bims-curels 2025-01-19 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–01–19
eightteen papers selected by
Cure Mito Foundation

Mitochondrial disorder diagnosis and management- what the pediatric neurologist wants to know.
Mitochondrial DNA Mutations as a Factor in the Heritability of Atherosclerosis and Other Diseases.
When the Expected Scenario Did Not Occur: A Novel NDUFA12 Mutation Resembling Neuromyelitis Optica Spectrum Disorder.
Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.
Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.
Complex I deficiency remains the most frequent cause of Leigh syndrome spectrum.
Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients.
Parents' Experiences and Views About Use of Wearable Technology for Research and Treatment Monitoring of Children with Neurodevelopmental Disorders.
Roadmap to advance therapeutics for SYNGAP1-related disorder: a patient organization perspective from SynGAP Research Fund.
Chronic Low-Level IFN-γ Expression Disrupts Mitochondrial Complex I Activity in Renal Macrophages: An Early Mechanistic Driver of Lupus Nephritis Pathogenesis.
Mitochondrial Complex I Deficiency: Unraveling the Relevance of NDUFAF1 in Pediatric Hypertrophic Cardiomyopathy.
The Emerging Role of Mitochondria Oxygen Redox in Pathological Progression of Neurodegenerative Disorders.
Incidental finding of MELAS in a young woman with decompensated heart failure and end stage kidney disease: a case report.
Challenges of sharing individual participant data for secondary research on neglected tropical diseases: the experience of Drugs for Neglected Diseases initiative and a call for action.
The role of mitochondrial remodeling in neurodegenerative diseases.
How patients and informal caregivers can be trained to effectively contribute to improved quality of healthcare services: action research on the development of the Dutch Patient As a Person Academy.
Mitochondrial HMG-CoA synthase deficiency.
Recommendations for mitochondria transfer and transplantation nomenclature and characterization.

Eur J Paediatr Neurol. 2024 Dec 15. pii: S1090-3798(24)00162-4. [Epub ahead of print]54 75-88

Mitochondrial disorder diagnosis and management- what the pediatric neurologist wants to know.

Oliver Heath, René G Feichtinger, Melanie T Achleitner, Peter Hofbauer, Doris Mayr, Kajus Merkevicius, Johannes Spenger, Katja Steinbrücker, Carina Steindl, Elke Tiefenthaler, Johannes A Mayr, Saskia B Wortmann.

  Childhood-onset mitochondrial disorders are rare genetic diseases that often manifest with neurological impairment due to altered mitochondrial structure or function. To date, pathogenic variants in 373 genes across the nuclear and mitochondrial genomes have been linked to mitochondrial disease, but the ensuing genetic and clinical complexity of these disorders poses considerable challenges to their diagnosis and management. Nevertheless, despite the current lack of curative treatment, recent advances in next generation sequencing and -omics technologies have laid the foundation for precision mitochondrial medicine through enhanced diagnostic accuracy and greater insight into pathomechanisms. This holds promise for the development of targeted treatments in this group of patients. Against a backdrop of inherent challenges and recent technological advances in mitochondrial medicine, this review discusses the current diagnostic approach to a child with suspected mitochondrial disease and outlines management considerations of particular relevance to paediatric neurologists. We highlight the importance of mitochondrial expertise centres in providing the laboratory infrastructure needed to supplement uninformative first line genomic testing with focused and/or further unbiased investigations where needed, as well as coordinating an integrated multidisciplinary model of care that is paramount to the management of patients affected by these conditions.

Keywords:  Exome sequencing; Leigh syndrome; Multi-omics; Muscle biopsy; Treatment; Vitamin

DOI:  https://doi.org/10.1016/j.ejpn.2024.10.009
Curr Med Chem. 2025 Jan 14.

Mitochondrial DNA Mutations as a Factor in the Heritability of Atherosclerosis and Other Diseases.

Alexander N Orekhov, Nikolay A Orekhov, Vasily N Sukhorukov, Victoria A Khotina, Tatiana I Kovianova, Igor A Sobenin.

