bims-mitmed 2025-02-23 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–02–23
25 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
Leber's hereditary optic neuropathy - current status of idebenone and gene replacement therapies.
Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
How are mitochondrial nucleoids trafficked?
Endurance swimming exacerbates mitochondrial myopathy in mice with high mtDNA deletions.
Heightened sensitivity to adverse effects of metformin in mtDNA mutant patient cells.
Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment.
Bioinformatics Tools for NGS-Based Identification of Single Nucleotide Variants and Large-Scale Rearrangements in Mitochondrial DNA.
Adult-onset Leigh Syndrome: An analysis of the North American Mitochondrial Disease Consortium Database (P3-11.017).
A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
AIF3 splicing variant elicits mitochondrial malfunction via the concurrent dysregulation of electron transport chain and glutathione-redox homeostasis.
Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
Frataxin deficiency and the pathology of Friedreich's Ataxia across tissues.
Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia.
Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
Gene therapies for neurogenetic disorders.
Mitochondrial control of ciliary gene expression and structure in striatal neurons.
Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis.
Targeting Mitochondrial Integrity as a New Senolytic Strategy.
Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.
AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration.
Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in Parkinson's disease.
iPSCs and iPSC-derived cells as a model of human genetic and epigenetic variation.

Nature. 2025 Feb 19.

Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.

Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.

Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.

DOI: https://doi.org/10.1038/s41586-025-08590-2
Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00024-5. [Epub ahead of print]

Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.

Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Amanda L Smythers, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Joao A Paulo, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.

  Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

Keywords:  MPST; ergothioneine; exercise; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.01.024
Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00013-0. [Epub ahead of print]

RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.

Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman.

  Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.

Keywords:  PGC1α; adipocyte; adipose thermogenesis; adipose tissue; cGAS-STING; inflammation; mRNA translation; mitochondria; obesity; oxidative metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.01.013
Med Genet. 2025 Apr;37(1): 57-63

Leber's hereditary optic neuropathy - current status of idebenone and gene replacement therapies.

Thomas Klopstock, Leopold H Zeng, Claudia Priglinger.

  Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease, and was the first to be linked to mitochondrial DNA (mtDNA) variations. Recently, autosomal recessive forms of LHON were described in addition to the classical mtDNA-associated forms. Clinically, LHON manifests with subacute and painless loss of central visual acuity, in most cases starting unilaterally, and involving the second eye a few weeks later. Almost all LHON cases are caused by pathogenic variants in genes that code for proteins relevant for function of Complex I of the respiratory chain. The Complex I dysfunction in LHON leads to decreased ATP synthesis and to increased production of reactive oxygen species which ultimately initiates dysfunction and apoptosis of retinal ganglion cells and their axons, the optic nerve. Idebenone, a synthetic CoQ derivative, is a potent intramitochondrial antioxidant and can shuttle electrons directly to complex III of the respiratory chain, thereby bypassing complex I deficiency. On the basis of several clinical trials, it has been approved as a treatment for LHON in 2015 (in the EU). In addition, direct intravitreal gene replacement therapy is being investigated, with several late-stage clinical trials already completed. In the future, gene editing of mtDNA variants may also become a therapeutic option.

Keywords:  Complex I; LHON; gene therapy; idebenone; mtDNA

DOI:  https://doi.org/10.1515/medgen-2024-2066
Nature. 2025 Feb 19.

Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.

Kate McArthur, Michael T Ryan.



Keywords:  Cell biology

DOI:  https://doi.org/10.1038/d41586-025-00303-z
Trends Cell Biol. 2025 Feb 20. pii: S0962-8924(24)00272-1. [Epub ahead of print]

How are mitochondrial nucleoids trafficked?

Josefa Macuada, Isidora Molina-Riquelme, Verónica Eisner.

  Mitochondria harbor their own DNA (mtDNA), which codifies essential proteins of the oxidative phosphorylation (OXPHOS) system and locally feeds them to their surrounding inner mitochondrial membrane (IMM), according to the 'sphere of influence' theory. mtDNA is compacted into nucleoids, which are tethered to the IMM and distributed throughout the mitochondrial network. Some nucleoid subpopulations present distinct intramitochondrial positioning during fission and their correct positioning is associated with mtDNA segregation and selective degradation. This opinion article focuses on different mechanisms that could control nucleoid positioning through intramitochondrial trafficking, either by cristae reshaping or by intercompartment-driven mechanisms involving the mitochondrial membranes and extramitochondrial elements. Understanding nucleoid trafficking promises insights into mitochondrial dysfunction in pathologies with mtDNA distribution and segregation issues.

