bims-mitmed 2025-03-09 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–03–09
forty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.
PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.
Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.
Dodging mitochondrial mislocalization.
Mitochondrial proteostasis and cellular health: insights from chaperones and autophagy.
Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.
Connecting the dots: Mitochondrial transfer in immunity, inflammation, and cancer.
Mitochondria in aging and age-associated diseases.
A global perspective on research advances and future challenges in Friedreich ataxia.
Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
Disruption of mitochondrial DNA integrity in cardiomyocyte injury upon ischemia/reperfusion.
Improving acute care for Primary Mitochondrial Disease: Development of a publicly available clinical care pathway.
Research progress on paternal mitochondrial inheritance: An overview.
Engineered mitochondria in diseases: mechanisms, strategies, and applications.
Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts.
NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish.
Urolithin A provides cardioprotection and mitochondrial quality enhancement preclinically and improves human cardiovascular health biomarkers.
Impact of SDHA Mutations on Yeast Growth and Mitochondrial Function. Case Study Linking Genetic Findings to Clinical Phenotypes.
Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.
Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.
Sengers syndrome caused by biallelic TIMM29 variants and RNAi silencing in Drosophila orthologue recapitulates the human phenotype.
Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.
Decreased Complex I Activity in Blood lymphocytes Correlates with Idiopathic Pulmonary Fibrosis Severity.
Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.
A long-lived pool of PINK1 imparts a molecular memory of depolarization-induced activity.
Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects.
Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.
EPAS1 induction drives myocardial degeneration in desmoplakin-cardiomyopathy.
Elesclomol rescues mitochondrial copper deficiency in disease models without triggering cuproptosis.
The multifaceted challenges faced by women in the field of inherited metabolic disorders.
Distinct gene regulatory dynamics drive skeletogenic cell fate convergence during vertebrate embryogenesis.
Microplastics/nanoplastics contribute to aging and age-related diseases: Mitochondrial dysfunction as a crucial role.
The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer's disease.
Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures.
Trophoblast-specific Deptor knockdown enhances trophoblast nutrient transport and fetal growth in mice.
Fetal malformations of cortical development: review and clinical guidance.
Spinocerebellar Ataxia Progression Measured with the Patient-Reported Outcome Measure of Ataxia.
Circulating mitochondrial DNA signature in cardiometabolic patients.
A novel, rapidly progressive ataxia due to a spontaneous Myo5a mutation in mice impairs transport proteins and alters mitochondria.
Altered Mitochondrial Morphology and Reduced Cardiolipin Levels in Oocytes of Endometriosis Model Mice: Implications for Mitochondrial Dysfunction in Infertility.

Sci Adv. 2025 Mar 07. 11(10): eadr0690

Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.

Yu Nie, Kornélia Szebényi, Lea M D Wenger, András Lakatos, Patrick F Chinnery.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.

DOI: https://doi.org/10.1126/sciadv.adr0690
Cell Death Dis. 2025 Mar 01. 16(1): 145

PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.

Xiayun Xu, Yingji Chen, Siqi Fei, Xinyue Jiang, Xiaoting Zhou, Yimeng Xue, Yao Li, Shi-Min Zhao, Yan Huang, Chenji Wang.

Mitophagy is a selective process that targets the damaged, dysfunctional, or superfluous mitochondria for degradation through autophagy. The SCFFBXL4 E3 ubiquitin ligase complex suppresses basal mitophagy by targeting BNIP3 and BNIP3L, two key mitophagy cargo receptors, for ubiquitin-proteasomal degradation. FBXL4 loss-of-function mutations lead to excessive BNIP3/3L-dependent mitophagy, thereby causing a devastating multi-system disorder called mitochondrial DNA depletion syndrome, type 13 (MTDPS13). PPTC7, a mitochondrial matrix phosphatase, is essential for proper mitochondrial function and biogenesis. Here, we show that a proportion of PPTC7 is located on the outer mitochondrial membrane, where it interacts with FBXL4 and BNIP3/3L. PPTC7 decreases BNIP3/3L protein stability in a protein phosphatase activity-independent manner. Using in vitro cell culture and Pptc7 knockout mouse model, we demonstrate that PPTC7 deficiency activates high levels of basal mitophagy in a BNIP3/3L-dependent manner. Mechanistically, PPTC7 facilitates SCFFBXL4-mediated ubiquitin-proteasomal degradation of BNIP3/3L. Overall, these findings establish PPTC7 as an essential co-factor of the SCFFBXL4 complex and a suppressor of BNIP3/3L-dependent mitophagy.

DOI: https://doi.org/10.1038/s41419-025-07463-w
EMBO J. 2025 Feb 28.

Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.

Scott A Jones, Alice P Sowton, Denis Lacabanne, Martin S King, Shane M Palmer, Thomas Zögg, Els Pardon, Jan Steyaert, Jonathan J Ruprecht, Edmund R S Kunji.

  Uncoupling protein 1 (UCP1, SLC25A7) is responsible for the thermogenic properties of brown adipose tissue. Upon fatty acid activation, UCP1 facilitates proton leakage, dissipating the mitochondrial proton motive force to release energy as heat. Purine nucleotides are considered to be the only inhibitors of UCP1 activity, binding to its central cavity to lock UCP1 in a proton-impermeable conformation. Here we show that pyrimidine nucleotides can also bind and inhibit its proton-conducting activity. All nucleotides bound in a pH-dependent manner, with the highest binding affinity observed for ATP, followed by dTTP, UTP, GTP and CTP. We also determined the structural basis of UTP binding to UCP1, showing that binding of purine and pyrimidine nucleotides follows the same molecular principles. We find that the closely related mitochondrial dicarboxylate carrier (SLC25A10) and oxoglutarate carrier (SLC25A11) have many cavity residues in common, but do not bind nucleotides. Thus, while UCP1 has evolved from dicarboxylate carriers, no selection for nucleobase specificity has occurred, highlighting the importance of the pH-dependent nucleotide binding mechanism mediated via the phosphate moieties.

Keywords:  Bioenergetics; Pyrimidine Nucleotides; SLC25; Thermogenesis; Uncoupling Protein

DOI:  https://doi.org/10.1038/s44318-025-00395-3
Nat Rev Mol Cell Biol. 2025 Mar 06.

Dodging mitochondrial mislocalization.

Lisa Heinke.

DOI: https://doi.org/10.1038/s41580-025-00840-5
J Physiol. 2025 Mar 06.

Mitochondrial proteostasis and cellular health: insights from chaperones and autophagy.

Yuvraj Anandrao Jagtap, Akash Choudhary, Sumit Kinger, Prashant Kumar, Sudipta Bhattacharyya, Hem Chandra Jha, Rohan Dhiman, Vivek Sharma, Anil K Suresh, Krishna Mohan Poluri, Amit Mishra.

  Mitochondria are a cell's powerhouse and also have a vital part in cellular processes. The emerging role of mitochondria in several crucial processes highlights their cellular and physiological importance. Mitochondrial homeostasis mechanisms, including proteostasis pathways, are vital for mitochondrial health. Failure of these processes has an important role in establishment of numerous complex disease conditions, such as neurodegeneration and imperfect ageing. However, details of mitochondrial impairments and their contribution to the pathology of neurodegeneration are poorly understood. This review systematically discusses the involvement of mitochondrial homeostasis mechanisms and their role in rejuvenating cellular health and fitness. We also focus on various cellular protein quality control mechanisms essential for mitochondrial proteostasis and how their failure leads to mitochondrial functional disturbances observed in disease conditions. We discuss recent findings based on mitostasis-associated chaperones, mitoproteases, and autophagy responses, which can lead to emergence of new possible therapeutic interventions against complex diseases.

Keywords:  chaperones; mitochondrial dynamics; mitochondrial homeostasis; mitophagy; mitoproteases; neurodegeneration; proteostasis

DOI:  https://doi.org/10.1113/JP287635
Mech Ageing Dev. 2025 Feb 27. pii: S0047-6374(25)00020-X. [Epub ahead of print] 112044

Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.