  This review discusses the possibility of inheritance of some diseases through mutations in mitochondrial DNA. These are examples of many mitochondrial diseases that can be caused by mutations in mitochondrial DNA. Symptoms and severity can vary widely depending on the specific mutation and affected tissues. An association between certain mutations in the mitochondrial genome and cancer was reported. In other studies of 2-4 generations in each family, we found that mitochondrial mutations associated with atherosclerosis are inherited. This may at least partially explain the inheritance of predisposition to atherosclerotic disease by maternal line. Furthermore, to prove the important role of mitochondrial mutations in the development of atherosclerotic manifestations at the cellular level, we developed a technique for editing the mitochondrial genome. A recent article described how one of the pro-atherogenic mutations, namely m.15059G>A, was eliminated from such monocyte-derived cells using the technique we developed. Elimination of this mutation resulted in the restoration to normal levels of initially defective mitophagy and impaired inflammatory response. These data strongly suggest that mitochondrial mutations are closely associated with the development of atherosclerotic lesions. Considering that they are inherited, it can be assumed that, at least partly, the genetic predisposition to atherosclerotic diseases is transmitted from mother to offspring. Thus, despite the small size of mitochondrial DNA, its mutations may play a role in the pathogenesis of diseases. Further study of their role will make it possible to consider mitochondrial mutations as promising diagnostic markers and disorders caused by mutations as pharmacological targets.

Keywords:  Atherosclerosis; chronification of inflammation; cybrid; genome editing; inflammatory reaction; innate immune system; intolerant immune response; low-density lipoprotein; mitochondrial DNA mutations.; mitochondrial dysfunctions

DOI:  https://doi.org/10.2174/0109298673291199241129044139
J Child Neurol. 2025 Jan 17. 8830738241313081

When the Expected Scenario Did Not Occur: A Novel NDUFA12 Mutation Resembling Neuromyelitis Optica Spectrum Disorder.

Ahmet Koçak, Emek Uyur Yalçin, Nilüfer Eldeş Hacifazlioğlu, İbrahim Taş, Rahşan Göçmen, Bahadır Konuşkan.

  Mitochondrial complex I transfers electrons from NADH (nicotinamide adenine dinucleotide) to ubiquinone, facilitating ATP synthesis via a proton gradient. Complex I defects are common among the mitochondrial diseases, especially in childhood. NDUFA12, located in complex I's transmembrane domain, is not directly involved in catalytic activity, but the NDUFA mutations are associated with Leigh syndrome and complex I defects. Complex I deficiency typically manifests as bilateral brainstem lesions and presents with dystonia, hypotonia, and optic nerve damage. This article discusses a patient with an NDUFA12 mutation resembling neuromyelitis optica spectrum disorder clinically and radiologically, highlighting the importance of considering NDUFA12 mutations in dystonia and optic neuritis diagnoses, particularly in neuromyelitis optica spectrum disorder cases that do not respond to standard treatments. Further research on NDUFA12 variants is needed for a better understanding of their phenotypic spectrum and to enhance diagnostic accuracy.

Keywords:  Leigh syndrome; NDUFA12; mitochondrial complex I; mitochondrial disease; neuromyelitis optica; symmetric brainstem lesion

DOI:  https://doi.org/10.1177/08830738241313081
Acta Pharm Sin B. 2024 Dec;14(12): 5435-5450

Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.

Yi Wang, Nahui Liu, Lifan Hu, Jingsong Yang, Mengmeng Han, Tianjiao Zhou, Lei Xing, Hulin Jiang.

  Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.

Keywords:  Complex I defect; Engineered mitochondria; Idebenone; Leber's hereditary optic neuropathy; Mitochondrial disease; Mitochondrial function; Mitochondrial transfer; Nanoparticle

DOI:  https://doi.org/10.1016/j.apsb.2024.08.007
bioRxiv. 2024 Dec 30. pii: 2024.12.30.630791. [Epub ahead of print]

Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.

María J Pérez, Rocío B Colombo, Sebastián M Real, María T Branham, Sergio R Laurito, Carlos T Moraes, Lía Mayorga.