Keywords:  cristae reshaping; mitochondrial nucleoid; mtDNA inheritance; nucleoid dynamics; sphere of influence

DOI:  https://doi.org/10.1016/j.tcb.2024.12.007
Mitochondrion. 2025 Feb 14. pii: S1567-7249(25)00007-8. [Epub ahead of print]81 102010

Endurance swimming exacerbates mitochondrial myopathy in mice with high mtDNA deletions.

Sho Hanada, Kaori Ishikawa, Takanaga Shirai, Tohru Takemasa, Kazuto Nakada.

  Recent studies have reported that endurance exercise enhances mitochondrial function, facilitating discussions of its potential as a therapeutic strategy for mitochondrial diseases caused by the accumulation of mutant mitochondrial DNA (mtDNA). In this study, we assessed the effects of endurance exercise on muscle pathology in a mitochondrial disease mouse model (mito-miceΔ) that is characterized by severe clinical phenotypes owing to the predominant accumulation of mtDNA with a large-scale deletion (ΔmtDNA). Contrary to expectations that endurance exercise may enhance mitochondrial function, endurance exercise exacerbated muscle pathology in mito-miceΔ. Therefore, exercise interventions should be potentially avoided in patients with severe mitochondrial diseases.

Keywords:  Endurance exercise; Mitochondrial diseases; Mitochondrial respiratory function; Mouse model; Muscle atrophy

DOI:  https://doi.org/10.1016/j.mito.2025.102010
Life Sci. 2025 Feb 19. pii: S0024-3205(25)00119-5. [Epub ahead of print]366-367 123486

Heightened sensitivity to adverse effects of metformin in mtDNA mutant patient cells.

Sanna Ryytty, Katriina Nurminen, Petri Mäkinen, Anu Suomalainen, Riikka H Hämäläinen.

   AIMS: Metformin (Met) is a widely used, cost-effective, and relatively safe drug, primarily prescribed for diabetes, that also exhibits beneficial effects in other conditions, such as in cardiovascular diseases, neurological disorders, and cancer. Despite its common use, the safety of Met in patients with primary mitochondrial disease remains uncertain, as both Met and mitochondrial dysfunction increase the risk of lactic acidosis. Here we have examined the effects of Met in patient cells with m.3243A>G mitochondrial DNA mutation.
MATERIALS AND METHODS: We utilized induced pluripotent stem cells (iPSCs) derived from two m.3243A>G patients, alongside cardiomyocytes differentiated from these iPSCs (iPSC-CMs). The cells were exposed to 10, 100, and 1000 μM Met for 24 h, and the effects on cellular metabolism and mitochondrial function were evaluated.
KEY FINDINGS: While low concentrations, relative to common therapeutic plasma levels, increased mitochondrial respiration, higher concentrations decreased respiration in both patient and control cells. Furthermore, cells with high level of the m.3243A>G mutation were more sensitive to Met than control cells. Additionally, we observed a clear patient-specific response to Met in cardiomyocytes.
SIGNIFICANCE: The findings emphasize the critical importance of selecting appropriate Met concentrations in cellular experiments and demonstrate the variability in Met's effects between individuals. Moreover, the results highlight the need for caution when considering Met use in patients with primary mitochondrial disorders.

Keywords:  Cardiomyocytes; Induced pluripotent stem cells; Metformin; Mitochondrial disease; m.3243A>G

DOI:  https://doi.org/10.1016/j.lfs.2025.123486
Brain Commun. 2025 ;7(1): fcae453

Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment.

Rauan Kaiyrzhanov, Kyle Thompson, Stephanie Efthymiou, Askhat Mukushev, Akbota Zharylkassyn, Chitra Prasad, Ehsan Ghayoor Karimiani, Javeria Raza Alvi, Dmitriy Niyazov, Ahmad Alahmad, Meisam Babaei, Homa Tajsharghi, Buthaina Albash, Ahmad Alaqeel, Majida Charif, Narges Hashemi, Morteza Heidari, Seyed Mehdi Kalantar, Guy Lenaers, Mohammad Yahya Vahidi Mehrjardi, Varunvenkat M Srinivasan, Vykuntaraju K Gowda, Seyed Hamidreza Mirabutalebi, Deanna Alexis Carere, Mojtaba Movahedinia, David Murphy, Robert McFarland, Mohamed S Abdel-Hamid, Rasha M Elhossini, Shahryar Alavi, Melanie Napier, Amaya Belanger-Quintana, Asuri N Prasad, Jessica Jakobczyk, Agathe Roubertie, Tony Rupar, Tipu Sultan, Mehran Beiraghi Toosi, Leonid Sazanov, Mariasavina Severino, Henry Houlden, Robert W Taylor, Reza Maroofian.