Claudie Gabillard-Lefort, Théophile Thibault, Guy Lenaers, Rudolf J Wiesner, Jeanne Mialet-Perez, Olivier R Baris.

  Cardiac pathological aging is a serious health issue, with cardiovascular diseases still being a leading cause of deaths worldwide. Therefore, there is an urgent need to identify culprit factors involved in this process. In the last decades, mitochondria, which are crucial for cardiac function, have emerged as major contributors. Mitochondria are organelles involved in a plethora of metabolic pathways and cell processes ranging from ATP production to calcium homeostasis or regulation of apoptotic pathways. This review provides a general overview of the pathomechanisms involving mitochondria during cardiac aging, with a focus on the role of mitochondrial dynamics and mitochondrial DNA (mtDNA). These mechanisms involve imbalanced mitochondrial fusion and fission, loss of mtDNA integrity leading to tissue mosaic of mitochondrial deficiency, as well as mtDNA release in the cytoplasm, promoting inflammation via the NLRP3, cGAS/STING and TLR9 pathways. Potential links between mtDNA, mitochondrial damage and the accumulation of senescent cells in the heart are also discussed. A better understanding of how these factors impact on heart function and accelerate its pathological aging should lead to the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.

Keywords:  Aging; Cardiovascular diseases; Inflammation; Mitochondria; Mitochondrial dynamics; Senescence; mtDNA

DOI:  https://doi.org/10.1016/j.mad.2025.112044
Immunol Lett. 2025 Mar 06. pii: S0165-2478(25)00024-0. [Epub ahead of print]274 106992

Connecting the dots: Mitochondrial transfer in immunity, inflammation, and cancer.

Valentina Artusa, Lara De Luca, Mario Clerici, Daria Trabattoni.

  Mitochondria are more than mere energy generators; they are multifaceted organelles that integrate metabolic, signalling, and immune functions, making them indispensable players in maintaining cellular and systemic health. Mitochondrial transfer has recently garnered attention due to its potential role in several physiological and pathological processes. This process involves multiple mechanisms by which mitochondria, along with mitochondrial DNA and other components, are exchanged between cells. In this review, we examine the critical roles of mitochondrial transfer in health and disease, focusing on its impact on immune cell function, the resolution of inflammation, tissue repair, and regeneration. Additionally, we explore its implications in viral infections and cancer progression. We also provide insights into emerging therapeutic applications, emphasizing its potential to address unmet clinical needs.

Keywords:  Cancer; Immunity; Inflammation; Mitochondrial transfer; Mitotherapy

DOI:  https://doi.org/10.1016/j.imlet.2025.106992
Mitochondrion. 2025 Feb 27. pii: S1567-7249(25)00019-4. [Epub ahead of print]82 102022

Mitochondria in aging and age-associated diseases.

Sonu Pahal, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Robert J Shmookler Reis, Srinivas Ayyadevara.

Mitochondria, essential for cellular energy, are crucial in neurodegenerative disorders (NDDs) and their age-related progression. This review highlights mitochondrial dynamics, mitovesicles, homeostasis, and organelle communication. We examine mitochondrial impacts from aging and NDDs, focusing on protein aggregation and dysfunction. Prospective therapeutic approaches include enhancing mitophagy, improving respiratory chain function, maintaining calcium and lipid balance, using microRNAs, and mitochondrial transfer to protect function. These strategies underscore the crucial role of mitochondrial health in neuronal survival and cognitive functions, offering new therapeutic opportunities.

DOI: https://doi.org/10.1016/j.mito.2025.102022
Nat Rev Neurol. 2025 Mar 03.

A global perspective on research advances and future challenges in Friedreich ataxia.

Elisabetta Indelicato, Martin B Delatycki, Jennifer Farmer, Marcondes C França, Susan Perlman, Myriam Rai, Sylvia Boesch.

Friedreich ataxia (FRDA) is a rare multisystem, life-limiting disease and is the most common early-onset inherited ataxia in populations of European, Arab and Indian descent. In recent years, substantial progress has been made in dissecting the pathogenesis and natural history of FRDA, and several clinical trials have been initiated. A particularly notable recent achievement was the approval of the nuclear factor erythroid 2-related factor 2 activator omaveloxolone as the first disease-specific therapy for FRDA. In light of these developments, we review milestones in FRDA translational and clinical research over the past 10 years, as well as the various therapeutic strategies currently in the pipeline. We also consider the lessons that have been learned from failed trials and other setbacks. We conclude by presenting a global roadmap for future research, as outlined by the recently established Friedreich's Ataxia Global Clinical Consortium, which covers North and South America, Europe, India, Australia and New Zealand.

DOI: https://doi.org/10.1038/s41582-025-01065-y
Nat Commun. 2025 Mar 06. 16(1): 2250

Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.

Alistair P Green, Florian Klimm, Aidan S Marshall, Rein Leetmaa, Juvid Aryaman, Aurora Gómez-Durán, Patrick F Chinnery, Nick S Jones.

Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mitochondrial DNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mitochondrial DNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mitochondrial DNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory we develop, hitting high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and endoplasmic reticulum stress. We identify mechanistic links to endoplasmic reticulum stress experimentally and further give an indication that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.

DOI: https://doi.org/10.1038/s41467-025-57286-8
Genes Dis. 2025 May;12(3): 101282

Disruption of mitochondrial DNA integrity in cardiomyocyte injury upon ischemia/reperfusion.

Shengnan Hu, Xueying Tang, Fangrui Zhu, Chen Liang, Sa Wang, Hongjie Wang, Peifeng Li, Yuzhen Li.

  Mitochondria serve as the energy provider and enable life activities, and they are the only organelles containing extra-chromosomal DNA. Each mitochondrion contains multiple copies of its genome, which is usually referred to as mitochondrial DNA (mtDNA). mtDNA encodes necessary electron transport chain complex subunits, as well as the essential RNAs for their translation within the organelle. Therefore, the precondition for intact mitochondrial function and cardiomyocyte survival is the integrity of mtDNA. Accumulating evidence suggests that the disruption of mtDNA integrity is involved in ischemia/reperfusion-induced mitochondrial dysfunction and cardiomyocyte injury. Here, we review the current opinions about the pathways of mtDNA integrity maintenance and discuss the role of mtDNA integrity in cardiomyocyte injury reacting to ischemia/reperfusion. We also discuss the mechanisms by which mtDNA mediates ischemia/reperfusion-induced cardiomyocyte injury, together with therapeutic strategies by targeting mtDNA.

Keywords:  Cardiomyocyte; Ischemia/reperfusion; Package; Repair; Replication; Transcription; mtDNA

DOI:  https://doi.org/10.1016/j.gendis.2024.101282
Mol Genet Metab. 2025 Feb 21. pii: S1096-7192(25)00049-6. [Epub ahead of print]144(4): 109058

Improving acute care for Primary Mitochondrial Disease: Development of a publicly available clinical care pathway.

Matthew M Demczko, Rebecca D Ganetzky, Cassandra Tormey, Brandon C Ku, Bridget Blowey, Jane Lavelle, Amy Goldstein.

  Primary mitochondrial diseases (PMD) are an increasingly recognized cause of multi-system organ dysfunction. Children frequently require acute care in an inpatient setting, though many hospitals do not have access to metabolic specialists. We developed a publicly available, evidenced-based clinical pathway utilizing expert consensus guidelines to guide the care of PMD patients during an emergency department visit and/or hospitalization. Utilization of the pathway may help improve triage time, clarify therapeutic options, and help initiate disease-specific screening.

Keywords:  Acute care; Care pathways; Mitochondrial disease; Rare disease

DOI:  https://doi.org/10.1016/j.ymgme.2025.109058
Mitochondrion. 2025 Feb 28. pii: S1567-7249(25)00016-9. [Epub ahead of print]82 102019

Research progress on paternal mitochondrial inheritance: An overview.

Wen Hu, Jiting Zhang, Zhaoqi Wu, Yi Wu, Yuhui Hu, Xiaohui Hu, Jinguo Cao.

