited access to healthcare was associated with an average delay of 21.8 months, whereas consulting more than ten general practitioners was associated with a 42.6-month delay. In summary, over half of the patients with rare diseases in Peru included in this study received a diagnosis within one year. However, the most significant delays were observed in non-genetic rare diseases. Key contributors to prolonged diagnostic timelines included limited access to healthcare and consultations with multiple general practitioners.

Keywords:  delayed diagnosis; developing countries; rare diseases; risk factors

DOI:  https://doi.org/10.5582/irdr.2025.01052