  Biallelic variants in NADH (nicotinamide adenine dinucleotide (NAD) + hydrogen (H))-ubiquinone oxidoreductase 1 alpha subcomplex 13 have been linked to mitochondrial complex I deficiency, nuclear type 28, based on three affected individuals from two families. With only two families reported, the clinical and molecular spectrum of NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13-related diseases remains unclear. We report 10 additional affected individuals from nine independent families, identifying four missense variants (including recurrent c.170G > A) and three ultra-rare or novel predicted loss-of-function biallelic variants. Updated clinical-radiological data from previously reported families and a literature review compiling clinical features of all reported patients with isolated complex I deficiency caused by 43 genes encoding complex I subunits and assembly factors are also provided. Our cohort (mean age 7.8 ± 5.4 years; range 2.5-18) predominantly presented a moderate-to-severe neurodevelopmental syndrome with oculomotor abnormalities (84%), spasticity/hypertonia (83%), hypotonia (69%), cerebellar ataxia (66%), movement disorders (58%) and epilepsy (46%). Neuroimaging revealed bilateral symmetric T2 hyperintense substantia nigra lesions (91.6%) and optic nerve atrophy (66.6%). Protein modeling suggests missense variants destabilize a critical junction between the hydrophilic and membrane arms of complex I. Fibroblasts from two patients showed reduced complex I activity and compensatory complex IV activity increase. This study characterizes NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13-related disease in 13 individuals, highlighting genotype-phenotype correlations.

Keywords:  Leigh syndrome; NDUFA13; complex I deficiency; mitochondrial disorders; neurodevelopmental disorder

DOI:  https://doi.org/10.1093/braincomms/fcae453
BioTech (Basel). 2025 Feb 12. pii: 9. [Epub ahead of print]14(1):

Bioinformatics Tools for NGS-Based Identification of Single Nucleotide Variants and Large-Scale Rearrangements in Mitochondrial DNA.

Marco Barresi, Giulia Dal Santo, Rossella Izzo, Andrea Zauli, Eleonora Lamantea, Leonardo Caporali, Daniele Ghezzi, Andrea Legati.

  The unique features of mitochondrial DNA (mtDNA), including its circular and multicopy nature, the possible coexistence of wild-type and mutant molecules (i.e., heteroplasmy) and the presence of nuclear mitochondrial DNA segments (NUMTs), make the diagnosis of mtDNA diseases particularly challenging. The extensive deployment of next-generation sequencing (NGS) technologies has significantly advanced the diagnosis of mtDNA-related diseases. However, the vast amounts and diverse types of sequencing data complicate the interpretation of these variants. From sequence alignment to variant calling, NGS-based mtDNA sequencing requires specialized bioinformatics tools, adapted for the mitochondrial genome. This study presents the use of new bioinformatics approaches, optimized for short- and long-read sequencing data, to enhance the accuracy of mtDNA analysis in diagnostics. Two recent and emerging free bioinformatics tools, Mitopore and MitoSAlt, were evaluated on patients previously diagnosed with single nucleotide variants or large-scale deletions. Analyses were performed in Linux-based environments and web servers implemented in Python, Perl, Java, and R. The results indicated that each tool demonstrated high sensitivity and specific accuracy in identifying and quantifying various types of pathogenic variants. The study suggests that the integrated and parallel use of these tools offers a significant advantage over traditional methods in interpreting mtDNA genetic variants, reducing the computational demands, and provides an accurate diagnostic solution.

Keywords:  NGS; bioinformatics; mitochondrial DNA; mtDNA

DOI:  https://doi.org/10.3390/biotech14010009
Neurology. 2024 Apr 09. 102(7_supplement_1): 6306

Adult-onset Leigh Syndrome: An analysis of the North American Mitochondrial Disease Consortium Database (P3-11.017).

Emanuele Barca, Adam Kroopnick, Alexander Houck, Kiran Thakur, Rachelle Dugue, Zarazuela Zolkipli-Cunningham, Marni Falk, Amy Goldstein, Matthew Demczko, Ralitza Gavrilova, Austin Larson, Johan Van Hove, Russell Saneto, Richard Buchsbaum, John Thompson, Michio Hirano.