  Mitochondria are self-replicating organelles with their own DNA. They play a crucial role in biological, cellular and functional processes, such as energy production, metabolism, and signal transduction. Abnormal mitochondrial function can cause various diseases such as diabetes, tumour, Parkinson's disease, hereditary optic neuropathy, and others. Although mitochondrial functions have been extensively and widely explored, studies on mitochondrial inheritance have been limited. Mitochondrial inheritance is traditionally thought to be maternal although small amounts of paternally transmitted mitochondria have been discovered on rare occasions, and the role of paternal mitochondria transmission to offspring has been largely ignored. This review highlights the present knowledge on mitochondrial inheritance, especially the controversy and the difficulties in investigating paternal mitochondrial inheritance. More significantly, we present a comprehensive description of the physiological functions of paternal mitochondria in children and discuss the animal model to explore the mechanism of paternal mitochondrial inheritance. This review may provide a theoretical and experimental basis for improving our understanding of paternal mitochondrial inheritance, and also provide new ideas for treating mitochondrial diseases.

Keywords:  Drosophila; Mitochondria; Mitochondrial inheritance; Paternal mitochondrial inheritance

DOI:  https://doi.org/10.1016/j.mito.2025.102019
Signal Transduct Target Ther. 2025 Mar 03. 10(1): 71

Engineered mitochondria in diseases: mechanisms, strategies, and applications.

Mingyang Li, Limin Wu, Haibo Si, Yuangang Wu, Yuan Liu, Yi Zeng, Bin Shen.

Mitochondrial diseases represent one of the most prevalent and debilitating categories of hereditary disorders, characterized by significant genetic, biological, and clinical heterogeneity, which has driven the development of the field of engineered mitochondria. With the growing recognition of the pathogenic role of damaged mitochondria in aging, oxidative disorders, inflammatory diseases, and cancer, the application of engineered mitochondria has expanded to those non-hereditary contexts (sometimes referred to as mitochondria-related diseases). Due to their unique non-eukaryotic origins and endosymbiotic relationship, mitochondria are considered highly suitable for gene editing and intercellular transplantation, and remarkable progress has been achieved in two promising therapeutic strategies-mitochondrial gene editing and artificial mitochondrial transfer (collectively referred to as engineered mitochondria in this review) over the past two decades. Here, we provide a comprehensive review of the mechanisms and recent advancements in the development of engineered mitochondria for therapeutic applications, alongside a concise summary of potential clinical implications and supporting evidence from preclinical and clinical studies. Additionally, an emerging and potentially feasible approach involves ex vivo mitochondrial editing, followed by selection and transplantation, which holds the potential to overcome limitations such as reduced in vivo operability and the introduction of allogeneic mitochondrial heterogeneity, thereby broadening the applicability of engineered mitochondria.

DOI: https://doi.org/10.1038/s41392-024-02081-y
Cell Rep. 2025 Mar 05. pii: S2211-1247(25)00148-2. [Epub ahead of print]44(3): 115377

Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts.

Brian M Spurlock, Yifang Xie, Yiran Song, Shea N Ricketts, James Rock Hua, Haley R Chi, Meenakshi Nishtala, Rustem Salmenov, Jiandong Liu, Li Qian.

  Cardiomyocytes (CMs) rely on mitochondrial energy produced in highly interconnected mitochondrial networks. Direct reprogramming of cardiac fibroblasts (CFs) into induced CMs (iCMs) shows promise for treating cardiac injury, but little work has investigated mitochondrial energetics and morphology during the conversion of CFs to iCMs. We characterized mitochondria during direct cardiac reprogramming of murine neonatal CFs (mnCFs). Reprogramming increased mitochondrial respiration and interconnectivity but not to the levels of native CMs. We therefore investigated whether perturbations to mitochondrial dynamics impacted reprogramming. Mitochondrial fusion (joining) was essential for iCM generation, while various fission (dividing) genes were reprogramming barriers. In particular, the loss of mitochondrial fission regulator 1 like (Mtfr1l) significantly increased the yield of functionally mature iCMs and induced mitochondrial fusion and respiration. These changes were countered by the concomitant loss of fusion effector optical atrophy protein 1 (Opa1). The present study advances our understanding of mitochondrial barriers to and mechanisms of direct cardiac reprogramming.

Keywords:  CP: Metabolism; CP: Stem cell research; Mtfr1l; cell fate conversion; direct cardiac reprogramming; machine learning; mitochondria; mitochondrial dynamics; mitochondrial energetics; mitochondrial fission; mitochondrial fusion; regenerative medicine

DOI:  https://doi.org/10.1016/j.celrep.2025.115377
Cell Death Discov. 2025 Mar 01. 11(1): 82

NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish.

Yen-Lin Chen, Brian Hon-Yin Chung, Masakazu Mimaki, Shumpei Uchino, Yin-Hsiu Chien, Christopher Chun-Yun Mak, Steven Shinn-Forng Peng, Wei-Chen Wang, Yu-Li Lin, Wuh-Liang Hwu, Shyh-Jye Lee, Ni-Chung Lee.

Complex I of the mitochondrial electron transfer chain is one of the largest membrane protein assemblies ever discovered. A patient carrying a homozygous NDUFB7 intronic mutation died within two months after birth due to cardiorespiratory defects, preventing further study. Here, we report another patient with compound heterozygous mutations in NDUFB7 who suffers from pons abnormality, lactic acidosis, prematurity, prenatal and postnatal growth deficiency, incomplete closure of the abdominal wall (ventral hernia), and a poorly functioning gastrointestinal tract (pseudo-obstruction). We demonstrated that the patient's skin fibroblasts are deficient in Complex I assembly and reduced supercomplex formation. This report further broadens the spectrum of mitochondrial disorders. The patient has had several surgeries. After receiving treatment with Coenzyme Q10 and vitamin B complex, she has remained stable up to this point. To further explore the functionality of NDUFB7 in vivo, we knocked down Ndufb7 in zebrafish embryos. This resulted in brain ventricle and neuronal defects, elevated lactic acid levels, and reduced oxygen consumption, indicating defective mitochondrial respiration. These phenotypes can be specifically rescued by ectopic expression of ndufb7. More importantly, Mitoquinone mesylate (MitoQ), a common remedy for mitochondrial disorders, can ameliorate these conditions. These results suggest a role for NDUFB7 in mitochondrial activity and the suitability of the zebrafish model for further drug screening and the development of therapeutic strategies for this rare disease.

DOI: https://doi.org/10.1038/s41420-025-02369-0
iScience. 2025 Feb 21. 28(2): 111814

Urolithin A provides cardioprotection and mitochondrial quality enhancement preclinically and improves human cardiovascular health biomarkers.

Sophia Liu, Julie Faitg, Charlotte Tissot, Dimitris Konstantopoulos, Ross Laws, Guillaume Bourdier, Pénélope A Andreux, Tracey Davey, Hector Gallart-Ayala, Julijana Ivanisevic, Anurag Singh, Chris Rinsch, David J Marcinek, Davide D'Amico.

  Cardiovascular diseases (CVDs) remain the primary cause of global mortality. Nutritional interventions hold promise to reduce CVD risks in an increasingly aging population. However, few nutritional interventions are proven to support heart health and act mostly on blood lipid homeostasis rather than at cardiac cell level. Here, we show that mitochondrial quality dysfunctions are common hallmarks in human cardiomyocytes upon heart aging and in chronic conditions. Preclinically, the post-biotic and mitophagy activator, urolithin A (UA), reduced both systolic and diastolic cardiac dysfunction in models of natural aging and heart failure. At a cellular level, this was associated with a recovery of mitochondrial ultrastructural defects and mitophagy. In humans, UA supplementation for 4 months in healthy older adults significantly reduced plasma ceramides clinically validated to predict CVD risks. These findings extend and translate UA's benefits to heart health, making UA a promising nutritional intervention to support cardiovascular function as we age.

Keywords:  Biological sciences; Cardiovascular medicine; Health sciences; Internal medicine; Medical specialty; Medicine; Natural sciences; Physiology

DOI:  https://doi.org/10.1016/j.isci.2025.111814
Clin Genet. 2025 Mar 06.