Mitochondrial diseases, caused by mutations in either nuclear or mitochondrial DNA (mtDNA), currently have limited treatment options. For mtDNA mutations, reducing mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising therapeutic option, though current approaches face significant challenges. Previous research has shown that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, characterized by changes in DNA methylation, which does not occur or is less important when mitochondrial impairment is subtle. Building on this, we hypothesized that targeting nuclear DNA methylation could selectively compromise cells with high levels of mutant mtDNA, favor ones with lower mutant load and thereby reduce overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations-m.13513G>A and m.8344A>G-at varying heteroplasmy levels, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern to be critical for the survival of high-heteroplasmy cells but not for the low-heteroplasmy ones. Consequently, by disrupting this epigenetic programming with FDA approved DNA methylation inhibitors we managed to selectively impact high-heteroplasmy cybrids and reduce heteroplasmy. These findings were validated in both cultured cells and an in vivo xenograft model. Our study reveals a previously unrecognized role for nuclear DNA methylation in regulating cell survival in the context of mitochondrial heteroplasmy. This insight not only advances our understanding of mitochondrial-nuclear interactions but also introduces epigenetic modulation as a possible therapeutic avenue for mitochondrial diseases.

DOI: https://doi.org/10.1101/2024.12.30.630791
Brain Commun. 2025 ;7(1): fcae470

Complex I deficiency remains the most frequent cause of Leigh syndrome spectrum.

Shamima Rahman.

This scientific commentary refers to 'Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment', by Kaiyrzhanov et al. (https://doi.org/10.1093/braincomms/fcae453).

DOI: https://doi.org/10.1093/braincomms/fcae470
iScience. 2025 Jan 17. 28(1): 111496

Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients.

Irena J J Muffels, Richard Rodenburg, Hanneke L D Willemen, Désirée van Haaften-Visser, Hans Waterham, Niels Eijkelkamp, Sabine A Fuchs, Peter M van Hasselt.

  Traditional classification by clinical phenotype or oxidative phosphorylation (OXPHOS) complex deficiencies often fails to clarify complex genotype-phenotype correlations in mitochondrial disease. A multimodal functional assessment may better reveal underlying disease patterns. Using imaging flow cytometry (IFC), we evaluated mitochondrial fragmentation, swelling, membrane potential, reactive oxygen species (ROS) production, and mitochondrial mass in fibroblasts from 31 mitochondrial disease patients. Significant changes were observed in 97% of patients, forming two overarching groups with distinct responses to mitochondrial pathology. One group displayed low-to-normal membrane potential, indicating a hypometabolic state, while the other showed elevated membrane potential and swelling, suggesting a hypermetabolic state. Literature analysis linked these clusters to complex I stability defects (hypometabolic) and proton pumping activity (hypermetabolic). Thus, our IFC-based platform offers a novel approach to identify disease-specific patterns through functional responses, supporting improved diagnostic and therapeutic strategies.

Keywords:  Biological sciences; Genetics; Health sciences; Human genetics; Medicine; Natural sciences

DOI:  https://doi.org/10.1016/j.isci.2024.111496
J Dev Behav Pediatr. 2025 Jan 09.

Parents' Experiences and Views About Use of Wearable Technology for Research and Treatment Monitoring of Children with Neurodevelopmental Disorders.

Rachel Xifaras, David J Amor, Erin Turbitt, Claudine M Kraan.

OBJECTIVE: Wearable technology has potential benefits for clinical measurement with children who have neurodevelopmental disorders (NDDs). However, this cohort may experience sensory processing disorder, behavioral dysregulation, and cognitive challenges. For effective and considerate implementation, the experiences and views of parents of children with NDDs on this topic need in-depth investigation.
METHOD: This qualitative semi-structured interview study used purposeful sampling of families with experience with wearable technology in a research setting. The cohort included 12 parents of 14 children with a diagnosis of Fragile X (n = 6), Prader-Willi (n = 4), or Angelman (n = 4) syndromes. The data were processed using NVivo software (QSR International Ltd. 1999-2013). Data analysis was conducted using reflexive thematic analysis.
RESULTS: Theme 1: Parents are willing to use wearable technology in the home or community if it is feasible. Aspects of feasibility were the ease of embedding technology into existing routines, device robustness, and device invasiveness. Theme 2: Parents are guided by previous healthcare and research experiences. Wearables were considered low burden in the context of everything else their child experiences through health care. Theme 3: Early engagement with families in the design and research process of new technologies is important. Parents had strong views on how to introduce a wearable to their child. In this article, parents stressed that the child's behavioral phenotype needs to be considered early in the design and rollout phases.
CONCLUSION: A shared decision-making approach between researchers and parents will improve the uptake and success of NDD-focused research adopting wearable technology approaches for clinical measurement.