OBJECTIVE: This analysis of Adult-Onset Leigh Syndrome (LS) patients from the North American Mitochondrial Disease Consortium (NAMDC) Registry aims to enhance clinical insights, improve diagnoses, and uncover potential modifiers.
BACKGROUND: LS is a rare syndrome linked to defects in more than one hundred genes. Most LS patients develop subacute neurological deterioration or regression before age two years. The pathological and radiological hallmarks are the subacute necrotizing degeneration of basal ganglia, cerebellum, brainstem, and/or cervical spinal cord, frequently triggered by metabolic stress. A small group of patients develop central nervous system involvement later in life.
DESIGN/METHODS: This retrospective study stemmed from a case of a twenty-five-year-old man with mild developmental delay and sensory-motor neuropathy admitted for worsening weakness. During his hospital stay, he developed a rapidly progressive encephalopathy and classic LS radiological findings. Intrigued by this observation, we interrogated the NAMDC registry to retrieve data from other adult-onset LS individuals. The registry contains demographic, manifestation, genetic, imaging, and biochemistry data from more than 2100 subjects enrolled from 17 centers in North America and Canada.
RESULTS: We identified six subjects with onset of CNS manifestations after age 18. Most of the subjects had been involved of other organ systems preceding the CNS lesions. Four probands had pathogenic variants in nuclear-encoded mitochondria metabolism genes, one in mitochondrial DNA-encoded ATP synthase subunit gene, and one patient remained genetically undefined. The disease progression varied among the cohort, with probands harboring nuclear variants experiencing a slower course compared to the individual with a mitochondrial DNA defect, who suffered a rapid, progressive, and fatal deterioration.
CONCLUSIONS: Our data show that mitochondrial patients with LS experience evolving and progressive phenotypes, and the presence of manifestations in other organs often precedes LS in adults, suggesting that clinicians should carefully avoid metabolic stressors known to precipitate neurodegeneration in subjects with the observed genetic variants. Disclosure: Dr. Barca has nothing to disclose. Dr. Kroopnick has nothing to disclose. Dr. Houck has nothing to disclose. Dr. Thakur has received personal compensation for serving as an employee of World Health Organization. Dr. Thakur has received personal compensation for serving as an employee of Pan American Health Organization. Dr. Thakur has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Delve Bio. The institution of Dr. Thakur has received research support from Center for Disease Control and Prevention. The institution of Dr. Thakur has received research support from National Institute of Health. Dr. Dugue has nothing to disclose. Dr. Zolkipli-Cunningham has nothing to disclose. An immediate family member of Marni Falk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lumiere. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mission Therapeutics. Marni Falk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Primera Therapeutics. Marni Falk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Imel Therapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MiMo Therapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GenoMind. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Casma Therapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mayflower, Inc.. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Precision Biosciences. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Foresite Labs. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stealth BioTherapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Taysha Gene Therapies. Marni Falk has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Larimar Therapeutics. Marni Falk has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Khondrion. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for United MItochondrial Disease Foundation. Marni Falk has stock in Rarefy Therapeutics. Marni Falk has stock in RiboNova Inc. The institution of Marni Falk has received research support from Merck. The institution of Marni Falk has received research support from Saol Therapeutics. The institution of Marni Falk has received research support from Stealth Biotherapeutics. The institution of Marni Falk has received research support from Astellas. The institution of Marni Falk has received research support from UMDF. The institution of Marni Falk has received research support from CureARS Foundation. The institution of Marni Falk has received research support from Mission Therapeutics. The institution of Marni Falk has received research support from Cyclerion. The institution of Marni Falk has received research support from NIH. The institution of Marni Falk has received research support from DOD. The institution of Marni Falk has received research support from FDA. Marni Falk has received intellectual property interests from a discovery or technology relating to health care. Marni Falk has received publishing royalties from a publication relating to health care. Dr. Goldstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Reneo Pharmaceuticals . Dr. Demczko has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck Manuals. Dr. Gavrilova has nothing to disclose. Austin Larson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Illumina. An immediate family member of Austin Larson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. An immediate family member of Austin Larson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Austin Larson has received personal compensation in the range of $0-$499 for serving as a Consultant for Tisento. Austin Larson has received personal compensation in the range of $0-$499 for serving as a Consultant for UCB. The institution of Austin Larson has received research support from Stealth Biotherapeutics. The institution of Austin Larson has received research support from Astellas. The institution of Austin Larson has received research support from Entrada. The institution of Austin Larson has received research support from Neuren. The institution of an immediate family member of Austin Larson has received research support from Neurocrine. Johan Van Hove has received intellectual property interests from a discovery or technology relating to health care. Dr. Saneto has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for REATA. Dr. Saneto has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GW Pharmaceuticals. The institution of Dr. Saneto has received research support from NIH. The institution of Dr. Saneto has received research support from Zogenix. The institution of Dr. Saneto has received research support from GW Pharmaceuticals. The institution of Dr. Thompson has received research support from NIH. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Modis Therapeutics (a subsidiary of Zogenix). Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Epirium Bio. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Innovation Specialist. Dr. Hirano has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Platform Q Health. The institution of Dr. Hirano has received research support from Modis Therapeutics (a subsidiary of Zogenix). The institution of Dr. Hirano has received research support from Cyclerion. Dr. Hirano has received intellectual property interests from a discovery or technology relating to health care. Dr. Hirano has received personal compensation in the range of $0-$499 for serving as a Study Section Reviewer with NIH. Dr. Hirano has a non-compensated relationship as a Research Advisory Board member with Muscular Dystrophy Association that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific and Medical Advisory Board member with United Mitochondrial Disease Foundation that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific Advisory Board member with Barth Syndrome Foundation that is relevant to AAN interests or activities.