Impact of SDHA Mutations on Yeast Growth and Mitochondrial Function. Case Study Linking Genetic Findings to Clinical Phenotypes.

Camilla Meossi, Alessandro De Falco, Marco Marchi, Anna Rubegni, Stefano Pagano, Rosanna Trovato, Claudia Nesti, Flavio Dal Canto, Emanuele Bartolini, Leonardo Salviati, Filippo Maria Santorelli.

  We present the case of a child who developed focal seizures, emotional and behavioral dysregulation, and sleep abnormalities at age 5. Trio whole genome sequencing identified biallelic mutations in the SDHA gene, which encodes a key component of mitochondrial complex II. Mitochondrial respiratory chain activities and muscle biopsy confirmed impaired oxidative metabolism. Yeast Saccharomyces cerevisiae complementation assays showed that all the mutations were presumably disease related. Mutations in SDHA are associated with developmental delay, hypotonia, ataxia, together with bilateral hyperintensities in the basal ganglia at brain MRI. This case corroborates the phenotypic variability of SDHA variants and highlights the relevance of functional assays in validating genetic findings.

Keywords:  chromatinopathies; functional tests; mitochondrial respiratory chain; neurodegenerative disorders; yeast complementation

DOI:  https://doi.org/10.1111/cge.14738
Nat Commun. 2025 Feb 28. 16(1): 2053

Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.

Dylan C Souder, Eric R McGregor, Josef P Clark, Timothy W Rhoads, Tiaira J Porter, Kevin W Eliceiri, Darcie L Moore, Luigi Puglielli, Rozalyn M Anderson.

The brain is a high-energy tissue, and although aging is associated with dysfunctional inflammatory and neuron-specific functional pathways, a direct connection to metabolism is not established. Here, we show that isoforms of mitochondrial regulator PGC-1α are driven from distinct brain cell-type specific promotors, repressed with aging, and integral in coordinating metabolism and growth signaling. Transcriptional and proteomic profiles of cortex from male adult, middle age, and advanced age mice reveal an aging metabolic signature linked to PGC-1α. In primary culture, a neuron-exclusive promoter produces the functionally dominant isoform of PGC-1α. Using growth repression as a challenge, we find that PGC-1α is regulated downstream of GSK3β independently across promoters. Broad cellular metabolic consequences of growth inhibition observed in vitro are mirrored in vivo, including activation of PGC-1α directed programs and suppression of aging pathways. These data place PGC-1α centrally in a growth and metabolism network directly relevant to brain aging.

DOI: https://doi.org/10.1038/s41467-025-57363-y
Front Mol Neurosci. 2025 ;18 1548255

Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.

Menekse Oeztuerk, Diran Herebian, Kale Dipali, Andreas Hentschel, Nina Rademacher, Florian Kraft, Rita Horvath, Felix Distelmaier, Sven G Meuth, Tobias Ruck, Ulrike Schara-Schmidt, Andreas Roos.

  Mitochondrial integrity is fundamental to cellular function, upheld by a network of proteases that regulate proteostasis and mitochondrial dynamics. Among these proteases, AFG3L2 is critical due to its roles in maintaining mitochondrial homeostasis, regulating mitochondrial protein quality, and facilitating mitochondrial biogenesis. Mutations in AFG3L2 are implicated in a spectrum of diseases, including spinocerebellar ataxia type 28 (SCA28) and spastic ataxia 5 (SPAX5), as well as other systemic conditions. This study employs a multi-omics approach to investigate the biochemical impact of AFG3L2 mutations in immortalized lymphoblastoid cell lines derived from a patient with biallelic variants leading to spastic ataxia (SPAX5). Our proteomic analysis revealed AFG3L2 impairment, with significant dysregulation of proteins critical for mitochondrial function, cytoskeletal integrity, and cellular metabolism. Specifically, disruptions were observed in mitochondrial dynamics and calcium homeostasis, alongside downregulation of key proteins like COX11, a copper chaperone for complex IV assembly, and NFU1, an iron-sulfur cluster protein linked to spastic paraparesis and infection-related worsening. Lipidomic analysis highlighted substantial alterations in lipid composition, with significant decreases in sphingomyelins, phosphatidylethanolamine, and phosphatidylcholine, reflecting disruptions in lipid metabolism and membrane integrity. Metabolomic profiling did not reveal any significant findings. Our comprehensive investigation into loss of functional AFG3L2 elucidates a pathophysiology extending beyond mitochondrial proteostasis, implicating a wide array of cellular processes. The findings reveal substantial cellular disturbances at multiple levels, contributing to neurodegeneration through disrupted mitochondrial respiratory chain, calcium homeostasis, cytoskeletal integrity, and altered lipid homeostasis. This study underscores the complexity of SPAX5 pathophysiology and the importance of multi-omics approaches in developing effective strategies to address the impact of loss of functional AFG3L2. Our data also highlight the value of immortalized lymphoblastoid cells as a tool for pre-clinical testing and research, offering a detailed biochemical fingerprint that enhances our understanding of SPAX5 and identifies potential areas for further investigation.

Keywords:  AFG3 like matrix AAA peptidase subunit 2; MCU; SPAX5; liquid biopsy; multi-omics lymphoblasts

DOI:  https://doi.org/10.3389/fnmol.2025.1548255
Hum Genomics. 2025 Feb 28. 19(1): 21

Sengers syndrome caused by biallelic TIMM29 variants and RNAi silencing in Drosophila orthologue recapitulates the human phenotype.

Adel Shalata, Ann Saada, Mohammed Mahroum, Yarin Hadid, Chaya Furman, Zaher Eldin Shalata, Robert J Desnick, Avraham Lorber, Asaad Khoury, Adnan Higazi, Avraham Shaag, Varda Barash, Ronen Spiegel, Euvgeni Vlodavsky, Pierre Rustin, Shmuel Pietrokovski, Irena Manov, Dan Gieger, Galit Tal, Adi Salzberg, Hanna Mandel.

   PURPOSE: Sengers-syndrome (S.S) is a genetic disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. All reported cases were genetically caused by biallelic mutations in the AGK gene. We herein report a pathogenic variant in TIMM29 gene, encoding Tim29 protein, as a novel cause of S.S. Notably, AGK and Tim29 proteins are components of the TIM22 complex, which is responsible for importing carrier proteins into the inner mitochondrial membrane.
METHOD: Clinical data of 17 consanguineous patients featuring S.S was obtained. Linkage analysis, and sequencing were used to map and identify the disease-causing gene. Tissues derived from the study participants and a Drosophila melanogaster model were used to evaluate the effects of TIMM29 variant on S.S.
RESULTS: The patients presented with a severe phenotype of S.S, markedly elevated serum creatine-phosphokinase, combined mitochondrial-respiratory-chain-complexes deficiency, reduced pyruvate-dehydrogenase complex activity, and reduced adenine nucleotide translocator 1 protein. Histopathological studies showed accumulation of abnormal mitochondria. Homozygosity mapping and gene sequencing revealed a biallelic variant in TIMM29 NM_138358.4:c.514T > C NP_612367.1:p.(Trp172Arg). The knockdown of the Drosophila TIMM29 orthologous gene (CG14270) recapitulated the phenotype and pathology observed in the studied cohort. We expand the clinical phenotype of S.S and provide substantial evidence supporting TIMM29 as the second causal gene of a severe type of S.S, designated as S.S- TIMM29.
CONCLUSION: The present study uncovers several biochemical differences between the two S.S types, including the hyperCPKemia being almost unique for S.S-TIMM29 cohort, the different frequency of MMRCC and PDHc deficiencies among the two S.S types. We propose to designate the S.S associated with TIMM29 homozygous variant as S.S-TIMM29.

Keywords:   TIMM29 ; AGK; CK; RCC; Sengers syndrome

DOI:  https://doi.org/10.1186/s40246-025-00723-y
Neurobiol Dis. 2025 Mar 04. pii: S0969-9961(25)00078-6. [Epub ahead of print] 106862

Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.

Yifei Zheng, Jiahui Yang, Xuanyao Li, Linjie Qi, Zhuo Zheng, Jiming Kong, Guohui Zhang, Ying Guo.

  Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.

Keywords:  Mitochondrial quality control; Neurodegenerative diseases; Neuron; Senescence; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.nbd.2025.106862
Biochem Genet. 2025 Mar 04.

Decreased Complex I Activity in Blood lymphocytes Correlates with Idiopathic Pulmonary Fibrosis Severity.

Emily Zifa, Sotirios Sinis, Anna-Maria Psarra, Andreas Mouikis, Aglaia Pozantzi, Konstantina Rossi, Foteini Malli, Ilias Dimeas, Paraskevi Kirgou, Konstantinos Gourgoulianis, Ourania S Kotsiou, Zoe Daniil.

  Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease linked to aging. Mitochondrial dysfunction in circulating T cells, often caused by disruption of mitochondrial DNA (mtDNA), may play a role in age-related conditions like IPF. In our previous study, we found high mtDNA mutational loads in blood lymphocytes from IPF patients, especially in regions critical for mtDNA expression. Since Complex I of the electron transport chain, partly encoded by mtDNA, is essential for energy production, we conducted a preliminary study on its activity. We found significantly reduced Complex I activity (p < 0.001) in lymphocytes from 40 IPF patients compared to 40 controls, which was positively correlated with lung function decline, specifically in functional vital capacity and diffusing capacity for carbon monoxide. These findings indicate that T cell mitochondrial dysfunction is associated with disease progression in IPF. Future work will explore the mechanisms linking T cell mitochondrial disruption with fibrosis, potentially uncovering new therapeutic targets.

Keywords:  Complex I Activity; Fibrosis; Idiopathic Pulmonary Fibrosis (IPF); Mitochondrial Dysfunction; T Cell Immunometabolism

DOI:  https://doi.org/10.1007/s10528-025-11071-w
Nat Metab. 2025 Mar 06.

Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.

Trine S Nicolaisen, Aslak E Lyster, Kim A Sjøberg, Daniel T Haas, Christian T Voldstedlund, Anne-Marie Lundsgaard, Jakob K Jensen, Ea M Madsen, Casper K Nielsen, Mads Bloch-Ibenfeldt, Nicolai J Wewer Albrechtsen, Adam J Rose, Natalie Krahmer, Christoffer Clemmensen, Erik A Richter, Andreas M Fritzen, Bente Kiens.

Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue.

DOI: https://doi.org/10.1038/s42255-025-01236-7
Sci Adv. 2025 Feb 28. 11(9): eadr1938

A long-lived pool of PINK1 imparts a molecular memory of depolarization-induced activity.

Liam Pollock, Ioanna Ch Georgiou, Emma V Rusilowicz-Jones, Michael J Clague, Sylvie Urbé.

The Parkinson's disease-linked kinase, PINK1, is a short-lived protein that undergoes cleavage upon mitochondrial import leading to its proteasomal degradation. Under depolarizing conditions, it accumulates on mitochondria where it becomes activated, phosphorylating both ubiquitin and the ubiquitin E3 ligase Parkin, at Ser65. Our experiments reveal that in retinal pigment epithelial cells, only a fraction of PINK1 becomes stabilized after depolarization by electron transport chain inhibitors. Furthermore, the observed accrual of PINK1 cannot be completely accounted for without an accompanying increase in biosynthesis. We have used a ubiquitylation inhibitor TAK-243 to accumulate cleaved PINK1. Under these conditions, generation of unconjugated "free" phospho-ubiquitin serves as a proxy readout for PINK1 activity. This has enabled us to find a preconditioning phenomenon, whereby an initial depolarizing treatment leaves a residual pool of active PINK1 that remains competent to seed the activation of nascent cleaved PINK1 following a 16-hour recovery period.

DOI: https://doi.org/10.1126/sciadv.adr1938
Elife. 2025 Mar 06. pii: RP97649. [Epub ahead of print]13

Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects.

Kayleigh Bozon, Hartmut Cuny, Delicia Z Sheng, Ella M M A Martin, Alena Sipka, Paul Young, David T Humphreys, Sally L Dunwoodie.

  Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis causes multiple malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD), highlighting the necessity of this pathway during embryogenesis. Previous work in mice shows that NAD deficiency perturbs embryonic development specifically when organs are forming. While the pathway is predominantly active in the liver postnatally, the site of activity prior to and during organogenesis is unknown. Here, we used a mouse model of human CNDD and assessed pathway functionality in embryonic livers and extraembryonic tissues via gene expression, enzyme activity and metabolic analyses. We found that the extra-embryonic visceral yolk sac endoderm exclusively synthesises NAD de novo during early organogenesis before the embryonic liver takes over this function. Under CNDD-inducing conditions, visceral yolk sacs had reduced NAD levels and altered NAD-related metabolic profiles, affecting embryo metabolism. Expression of requisite pathway genes is conserved in the equivalent yolk sac cell type in humans. Our findings show that visceral yolk sac-mediated NAD de novo synthesis activity is essential for mouse embryogenesis and its perturbation causes CNDD. As mouse and human yolk sacs are functionally homologous, our data improve the understanding of human congenital malformation causation.

Keywords:  NAD; birth defects; congenital malformation; developmental biology; embryogenesis; metabolism; mouse; yolk sac

DOI:  https://doi.org/10.7554/eLife.97649
Am J Hum Genet. 2025 Feb 25. pii: S0002-9297(25)00053-9. [Epub ahead of print]

Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.

Huw B Thomas, Leigh A M Demain, Alfredo Cabrera-Orefice, Isabelle Schrauwen, Hanan E Shamseldin, Alessandro Rea, Thashi Bharadwaj, Thomas B Smith, Monika Oláhová, Kyle Thompson, Langping He, Namanpreet Kaur, Anju Shukla, Musaad Abukhalid, Muhammad Ansar, Sakina Rehman, Saima Riazuddin, Firdous Abdulwahab, Janine M Smith, Zornitza Stark, Hanifenur Mancilar, Sait Tumer, Fatma N Esen, Eyyup Uctepe, Vehap Topcu, Ahmet Yesilyurt, Erum Afzal, Mehri Salari, Christopher Carroll, Giovanni Zifarelli, Peter Bauer, Deniz Kor, Fatma D Bulut, Henry Houlden, Reza Maroofian, Samantha Carrera, Wyatt W Yue, Kevin J Munro, Fowzan S Alkuraya, Peter Jamieson, Zubair M Ahmed, Suzanne M Leal, Robert W Taylor, Ilka Wittig, Raymond T O'Keefe, William G Newman.

  Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.

Keywords:  MRPL49; Perrault syndrome; combined oxidative phosphorylation deficiency; learning disability; leukodystrophy; mitochondria; mitoribosome; primary ovarian insufficiency; rare disease; sensorineural hearing loss

DOI:  https://doi.org/10.1016/j.ajhg.2025.02.005
iScience. 2025 Mar 21. 28(3): 111895

EPAS1 induction drives myocardial degeneration in desmoplakin-cardiomyopathy.

Eirini Kyriakopoulou, Sebastiaan J van Kampen, Martijn Wehrens, Su Ji Han, Hesther de Ruiter, Jantine Monshouwer-Kloots, Emma Marshall, Andreas Brodehl, Petra van der Kraak, Anneline S J M Te Riele, Egidius E H L van Aarnhem, Linda W van Laake, Hoyee Tsui, Cornelis J Boogerd, Eva van Rooij.

  Arrhythmogenic cardiomyopathy (ACM) is frequently attributed to desmosomal mutations, such as those in the desmoplakin (DSP) gene. Patients with DSP-cardiomyopathy are predisposed to myocardial degeneration and arrhythmias. Despite advancements, the underlying molecular mechanisms remain incompletely understood, thus limiting therapeutic options. Here, we employed spatial transcriptomics on an explanted heart from a patient with a pathogenic DSP variant. Our transcriptional analysis revealed endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. Elevated EPAS1 levels were associated with mitochondrial dysfunction and hypoxic stress in both human-relevant in vitro ACM models and additional explanted hearts with genetic cardiomyopathy. Collectively, cardiomyocytes bearing pathogenic DSP variants exhibit mitochondrial dysfunction, increased apoptosis, and impaired contractility, which are linked to the increased EPAS1 levels. These findings implicate EPAS1 as a key regulator of myocardial degeneration in DSP-cardiomyopathy, which expand to other forms of ACM.