DOI: https://doi.org/10.1097/DBP.0000000000001337
Ther Adv Rare Dis. 2025 Jan-Dec;6:6 26330040241308285

Roadmap to advance therapeutics for SYNGAP1-related disorder: a patient organization perspective from SynGAP Research Fund.

J Michael Graglia, Aaron J Harding, Kathryn A Helde.

  SYNGAP1-related disorder (SRD) is a developmental and epileptic encephalopathy caused by a disruption of the SYNGAP1 gene. At the beginning of 2024, it is one of many rare monogenic brain disorders without disease-modifying treatments, but that is changing. This article chronicles the last 5 years, beginning when treatments for SRD were not publicly in development, to the start of 2024 when many SRD-specific treatments are advancing. We discuss the progress across many realms that have brought SRD to the forefront of drug development and highlight how Patient Advocacy Groups (PAGs) have had direct roles in accelerating the route to meaningful treatments for our children. We start with a summary of why SRD is an attractive pharmaceutical target. Second, we introduce the disease, the clinical features, and the number of patients. Next, we describe our PAG, our international partners and cite examples of the broad range of activities we believe are accelerating our pace toward treatments. We summarize the current SYNGAP1 pipeline and the status of each public project. Finally, we discuss two open questions that urgently need to be addressed in advance of clinical trials for SRD.

Keywords:  MRD5; SYNGAP1; SYNGAP1-epileptic encephalopathy; SYNGAP1-related disorder; SYNGAP1-related intellectual disability; SynGAP research fund; Syngap syndrome; Time is Brain; de novo haploinsufficiency; disease-modifying treatments; monogenic epilepsy; neurodevelopmental disorders; patient advocacy; rare neurodevelopmental disorder

DOI:  https://doi.org/10.1177/26330040241308285
Int J Mol Sci. 2024 Dec 25. pii: 63. [Epub ahead of print]26(1):

Chronic Low-Level IFN-γ Expression Disrupts Mitochondrial Complex I Activity in Renal Macrophages: An Early Mechanistic Driver of Lupus Nephritis Pathogenesis.

Heekyong R Bae, Su-Kyung Shin, Ji-Yoon Lee, Yeo Jin Ko, Suntae Kim, Howard A Young, Eun-Young Kwon.

  Mitochondrial dysfunction and macrophage dysregulation are well recognized as significant contributors to the pathogenesis of autoimmune diseases. However, the detailed mechanisms connecting these two factors remain poorly understood. This study hypothesizes that low but chronic interferon-gamma (IFN-γ) plays a critical role in these processes. To explore this, we utilized ARE-Del mice, a model characterized by sustained low-level IFN-γ expression and lupus nephritis (LN)-like symptoms. Age- and tissue-dependent gene expression analyses in ARE-Del mice revealed significant suppression of mitochondrial complex I components and activities, particularly in the kidneys. The genotype-dependent suppression of mitochondrial complex I indicates early disruption, which leads to macrophage dysfunction. Notably, remission restored gene expression of mitochondrial complex I and macrophage dysfunction in isolated renal macrophages from NZB/W lupus-prone mice. These findings suggest that chronic low-level IFN-γ disrupts mitochondrial complex I activity in macrophages, highlighting its role in the early pathogenesis of autoimmune diseases like lupus nephritis. This provides new insights into the molecular interactions underlying autoimmune pathogenesis and suggests potential targets for therapeutic intervention.

Keywords:  autoimmune diseases; interferon gamma; lupus nephritis; macrophage dysfunction; mitochondrial complex I

DOI:  https://doi.org/10.3390/ijms26010063
Am J Med Genet A. 2025 Jan 16. e63994

Mitochondrial Complex I Deficiency: Unraveling the Relevance of NDUFAF1 in Pediatric Hypertrophic Cardiomyopathy.

Silvia Kalantari, Daniele Veraldi, Davide Politano, Antonia Apicella, Riccardo Castagnoli, Thomas Foiadelli, Fulvio D'Abrusco, Elisa Giorgio, Angela Berardinelli, Alessia Claudia Codazzi, Gianluigi Marseglia, Enza Maria Valente, Fabio Sirchia.