DOI: https://doi.org/10.1212/WNL.0000000000206383
bioRxiv. 2025 Feb 08. pii: 2025.02.03.635951. [Epub ahead of print]

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.

Anna S Monzel, Jack Devine, Darshana Kapri, Jose Antonio Enriquez, Caroline Trumpff, Martin Picard.

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3 . All mitochondria share general features, but not all mitochondria are created equal 4 .Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes . By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5 ) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8 , we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.

DOI: https://doi.org/10.1101/2025.02.03.635951
Nat Commun. 2025 Feb 20. 16(1): 1804

AIF3 splicing variant elicits mitochondrial malfunction via the concurrent dysregulation of electron transport chain and glutathione-redox homeostasis.

Mi Zhou, Shuiqiao Liu, Yanan Wang, Bo Zhang, Ming Zhu, Jennifer E Wang, Veena Rajaram, Yisheng Fang, Weibo Luo, Yingfei Wang.

Genetic mutations in apoptosis-inducing factor (AIF) have a strong association with mitochondrial disorders; however, little is known about the aberrant splicing variants in affected patients and how these variants contribute to mitochondrial dysfunction and brain development defects. We identified pathologic AIF3/AIF3-like splicing variants in postmortem brain tissues of pediatric individuals with mitochondrial disorders. Mutations in AIFM1 exon-2/3 increase splicing risks. AIF3-splicing disrupts mitochondrial complexes, membrane potential, and respiration, causing brain development defects. Mechanistically, AIF is a mammalian NAD(P)H dehydrogenase and possesses glutathione reductase activity controlling respiratory chain functions and glutathione regeneration. Conversely, AIF3, lacking these activities, disassembles mitochondrial complexes, increases ROS generation, and simultaneously hinders antioxidant defense. Expression of NADH dehydrogenase NDI1 restores mitochondrial functions partially and protects neurons in AIF3-splicing mice. Our findings unveil an underrated role of AIF as a mammalian mitochondrial complex-I alternative NAD(P)H dehydrogenase and provide insights into pathologic AIF-variants in mitochondrial disorders and brain development.

DOI: https://doi.org/10.1038/s41467-025-57081-5
Nat Metab. 2025 Feb 19.

Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.

Alva M Casey, Dylan G Ryan, Hiran A Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V Gruszczyk, Ming Yang, Dane M Wolf, Jan Lj Miljkovic, Joyce Valadares, Patrick F Chinnery, Richard C Hartley, Christian Frezza, Julien Prudent, Michael P Murphy.

Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

DOI: https://doi.org/10.1038/s42255-025-01224-x
Tissue Barriers. 2025 Feb 21. 2462357

Frataxin deficiency and the pathology of Friedreich's Ataxia across tissues.

Wesley S Ercanbrack, Mateo Ramirez, Austin Dungan, Ella Gaul, Sarah J Ercanbrack, Rebecca A Wingert.

  Friedreich's Ataxia (FRDA) is a neurodegenerative disease that affects a variety of different organ systems. The disease is caused by GAA repeat expansions in intron 1 of the Frataxin gene (FXN), which results in a decrease in the expression of the FXN protein. FXN is needed for the biogenesis of iron-sulfur clusters (ISC) which are required by key metabolic processes in the mitochondria. Without ISCs those processes do not occur properly. As a result, reactive oxygen species accumulate, and the mitochondria cease to function. Iron is also thought to accumulate in the cells of certain tissue types. These processes are thought to be intimately related to the pathologies affecting a myriad of tissues in FRDA. Most FRDA patients suffer from loss of motor control, cardiomyopathy, scoliosis, foot deformities, and diabetes. In this review, we discuss the known features of FRDA pathology and the current understanding about the basis of these alterations.

Keywords:  Central nervous system; Friedreich’s Ataxia; degeneration; dorsal root; frataxin; heart; kidney; pancreas; peripheral nervous system; scoliosis

DOI:  https://doi.org/10.1080/21688370.2025.2462357
Free Radic Biol Med. 2025 Feb 13. pii: S0891-5849(25)00087-5. [Epub ahead of print]

Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia.