Keywords:  Cardiovascular medicine; Cell biology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.111895
J Pharmacol Exp Ther. 2025 Feb;pii: S0022-3565(24)30197-1. [Epub ahead of print]392(2): 100048

Elesclomol rescues mitochondrial copper deficiency in disease models without triggering cuproptosis.

Mohammad Zulkifli, Krishna P Maremanda, Adriana U Okonkwo, Ifrah Farid, Vishal M Gohil.

  Copper (Cu) is an essential cofactor for metalloenzymes such as cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial electron transport chain. Mutations that directly or indirectly prevent Cu transport to mitochondria result in lethal pediatric diseases, such as Menkes disease. There is no clinically approved treatment for Menkes disease. We recently discovered that an investigational chemotherapy drug, elesclomol (ES), when complexed with Cu (ES-Cu), rescues mitochondrial Cu deficiency, activates CcO, and prevents perinatal lethality in a mouse model of Menkes disease. However, ES-Cu also has the potential to trigger cuproptosis, a type of Cu-dependent cell death. Therefore, to develop ES-Cu as a therapeutic agent for Menkes disease, it is critical to determine the therapeutic index of ES-Cu in Cu-deficient models. To this end, we used a Cu-deficient rat cardiomyocyte cell line and a mottled-brindled mouse model of severe Menkes disease to determine the toxicity and efficacy of ES-Cu. Our cell culture studies demonstrated that the EC50 of ES-Cu is ∼50-fold lower than IC50. Moreover, the biomarkers of Cu toxicity, including lipoylated proteins and a subset of iron-sulfur cluster-containing proteins of mitochondria, are activated only when ES-Cu is used at ∼10-fold to 25-fold higher than its EC50. Importantly, none of these biomarkers are activated in mottled-brindled mice treated with therapeutic doses of ES-Cu. Our study shows that ES-Cu can deliver Cu to CcO both in vitro and in vivo without triggering cuproptosis, a finding that could facilitate its use in Cu deficiency disorders, such as Menkes disease. SIGNIFICANCE STATEMENT: Genetic copper (Cu) deficiency causes lethal pediatric diseases, such as Menkes disease, which lacks approved treatment. Recently, the therapeutic potential of elesclomol (ES), a Cu-transporting chemotherapeutic drug, in a mouse model of Menkes disease has been reported. Because of the potential risk of Cu-induced toxicity from ES-Cu, it is crucial to determine its therapeutic index. Here, the biomarkers of ES-Cu efficacy and toxicity in Cu-deficient disease models were measured to demonstrate that ES-Cu can restore cuproenzymes without triggering toxicity biomarkers.

Keywords:  Copper; Cuproptosis; Elesclomol; Menkes disease; Mitochondria

DOI:  https://doi.org/10.1016/j.jpet.2024.100048
Orphanet J Rare Dis. 2025 Mar 05. 20(1): 104

The multifaceted challenges faced by women in the field of inherited metabolic disorders.

Livia Lenzini, Sara Bianconi, Giorgia Gugelmo, Vincenza Gragnaniello, Simone Messerotti Benvenuti, Gian Paolo Fadini, Nicola Vitturi.

  Inherited metabolic disorders (IMDs) are heritable conditions that affect up to 125:100,000 people worldwide. In addition to severe disabling forms that require continuous and costly assistance in both pediatric and adult patients, some IMDs can have mild forms, with the first clinical signs starting in adolescence or very late in adulthood. In the complex field of IMDs, featuring multifaceted challenges that span from scientific discoveries to patient care, women play a central role in contributing to clinical practice, research, patient advocacy, care, and education. In this narrative review, we focused on the involvement of women in the field of IMDs, highlighting not only their extensive contributions but also the undervaluation of the psychological and emotional tolls paid by women dealing with these diseases. Moreover, from a female-centered perspective, we explored the condition of an adult patient with an IMD to highlight the importance of changing the current approach to the clinical management of these diseases toward a more gender-focused approach.

Keywords:  Care-giver; Gender-based medicine; Inherited metabolic disorders

DOI:  https://doi.org/10.1186/s13023-025-03604-8
Nat Commun. 2025 Mar 04. 16(1): 2187

Distinct gene regulatory dynamics drive skeletogenic cell fate convergence during vertebrate embryogenesis.

Menghan Wang, Ana Di Pietro-Torres, Christian Feregrino, Maëva Luxey, Chloé Moreau, Sabrina Fischer, Antoine Fages, Danilo Ritz, Patrick Tschopp.

Cell type repertoires have expanded extensively in metazoan animals, with some clade-specific cells being crucial to evolutionary success. A prime example are the skeletogenic cells of vertebrates. Depending on anatomical location, these cells originate from three different precursor lineages, yet they converge developmentally towards similar cellular phenotypes. Furthermore, their 'skeletogenic competency' arose at distinct evolutionary timepoints, thus questioning to what extent different skeletal body parts rely on truly homologous cell types. Here, we investigate how lineage-specific molecular properties are integrated at the gene regulatory level, to allow for skeletogenic cell fate convergence. Using single-cell functional genomics, we find that distinct transcription factor profiles are inherited from the three precursor states and incorporated at lineage-specific enhancer elements. This lineage-specific regulatory logic suggests that these regionalized skeletogenic cells are distinct cell types, rendering them amenable to individualized selection, to define adaptive morphologies and biomaterial properties in different parts of the vertebrate skeleton.

DOI: https://doi.org/10.1038/s41467-025-57480-8
Food Chem Toxicol. 2025 Feb 26. pii: S0278-6915(25)00122-X. [Epub ahead of print]199 115355

Microplastics/nanoplastics contribute to aging and age-related diseases: Mitochondrial dysfunction as a crucial role.

Liang Kong, Shuhao Li, Yu Fu, Qinyun Cai, Zhengyu Zhai, Jingyan Liang, Tan Ma.

  The pervasive utilization of plastic products has led to a significant escalation in plastic waste accumulation. Concurrently, the implications of emerging pollutants such as microplastics (MPs) and nanoplastics (NPs) on human health are increasingly being acknowledged. Recent research has demonstrated that MPs/NPs may contribute to the onset of human aging and age-related diseases. Additionally, MPs/NPs have the potential to induce mitochondrial damage, resulting in mitochondrial dysfunction. Mitochondrial dysfunction is widely recognized as a hallmark of aging; thus, it is necessary to elucidate the relationship between them. In this article, we first elucidate the distribution of MPs/NPs in various environmental media, their pathways into the human body, and their subsequent distribution within human tissues and organs. Subsequently, we examine the interplay between MPs/NPs, mitochondrial dysfunction, and the aging process. We aspire that this article will enhance awareness regarding the toxicity of MPs/NPs while also offering a theoretical framework to support the development of improved regulatory policies in the future.

Keywords:  Aging; MPs; Mitochondrial dysfunction; NPs

DOI:  https://doi.org/10.1016/j.fct.2025.115355
Mol Neurodegener. 2025 Mar 04. 20(1): 25

The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer's disease.

Shuiyue Quan, Xiaofeng Fu, Huimin Cai, Ziye Ren, Yinghao Xu, Longfei Jia.

  The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing cytosolic damage-associated molecular patterns (DAMPs), and inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation of this pathway culminates in AD-related neuroinflammation and neurodegeneration. A substantial body of evidence indicates that mitochondria are involved in the critical pathogenic mechanisms of AD, whose damage leads to the release of mitochondrial DNA (mtDNA) into the extramitochondrial space. This leaked mtDNA serves as a DAMP, activating various pattern recognition receptors and immune defense networks in the brain, including the cGAS-STING pathway, ultimately leading to an imbalance in immune homeostasis. Therefore, modulation of the mtDNA-cGAS-STING pathway to restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In this review, we focus on the mechanisms of mtDNA release during stress and the activation of the cGAS-STING pathway. Additionally, we delve into the research progress on this pathway in AD, and further discuss the primary directions and potential hurdles in developing targeted therapeutic drugs, to gain a deeper understanding of the pathogenesis of AD and provide new approaches for its therapy.