  Hypertrophic cardiomyopathy (HCM) is rare in childhood, but it is associated with significant morbidity and mortality. Genetic causes of HCM are mostly related to sarcomeric genes abnormalities; however, syndromic, metabolic, and mitochondrial disorders play an important role in its etiopathogenesis in pediatric patients. We here describe a new case of apparently isolated HCM due to mitochondrial assembly factor gene NDUFAF1 biallelic variants (c.631C > T and an intragenic deletion encompassing exon 3, NM_016013.4). Alterations of this nuclear gene have been associated to Mitochondrial complex I deficiency, nuclear type 11 (OMIM *618234). We here report the fourth case of a child affected by complex I deficiency due to alterations in NDUFAF1 gene. His clinical features appear simpler when compared to the other cases described in the medical literature, increasing our knowledge regarding the highly heterogeneous clinical presentation associated with this disorder.

Keywords:  NDUFAF1; hypertrophic cardiomiopathy; mitochondrial complex I deficiency

DOI:  https://doi.org/10.1002/ajmg.a.63994
Ageing Res Rev. 2025 Jan 11. pii: S1568-1637(25)00006-6. [Epub ahead of print] 102660

The Emerging Role of Mitochondria Oxygen Redox in Pathological Progression of Neurodegenerative Disorders.

Shuang-Yu Li, Xue-Yan Gong, Ferdinand Ndikuryayo, Wen-Chao Yang.

  Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington disease, pose serious threats to human health, leading to substantial economic burdens on society and families. Despite extensive research, the underlying mechanisms driving these diseases remain incompletely understood, impeding effective diagnosis and treatment. In recent years, growing evidence has highlighted the crucial role of oxidative stress in the pathogenesis of various neurodegenerative diseases. However, there is still a lack of comprehensive reviews that systematically summarize the impact of mitochondrial oxidative stress on neurodegenerative diseases. This review aims to address this gap by summarizing the molecular mechanisms by which mitochondrial oxidative stress promotes the initiation and progression of neurodegenerative disorders. Furthermore, it discusses the potential of antioxidant-based therapeutic strategies for the treatment of these diseases. By shedding light on the role of mitochondrial oxidative stress in neurodegenerative diseases, this review not only serves as a valuable reference for further research on the disease mechanisms, but also offers novel perspectives for the treatment of these disorders.

Keywords:  Alzheimer's disease; Huntington disease; Mitochondria; Molecular mechanism; Oxidative stress; Parkinson's disease

DOI:  https://doi.org/10.1016/j.arr.2025.102660
Eur Heart J Case Rep. 2025 Jan;9(1): ytae690

Incidental finding of MELAS in a young woman with decompensated heart failure and end stage kidney disease: a case report.

Novi Yanti Sari, Ching-Hui Sia, Raymond Ching Chiew Wong, Weiqin Lin, Yoke Ching Lim.

   Background: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare and progressive mitochondrial disorder characterized by multi-systemic involvement. This disease manifests in various clinical manifestations, with heart and kidney disorders being among the most common. Accurate diagnosis of MELAS often necessitates a range of complex investigations. Prompt and comprehensive management can significantly improve the prognosis of the disease.
Case summary: A 40-year-old female presented with elevated blood pressure (BP) associated with shortness of breath prior to dialysis. She was found to be hypertensive with a systolic BP of 190 mmHg with prominent signs of congestion. Laboratory examination showed elevated troponin and NT-proBNP. Arterial blood gas revealed severe lactic acidosis, which prompted urgent dialysis. On the latest admission, an echocardiogram showed a left ventricular ejection fraction of 50% with much thickened myocardium compared with the previous study. Linking the past history of hearing impairment, kidney disease, giddiness, and progression of myocardial thickness warranted a genetic test, which revealed the diagnosis of MELAS.
Discussion: This case involved a patient initially diagnosed with hypertensive heart disease based on asymptomatic left ventricular hypertrophy. Further deterioration led to the identification of MELAS syndrome through extensive diagnostic evaluation. This highlights the importance of considering mitochondrial diseases in unexplained cardiac symptoms, especially in younger patients, for timely and appropriate management.