Juan Wang, Rongjuan Zhao, Jing Ma, Jiangbo Qin, Huiqiu Zhang, Junhong Guo, Xueli Chang, Wei Zhang.

  Biallelic mutations in the FDXR are known to cause rare mitochondrial diseases. However, the underlying pathogenic mechanisms remain elusive. This study investigated a patient affected by optic atrophy, ataxia, and peripheral neuropathy resulting from compound heterozygous mutations in FDXR. Structural abnormalities in mitochondria were observed in muscle and nerve tissues. Lymphoblastic cell lines (LCLs) and muscle samples from the patient exhibited signs of mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation. Dysregulation of the glutathione peroxidase-4 was noted in the LCLs. Furthermore, treatment with deferoxamine, N-acetyl-cysteine, and ferrostatin-1 effectively alleviated oxidative stress and cell death. Cortical neurons demonstrate that FDXR deficiency impacts the morphogenesis of neurites. Collectively, these findings suggest that ferroptosis plays a significant role in the pathogenesis of FDXR-associated diseases. Additionally, idebenone appeared to have protective effects against various cellular injuries induced by FDXR mutations, providing novel insights and therapeutic approaches for the treatment of FDXR-associated diseases.

Keywords:  FDXR; ataxia; ferroptosis; idebenone; mitochondrial diseases

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.012
bioRxiv. 2025 Jan 31. pii: 2025.01.28.635306. [Epub ahead of print]

Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.

Caroline Trumpff, Qiuhan Huang, Jeremy Michelson, Cynthia C Liu, David Shire, Christian G Habeck, Yaakov Stern, Martin Picard.

Altered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1) cell-free mitochondrial DNA (cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2) growth differentiation factor 15 (GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.

DOI: https://doi.org/10.1101/2025.01.28.635306
Trends Mol Med. 2025 Feb 17. pii: S1471-4914(25)00015-2. [Epub ahead of print]

Gene therapies for neurogenetic disorders.

Orrin Devinsky, Jeff Coller, Rebecca Ahrens-Nicklas, X Shawn Liu, Nadav Ahituv, Beverly L Davidson, Kathie M Bishop, Yael Weiss, Ana Mingorance.

  Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.g., BBB-crossing capsids, engineered viral-like proteins, lipid nanoparticles (LNPs)] and novel therapeutic strategies (e.g., regulatory elements, novel RNA therapeutics, tRNA therapies, epigenetic and gene editing). Patient-led disease foundations have accelerated treatment development by addressing trial readiness and supporting translational research. We review the current landscape and future directions in developing gene therapies for neurogenetic disorders.

Keywords:  blood–brain barrier; gene regulation; gene therapy; neurological disorders

DOI:  https://doi.org/10.1016/j.molmed.2025.01.015
J Physiol. 2025 Feb 18.

Mitochondrial control of ciliary gene expression and structure in striatal neurons.

Dogukan H Ulgen, Alessandro Chioino, Olivia Zanoletti, Albert Quintana, Elisenda Sanz, Carmen Sandi.

  Mitochondria play essential metabolic roles and are increasingly understood to interact with other organelles, influencing cellular function and disease. Primary cilia, as sensory and signalling organelles, are crucial for neuronal communication and function. Emerging evidence suggests that mitochondria and primary cilia may interact to regulate cellular processes, as recently shown in brain cells such as astrocytes. Here, we investigated whether mitochondria also regulate primary cilia in neurons, focusing on molecular pathways linking both organelles and structural components within cilia. We employed a cross-species, molecular pathway-focused approach to explore connections between mitochondrial and ciliary pathways in neurons, revealing strong associations suggesting coordinated functionality. Furthermore, we found that viral-induced downregulation of the mitochondrial fusion gene mitofusin 2 (Mfn2) in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the nucleus accumbens (NAc) altered ciliary gene expression, with Crocc - the gene encoding rootletin - showing the most pronounced downregulation. This reduction in Crocc expression was linked to decreased levels of rootletin protein, a key structural component of the ciliary rootlet. Notably, viral-mediated overexpression of rootletin restored ciliary complexity and elongation, without compromising neuronal adaptation to Mfn2 downregulation. Our findings provide novel evidence of a functional mitochondria-cilia interaction in neurons, specifically in striatal D1-MSNs. These results reveal a previously unrecognized role of mitochondrial dynamics in regulating ciliary structure in neurons, with potential implications for neuropsychiatric and neurodegenerative disease mechanisms. KEY POINTS: Mitochondria are cell structures known for producing energy but are also emerging as regulators of other cellular components, including primary cilia, antenna-like structures involved in cell communication. Previous studies suggest that mitochondria may influence cilia structure and function, including in astrocytes. However, this has not been explored in neurons. This study shows that natural variation in mitochondrial molecular pathways correlates with primary cilia pathways in striatal medium spiny neurons in both rats and mice. Reducing expression of mitofusin 2 (Mfn2), a key mitochondrial protein involved in fusion and mitochondria-endoplasmic reticulum interactions, changes specific molecular ciliary pathways, notably including Crocc, a gene essential for cilia structure, and reduces the levels of its protein product, rootletin, which supports cilia integrity. Our findings reveal an important role for mitochondria in regulating ciliary structure in neurons, highlighting a potential pathway for mitochondrial regulation of neuronal signalling.