Keywords:  Alzheimer’s disease; MtDNA; Neuroinflammation; STING; Treatment; cGAS

DOI:  https://doi.org/10.1186/s13024-025-00815-2
Neurology. 2025 Apr 08. 104(7): e213373

Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures.

Luca Bergonzini, Sara Carli, Silvia Pelle, Ilaria Pettenuzzo, Silvia Bonetti, Erika Santi, Caterina Visconti, Monica Maffei, Marta Sheremet, Eleonora Lamantea, Andrea Marsala, Olena Klub, Valentina Gentile, Duccio Maria Cordelli, Caterina Garone.

OBJECTIVE: Recessive variants in the TK2 gene cause thymidine kinase 2 deficiency (TK2d) presenting with infantile, childhood, or adult-onset myopathy. CNS involvement is reported in only 25% of the infantile form. Compassionate use of deoxynucleoside substrate enhancement therapy (dC/dT) has been demonstrated safe and effective in TK2d myopathy, but no data are available on the potential efficacy on the human brain disease.
METHODS: Here, we report for the first time a patient with infantile TK2d epileptic encephalomyopathy enrolled in an early access program with dC/dT treatment (MT1621).
RESULTS: At age 3 months, he presented progressive hypotonia, motor regression, failure to thrive, and respiratory failure. At age 8 months, he developed drug-resistant epilepsy with migrating focal seizures. Brain MRI showed progressive atrophy and bilateral subcortical lesions with lactate peak. Exome sequencing revealed 2 novel biallelic heterozygous variants in the TK2 gene (c.182G>A, p.Ser61Asn, c.704 T>C, p.Ile235Thr) whose pathogenicity was confirmed with in vitro studies. Early access compassionate use of dC/dT at 400 mg/kg prolonged the survival and stabilized the muscle disease but was not effective on the brain.
DISCUSSION: Our report highlights the importance of deep-phenotyping infantile TK2d before dC/dT supplementation to stratify disease severity further and suggests a limited tissue-specific brain efficacy.

DOI: https://doi.org/10.1212/WNL.0000000000213373
Acta Physiol (Oxf). 2025 Apr;241(4): e70012

Trophoblast-specific Deptor knockdown enhances trophoblast nutrient transport and fetal growth in mice.

Lance G A Nunes, Rodrigo B Weingrill, Sam Blessen J Fredrick, Ramon Lorca, Men-Jean Lee, Shaikh M Atif, Adam J Chicco, Fredrick J Rosario, Johann Urschitz.

   AIM: Silencing of DEP-domain containing mTOR-interacting protein (DEPTOR), an endogenous inhibitor of the mammalian target of rapamycin (mTOR) pathway, increases mTOR signaling and System A/L amino acid transport activity in cultured primary human trophoblast cells. However, there is no evidence supporting the regulatory role of DEPTOR signaling in placental function in vivo. We hypothesized that trophoblast-specific Deptor knockdown (KD) in mice increases trophoblast mTOR signaling, amino acid transport, and enhances fetal growth.
METHODS: We generated trophoblast-specific DeptorKD transgenic mice, and at embryonic day 18.5, placentas were analyzed to confirm knockdown efficiency, specificity, and mTOR signaling pathway levels. Trophoblast plasma membrane (TPM) System A/L amino acid transport expression and activity were also determined. We also examined the relationship between birthweight and DEPTOR protein levels in human placentas collected at term from appropriate for gestational age (AGA) and large for gestational age (LGA) pregnancies.
RESULTS: Reducing trophoblast Deptor RNA levels increased placental mTOR signaling, System A/L transporter expression/activity, and fetal growth in mice. Similarly, human LGA placentas displayed decreased DEPTOR protein levels, inversely correlated to birthweight and BMI.
CONCLUSIONS: This is the first report showing that trophoblast-specific DeptorKD is sufficient to activate mTOR signaling, a master regulator of placental function, which increases the TPM System A and L amino acid transporter expression and activity. We also propose that Deptor expression is mechanistically linked to placental mTOR signaling and fetal growth. Furthermore, modulation of DEPTOR signaling may represent a promising approach to improve outcomes in pregnancies characterized by abnormal fetal growth.

Keywords:  fetal development; maternal‐fetal exchange; mechanistic target of rapamycin; placenta; transposase‐enhanced pronuclear injection

DOI:  https://doi.org/10.1111/apha.70012
Brain. 2025 Mar 06. pii: awaf094. [Epub ahead of print]

Fetal malformations of cortical development: review and clinical guidance.

Jeffrey B Russ, Sonika Agarwal, Charu Venkatesan, Barbara Scelsa, Brigitte Vollmer, Tomo Tarui, Andrea C Pardo, Monica E Lemmon, Sarah B Mulkey, Anthony R Hart, Usha D Nagaraj, Jeffrey A Kuller, Matthew T Whitehead, Jennifer L Cohen, Juliana S Gebb, Orit A Glenn, Mary E Norton, Dawn Gano.

  Malformations of cortical development (MCDs) are a heterogeneous family of congenital brain malformations that originate from disturbed development of the cerebral cortex. MCDs can arise from primary genetic disorders that lead to dysfunction of the molecular processes controlling neuronal proliferation, neuronal migration, cortical folding, or cortical organization. MCDs can also result from secondary, disruptive causes, such as congenital infection or other in utero brain injuries. Sequelae of MCDs can include epilepsy, intellectual disability, and cerebral palsy, among other symptoms, with a high burden of pediatric morbidity. Advances in antenatal genetic testing and imaging have improved the ability to diagnose MCDs, yet limited literature exists to aid clinicians in prognostication of outcomes and perinatal management. These clinical realities can make it challenging for clinicians caring for fetal neurological conditions to counsel families and make recommendations for interdisciplinary care. We aim to review the literature on fetal MCDs and present practice guidelines for clinicians regarding the pre- and postnatal management of MCDs.

Keywords:  fetal neurology; heterotopia; lissencephaly; polymicrogyria; prenatal diagnosis; schizencephaly

DOI:  https://doi.org/10.1093/brain/awaf094
Mov Disord. 2025 Mar 04.

Spinocerebellar Ataxia Progression Measured with the Patient-Reported Outcome Measure of Ataxia.

Anna L Burt, Gilbert L'Italien, Susan L Perlman, Liana S Rosenthal, Sheng-Han Kuo, Tetsuo Ashizawa, Theresa Zesiewicz, Cameron Dietiker, Puneet Opal, Antoine Duquette, George R Wilmot, Vikram G Shakkottai, Christopher M Gomez, Sharan R Srinivasan, Henry Paulson, Michael D Geschwind, Sandie Worley, Chiadi U Onyike, Andrew Billnitzer, Amy Ferng, Kristen Matulis, Marie Y Davis, Sub H Subramony, Anoopum Gupta, Christopher D Stephen, Jeremy D Schmahmann.

   BACKGROUND: The Patient-Reported Outcome Measure of Ataxia (PROM-Ataxia) has been validated cross-sectionally but not longitudinally.
OBJECTIVE: We aimed to validate PROM-Ataxia as a measure of patient experience of disease over time, examine overall and domain-specific progression, and test convergent validity with other clinical outcome assessments (COAs).
METHODS: We derived PROM-Ataxia data from 176 patients with spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, or 10 in the Clinical Research Consortium for the Study of Cerebellar Ataxia at baseline and 1 year. We classified patients' ataxia severity stage ("severity") according to the Friedreich's Ataxia Rating Scale Functional Staging into mild, moderate, and severe subgroups. Analyses of the entire cohort and by severity subgroup included internal consistency, sensitivity to disease severity, predictive modeling of score changes, correlations with COAs: Brief Ataxia Rating Scale, Scale for Assessment and Rating of Ataxia, Fatigue Severity Scale, Cerebellar Cognitive Affective Syndrome scale, EuroQol 5-Dimension, and responsiveness to disease progression.
RESULTS: The PROM-Ataxia exhibited high internal consistency and correlated with other COAs. Scores demonstrated sensitivity to disease severity and evolving patient experience. Progression was sigmoidal, with the greatest change in moderate patients. Compared with other COAs, PROM-Ataxia captured the most change. Mental features worsened fastest in mild patients, physical in moderate patients, and activities of daily living in severe patients.
CONCLUSION: PROM-Ataxia is more sensitive to change than ataxia COAs, captures the evolution of patients' experience of disease over 1 year, and reveals domain-specific progression. Studies of larger cohorts and different ataxia diagnoses over longer periods may provide insights to further enhance clinical care and research. © 2025 International Parkinson and Movement Disorder Society.