Keywords:  Case report; Heart failure; Kidney disease; MELAS

DOI:  https://doi.org/10.1093/ehjcr/ytae690
BMJ Open. 2024 Dec 20. 14(12): e078862

Challenges of sharing individual participant data for secondary research on neglected tropical diseases: the experience of Drugs for Neglected Diseases initiative and a call for action.

Justyna Tarwid, Michelle Childs, Dominique Junod-Moser, Anastassia Negrouk, Thaddaeus Egondi, Craig Tipple.

   INTRODUCTION: The Drugs for Neglected Diseases initiative (DNDi) is committed to maximising the scientific value of the individual participant data (IPD) it has collected during its 20 years of activity and the IPD it will collect in the future, while safeguarding research participants' privacy and their right to know how their data will be processed.
OBJECTIVE: The objective of this article is to share what DNDi has learnt while working on its commitment to data sharing. It also aims to advance the debate about best practice in the research community to avoid 'IPD sharing paralysis', with a focus on multistakeholder projects involving patients and researchers based in countries with various levels of data privacy regulations and measures.
RESULTS: The article describes a practical case study outlining the ethical, legal and technical challenges encountered by DNDi in the context of IPD data sharing. The case study demonstrates that each individual research project presents new challenges, which frequently require external support, delaying the process of data sharing and increasing the overall cost.
CONCLUSION: These challenges mean that a case-by-case approach is required for each IPD project to ensure an appropriate balance between the rights of the individual, the integrity of the research and the maximum use of IPD for scientific progress. A collective and inclusive approach is needed to streamline the process of IPD sharing and accelerate research into pressing unmet medical needs.

Keywords:  Clinical Trial; Health Equity; Neglected Diseases

DOI:  https://doi.org/10.1136/bmjopen-2023-078862
Neurochem Int. 2025 Jan 09. pii: S0197-0186(24)00254-7. [Epub ahead of print]183 105927

The role of mitochondrial remodeling in neurodegenerative diseases.

Duanqin Guan, Congmin Liang, Dongyan Zheng, Shizhen Liu, Jiankun Luo, Ziwei Cai, He Zhang, Jialong Chen.

  Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.

Keywords:  Biosynthesis; Mitochondrial quality control; Mitochondrial remodeling; Neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.neuint.2024.105927
BMJ Open. 2024 Dec 20. 14(12): e079712

How patients and informal caregivers can be trained to effectively contribute to improved quality of healthcare services: action research on the development of the Dutch Patient As a Person Academy.

Sjim Romme, Max Hermans, Matthijs Hugo Bosveld, Angela Plak, Carolin Sehlbach, Marloes Amantia van Bokhoven.

   OBJECTIVES: Patient and public involvement is regarded as vital in fostering high-quality care. While involvement has clear societal advantages, it is still widely viewed as tokenistic and surrounded by issues of representation. This study aims to understand how patients and informal caregivers can be trained to effectively contribute to improved quality of healthcare services.
DESIGN: Using an action research approach, a 15-week training programme for patients and informal caregivers called the Patient As a Person Academy was developed, tested and evaluated in three development cycles. Evaluation methods varied per development cycle and included open-ended questionnaires (N=27) and semistructured interviews (N=35) as well as agile evaluation sessions of all 15 training sessions.
SETTING AND PARTICIPANTS: We purposively sampled patients and informal caregivers who had prior experience in patient and public involvement. Patients and informal caregivers who participated as patient and partner educators in health professions education in the Netherlands could participate.
INTERVENTION: Participants followed the Patient As a Person Academy, a 15-week training programme that aims to prepare patients and informal caregivers to become patient partners.
RESULTS: Participants reported that the Patient As a Person Academy's focus on self-management skills, understanding healthcare professionals' perspectives and communication skills helped them to engage in meaningful dialogue with healthcare professionals as patient partners and made them more confident in their roles. However, tailoring towards individual participants' levels of acceptance of illness and reflexivity was needed. Participants reported that, next to the training programme, peer-to-peer coaching and guidance towards roles in quality improvement initiatives would be necessary to optimise their contributions.
CONCLUSIONS: Initiatives like the Patient As a Person Academy may alleviate the problems of tokenism in patient and public involvement. However, extensively preparing patients and informal caregivers raises issues around representation.