Keywords:  RiboTag sequencing; cilium; gene manipulation; mitochondria; mitofusin 2; single nucleus RNA sequencing

DOI:  https://doi.org/10.1113/JP287948
Sci Adv. 2025 Feb 21. 11(8): eadu3011

Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis.

Tatsuya Morishima, Md Fakruddin, Yohei Kanamori, Takeshi Masuda, Akiko Ogawa, Yuxin Wang, Vivien A C Schoonenberg, Falk Butter, Yuichiro Arima, Takaaki Akaike, Toshiro Moroishi, Kazuhito Tomizawa, Toshio Suda, Fan-Yan Wei, Hitoshi Takizawa.

Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with MTO1 gene mutation showed severe anemia led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in Mto1 cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.

DOI: https://doi.org/10.1126/sciadv.adu3011
Aging Dis. 2025 Feb 08.

Targeting Mitochondrial Integrity as a New Senolytic Strategy.

Eliska Vacurova, Edita Vlachova, Jan Stursa, Klara Bohacova, Tereza Havrlantova, Vojtech Skop, Barbora Judita Kasperova, Lukas Werner, Jiri Neuzil, Martin Haluzik, Sona Stemberkova Hubackova.

Aging, characterized by accumulation of senescent cells, is a driving factor of various age-related diseases. These conditions pose significant health risks globally due to their increasing prevalence and serious complications. Reduction of senescent cells therefore represents a promising strategy promoting healthy aging. Here we demonstrate that targeting tamoxifen to mitochondria via triphenyl and tricyclohexyl phosphine selectively eliminates senescent cells. Our findings show a complex effect of mitochondrially targeted tamoxifen on mitochondrial function and integrity of senescent cells, including inhibition of oxidative phosphorylation and activity of respiratory complex IV. These changes result in activation of ferroptosis as the major mode of cell death, which results in rejuvenation of tissues. Targeting mitochondria of senescent cells represents a general senolytic strategy and may extend the healthspan and improve the quality of life in aging populations.

DOI: https://doi.org/10.14336/AD.2024.1100
Cell Death Dis. 2025 Feb 14. 16(1): 99

Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.

Irene Pertici, Donato D'Angelo, Denis Vecellio Reane, Massimo Reconditi, Ilaria Morotti, Elena Putignano, Debora Napoli, Giorgia Rastelli, Gaia Gherardi, Agnese De Mario, Rosario Rizzuto, Simona Boncompagni, Laura Baroncelli, Marco Linari, Marco Caremani, Anna Raffaello.

Creatine (Cr) is essential for cellular energy homeostasis, particularly in muscle and brain tissues. Creatine Transporter Deficiency (CTD), an X-linked disorder caused by mutations in the SLC6A8 gene, disrupts Cr transport, leading to intellectual disability, speech delay, autism, epilepsy, and various non-neurological symptoms. In addition to neurological alterations, Creatine Transporter knockout (CrT-/y) mice exhibit severe muscle atrophy and functional impairments. This study provides the first characterization of the skeletal muscle phenotype in CrT-/y mice, revealing profound ultrastructural abnormalities accompanied by reduced fiber cross-sectional area and muscle performance. Notably, mitochondria are involved, as evidenced by disrupted cristae, increased mitochondrial size, impaired Ca2+ uptake, reduced membrane potential and ATP production. Mechanistically, the expression of atrophy-specific E3 ubiquitin ligases and suppression of the IGF1-Akt/PKB pathway, regulated by mitochondrial Ca2+ levels, further support the atrophic phenotype. These findings highlight the profound impact of Cr deficiency on skeletal muscle, emphasizing the need for targeted therapeutic strategies to address both the neurological and peripheral manifestations of CTD. Understanding the underlying mechanisms, particularly mitochondrial dysfunction, could lead to novel interventions for this disorder.

DOI: https://doi.org/10.1038/s41419-025-07381-x
Hum Gene Ther. 2025 Feb 20.

AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration.

Maria Carla Carisi, Claire Shamber, Martha Bishop, Madison Sangster, Uma Chandrachud, Brandon Meyerink, Louis Jean Pilaz, Yulia Grishchuk.

  Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the WDR45 gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurological decline with dystonia/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia. WDR45 encodes β-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays an important role in autophagosome formation. While the mechanisms of how WIPI4 loss of function results in neurological decline and brain pathology have not yet been established, findings of lower autophagic activity provide a direct link between impaired autophagy and neurological disease in BPAN. Here we performed phenotypical characterization of a novel mouse model of BPAN, Wdr45_ex9+1g>a mouse. We identified hyperactive behavior and reduction of autophagy markers in brain tissue in Wdr45_ex9+1g>a hemizygous males as early as at 2 months of age. Given the early onset and spectrum of neurological symptoms such as hyper-arousal and attention deficits in human patients, this model presents a disease-relevant phenotype and can be used in preclinical studies. We used this mouse model for a proof-of-concept study to evaluate whether adeno-associated virus (AAV)-mediated central nervous system (CNS)-targeted gene transfer of WDR45 can provide therapeutic benefit and be considered a therapeutic paradigm for BPAN. We observed successful expression of human WDR45 transcripts and WIPI4 protein in the brain tissue, rescue of hyperactive behavior, and correction of autophagy markers. These data demonstrate that WDR45 gene transfer can be a promising therapeutic strategy for BPAN.

Keywords:  WDR45; WIPI4; adeno-associated virus; autophagy; gene addition; gene transfer

DOI:  https://doi.org/10.1089/hum.2024.224
Cell Stem Cell. 2025 Feb 06. pii: S1934-5909(25)00006-2. [Epub ahead of print]

Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in Parkinson's disease.

Jeha Jeon, Young Cha, Yean Ju Hong, In-Hee Lee, Heejin Jang, Sanghyeok Ko, Serhiy Naumenko, Minseon Kim, Hannah L Ryu, Zenith Shrestha, Nayeon Lee, Tae-Yoon Park, HoeWon Park, Seo-Hyun Kim, Ki-Jun Yoon, Bin Song, Jeffrey Schweitzer, Todd M Herrington, Sek Won Kong, Bob Carter, Pierre Leblanc, Kwang-Soo Kim.

  Human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic cells (mDACs) represent a promising source for autologous cell therapy in Parkinson's disease (PD), but standardized regulatory criteria are essential for clinical translation. In this pre-clinical study, we generated multiple clinical-grade hiPSC lines from freshly biopsied fibroblasts of four sporadic PD patients using episomal reprogramming and differentiated them into mDACs using a refined 21-day protocol. Rigorous evaluations included whole-genome/exome sequencing, RNA sequencing, and in vivo studies, including a 39-week Good Laboratory Practice-compliant mouse safety study. While mDACs from all lines met safety criteria, mDACs from one patient failed to improve rodent behavioral outcomes, underscoring inter-individual variability. Importantly, in vitro assessments did not reliably predict in vivo efficacy, identifying dopaminergic fiber density as a key efficacy criterion. These findings support comprehensive quality control guidelines for autologous cell therapy and pave the way for a clinical trial with eight sporadic PD patients, scheduled to commence in 2025.

Keywords:  Parkinson's disease; autologous cell therapy; dopaminergic fiber density; genome integrity; human induced pluripotent stem cells; inter-individual variability; midbrain dopaminergic cells; phase 1 clinical trial; pre-clinical study; safety and efficacy

DOI:  https://doi.org/10.1016/j.stem.2025.01.006
Nat Commun. 2025 Feb 18. 16(1): 1750

iPSCs and iPSC-derived cells as a model of human genetic and epigenetic variation.

Kara Quaid, Xiaoyun Xing, Yi-Hsien Chen, Yong Miao, Amber Neilson, Vijayalingam Selvamani, Aaron Tran, Xiaoxia Cui, Ming Hu, Ting Wang.

Understanding the interaction between genetic and epigenetic variation remains a challenge due to confounding environmental factors. We propose that human induced Pluripotent Stem Cells (iPSCs) are an excellent model to study the relationship between genetic and epigenetic variation while controlling for environmental factors. In this study, we have created a comprehensive resource of high-quality genomic, epigenomic, and transcriptomic data from iPSC lines and three iPSC-derived cell types (neural stem cell (NSC), motor neuron, monocyte) from three healthy donors. We find that epigenetic variation is most strongly associated with genetic variation at the iPSC stage, and that relationship weakens as epigenetic variation increases in differentiated cells. Additionally, cell type is a stronger source of epigenetic variation than genetic variation. Further, we elucidate a utility of studying epigenetic variation in iPSCs and their derivatives for identifying important loci for GWAS studies and the cell types in which they may be acting.

DOI: https://doi.org/10.1038/s41467-025-56569-4