Keywords:  PROM‐ataxia; cerebellar cognitive affective syndrome; cerebellum; clinical outcome assessment; progression; spinocerebellar ataxia

DOI:  https://doi.org/10.1002/mds.30158
Cardiovasc Diabetol. 2025 Mar 05. 24(1): 106

Circulating mitochondrial DNA signature in cardiometabolic patients.

Alessandro Mengozzi, Silvia Armenia, Nicolò De Biase, Lavinia Del Punta, Federica Cappelli, Emiliano Duranti, Virginia Nannipieri, Rossana Remollino, Domenico Tricò, Agostino Virdis, Stefano Taddei, Nicola Riccardo Pugliese, Stefano Masi.

   BACKGROUND: Mitochondrial dysfunction is a hallmark of cardiometabolic diseases. Circulating mitochondrial DNA (mtDNA) profiles could refine risk stratification, but current methods do not account for different fractions of circulating mtDNA. We investigated whether patients with type 2 diabetes and/or heart failure (HF) have a specific signature of the total circulating mtDNA profile, including intracellular and cell-free fractions.
METHODS: We performed a complete clinical assessment, including blood tests, 12-lead ECG and ultrasound at rest and during cardiopulmonary exercise. Ultrasound congestion was defined at rest as inferior vena cava of ≥ 21 mm, lung B-lines ≥ 4, or discontinuous renal venous flow. In fasting whole blood and plasma samples collected at rest, we simultaneously measured the copy number of the cellular and cell-free components of mtDNA by real-time quantitative polymerase chain reaction (qPCR) using custom standards. We calculated the ratio of cell mtDNA to cell-free mtDNA as an index of mitochondrial efficiency.
RESULTS: We enrolled 120 consecutive patients: 50 (42%) with HF and preserved ejection fraction (HFpEF), 40 (33%) with HF and reduced ejection fraction (HFrEF) and 30 (25%) at risk of developing HF; 42/120 (35%) had diabetes. Cell-free mtDNA was increased in patients with HF (with higher levels in HFrEF than HFpEF) and those with diabetes. Cell-free mtDNA was also higher in patients with systemic inflammation (expressed by high-sensitivity C-reactive protein [hs-CRP] ≥ 0.2 mg/dL with neutrophil-lymphocyte ratio [NLR] > 3) and more ultrasound signs of congestion. The cell/cell-free mtDNA ratio showed opposite trends (all p < 0.05), but there were no significant differences in cell mtDNA. Cell-free mtDNA and mtDNA ratio independently predicted the presence of ≥ 2 ultrasound signs of congestion and effort intolerance (peak oxygen consumption < 16 mL/kg/min) at ROC analysis and using multivariable regressions after adjustment for age, sex, hs-CRP, NLR, high-sensitivity Troponin T and NT-proBNP.
CONCLUSIONS: Patients with HF and diabetes have an altered circulating mtDNA signature characterised by higher cell-free mtDNA and lower mtDNA ratio, whereas cellular mtDNA remains unaffected. Cell-free mtDNA and mtDNA ratio are associated with impaired response to exercise, higher systemic inflammation and increased congestion. Circulating mitochondrial profile could be a new biomarker of mitochondrial status in cardiometabolic diseases.

Keywords:  Circulating mitochondrial DNA; Congestion; Effort intolerance; Heart failure; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12933-025-02656-1
FASEB J. 2025 Mar 15. 39(5): e70423

A novel, rapidly progressive ataxia due to a spontaneous Myo5a mutation in mice impairs transport proteins and alters mitochondria.

Alexander M Telenson, Ryan R Hsieh, Gabrielle J Cowen, Eoin P Sode, Jason M Kwon, Andy H Vo, Michele Hadhazy, Patrick G Page, Nalini R Rao, Lorenzo Pesce, Alexis R Demonbreun, Megan J Puckelwartz, Jeffrey N Savas, Elizabeth M McNally.

  Spontaneous mouse mutants have helped define genetic contributions to many phenotypes. Here we report a spontaneous Novel Ataxic Phenotype in mice. Ataxia findings were evident at post-natal day 11 in NAP mice and rapidly worsened, resulting in preweaning lethality. Using genome sequencing and genome-wide mapping, we identified a 3' donor splice variant in exon 14 of Myo5a, encoding an actin-based motor protein. The variant in Myo5a (c.1752g>a) excises exon 14 and ablates MYO5A protein expression, which is implicated in intracellular transport and Griscelli syndrome type I in humans. NAP mice displayed expansion of PAX6-positive cells in the external granule layer of the cerebellum, and mass spectrometry analysis of cerebellar extracts uncovered differentially abundant proteins involved in short-range organelle transport, and specifically proteins implicated with early endosomes. Using cerebellar lysates and primary neurons, we provide evidence for an interaction between MYO5A and ANKFY1, a known effector for the endosomal protein, RAB5A. We also found neurons from NAP mice had elongated mitochondria, linking MYO5A to mitochondrial homeostasis. This allele provides new insight into Myo5a function in developmental neuropathology.

Keywords:  Myo5a; ataxia; cerebellum; mitochondria; motor proteins; spontaneous phenotype; transport; whole genome sequencing

DOI:  https://doi.org/10.1096/fj.202402274R
Med Sci Monit. 2025 Mar 05. 31 e947194

Altered Mitochondrial Morphology and Reduced Cardiolipin Levels in Oocytes of Endometriosis Model Mice: Implications for Mitochondrial Dysfunction in Infertility.

Ody Wijaya, Jimmy Yanuar Anas, Widjiati Widjiati, M Y Ardianta Widyanugraha, Samsulhadi Samsulhadi, Hartanto Bayuaji, Sri Ratna Dwiningsih, Budi Y Utomo, Bella Stevanny.

BACKGROUND Women with endometriosis experience significantly reduced fertility, potentially linked to mitochondrial dysfunction. This study investigates the impact of endometriosis on oocyte mitochondrial morphology and cardiolipin levels, key indicators of mitochondrial health and function. MATERIAL AND METHODS Thirty-two healthy mice were randomly allocated into 2 groups: a control group (P0, n=16) and an endometriosis model group (P1, n=16). Endometriosis was induced via intraperitoneal injection of endometrial tissue, and oocytes were retrieved following superovulation. Mitochondrial morphology was analyzed using transmission electron microscopy, and cardiolipin levels were measured via ELISA. Statistical analyses included the Fisher exact test, Mann-Whitney U test, and Spearman correlation. RESULTS Mitochondrial morphology in oocytes from the endometriosis group exhibited significant structural abnormalities, compared with controls (P<0.001). Class III and IV mitochondria, characterized by disrupted membranes and cristae, were predominantly observed in the endometriosis group. Cardiolipin levels were significantly reduced in the endometriosis group, compared with controls (P<0.001). A positive correlation (r=0.73, P<0.001) was identified between mitochondrial morphological changes and cardiolipin levels, indicating that structural mitochondrial damage was strongly associated with reduced cardiolipin levels. CONCLUSIONS Endometriosis induces significant mitochondrial abnormalities and decreases cardiolipin levels in oocytes, suggesting mitochondrial dysfunction as a critical factor in reduced fertility. These findings underscore the potential of targeting mitochondrial health to improve reproductive outcomes in women with endometriosis.

DOI: https://doi.org/10.12659/MSM.947194