Keywords:  Health policy; MEDICAL EDUCATION & TRAINING; Patient Participation; Patient Satisfaction; Patient-Centered Care; Quality in health care

DOI:  https://doi.org/10.1136/bmjopen-2023-079712
Mol Genet Metab. 2025 Jan;pii: S1096-7192(24)00891-6. [Epub ahead of print]144(1): 109007

Mitochondrial HMG-CoA synthase deficiency.

Bram Decru, Marine Lys, Kobe Truijens, Nathalie Mercier, Jean Papadopoulos, Daisy Rymen, Dominique Roland, Joseph P Dewulf, Pieter Vermeersch.

  Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) deficiency is a rare, potentially life-threatening autosomal recessive disorder resulting from mutations in the HMGCS2 gene, leading to impaired ketogenesis. We systematically reviewed the clinical presentations, biochemical and genetic abnormalities in 93 reported cases and 2 new patients diagnosed based on biochemical findings. Reported onset ages ranged from 3 months to 6 years, mostly before the age of 3. Children younger than one year old are more prone to a severe clinical course. In most patients, the initial metabolic decompensation occurs after an episode of gastroenteritis or gastroenteritis-like symptoms. Other commonly observed symptoms during the first clinical episode included poor intake, altered consciousness, dyspnea, seizures and hepatomegaly. Severity was correlated with the number of truncating mutations. Most patients presented with acute metabolic decompensation with hypoglycemia, dicarboxyluria and inadequate ketonuria. Dicarboxylic acid levels were elevated in 54/56 cases. The organic acid 4-hydroxy-6-methyl-2-pyrone (4HMP) was detected in 33/35 urine samples taken during the acute episodes, but typically only retrospectively. The plasma C2/C0 acylcarnitine ratio was abnormal in 16/18 (88.9 %) of acute plasma samples, but only in 2/6 (33 %) of DBS samples. Other metabolites that have been reported are hydroxyhexenoic acid, 3,5-dihydroxyhexanoic (1,5 lactone), glutaric acidand 3-OH-isovaleric acid. Laboratories should look for 4HMP in urinary organic acid analysis and an increased plasma C2/C0 acylcarnitine ratio to facilitate the diagnosis of HMGCS2 deficiency, especially in cases of metabolic decompensation with dicarboxyluria without adequate ketonuria.

Keywords:  4-hydroxy-6-methyl-2-pyrone; HMGCS2; Hypoketotic hypoglycemia; Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase

DOI:  https://doi.org/10.1016/j.ymgme.2024.109007
Nat Metab. 2025 Jan 16.

Recommendations for mitochondria transfer and transplantation nomenclature and characterization.

Jonathan R Brestoff, Keshav K Singh, Katia Aquilano, Lance B Becker, Michael V Berridge, Eric Boilard, Andrés Caicedo, Clair Crewe, José Antonio Enríquez, Jianqing Gao, Åsa B Gustafsson, Kazuhide Hayakawa, Maroun Khoury, Yun-Sil Lee, Daniele Lettieri-Barbato, Patricia Luz-Crawford, Heidi M McBride, James D McCully, Ritsuko Nakai, Jiri Neuzil, Martin Picard, Alexander G Rabchevsky, Anne-Marie Rodriguez, Shiladitya Sengupta, Alexander J Sercel, Toshio Suda, Michael A Teitell, Alain R Thierry, Rong Tian, Melanie Walker, Minghao Zheng.

Intercellular mitochondria transfer is an evolutionarily conserved process in which one cell delivers some of their mitochondria to another cell in the absence of cell division. This process has diverse functions depending on the cell types involved and physiological or disease context. Although mitochondria transfer was first shown to provide metabolic support to acceptor cells, recent studies have revealed diverse functions of mitochondria transfer, including, but not limited to, the maintenance of mitochondria quality of the donor cell and the regulation of tissue homeostasis and remodelling. Many mitochondria-transfer mechanisms have been described using a variety of names, generating confusion about mitochondria transfer biology. Furthermore, several therapeutic approaches involving mitochondria-transfer biology have emerged, including mitochondria transplantation and cellular engineering using isolated mitochondria. In this Consensus Statement, we define relevant terminology and propose a nomenclature framework to describe mitochondria transfer and transplantation as a foundation for further development by the community as this dynamic field of research continues to evolve.

DOI: https://doi.org/10.1038/s42255-024-01200-x