bims-mitmed 2025-12-28 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–12–28
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.
Targeted antisense oligonucleotide treatment rescues developmental alterations in spinal muscular atrophy organoids.
Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
Neuropathology of Friedreich ataxia and its links to metabolic pathways.
Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.
Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.
Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.
From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.
Unrecognized high prevalence of expanded composite repeats in Friedreich ataxia.
A systematic analysis of mitochondrial aminoacyl tRNA synthetase variants in a rare disease cohort.
Dynamic and differential renal cortical cell-specific mitochondrial metabolism in response to fasting.
Human midbrain organoids reveal the characteristics of axonal mitochondria specific to dopaminergic neurons.
Model organisms in POLG-related disorders: insights from yeast to multicellular systems.
A Novel Variant in the TAMM41-Associated Mitochondrial Myopathy.
Sequential development of three syndromes in a patient with m.3243A>G mutation: a case report.
Leveraging engineered mitochondria through intercellular communication network for accelerated transport and delivery.
A role for Fis1 in dendritic development.
Deciphering the PGC-1α-TFAM Axis in Parkinson's Disease (PD) - A Mechanism Approach Targeting Therapeutics for PD.
Targeting mitochondrial autophagy for anti-aging.
Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.
A new subset of mitochondrial-derived vesicles perform inter-mitochondrial communications.
Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
Integration of artificial intelligence and high-content screening enabled identification of drugs for long-term treatment of cerebral cavernous malformation disease.

EMBO Mol Med. 2025 Dec 22.

Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.

Sahitya Ranjan Biswas, Porter L Tomsick, Colin Kelly, Brooke A Lester, Julia P Milner, Sara N Henry, Yairis Soto, Samantha Brindley, Nicole DeFoor, Paul D Morton, Alicia M Pickrell.

  Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Loss of Complex I significantly impacted neural stem cell proliferation, neuronal and oligodendroglial progeny, lineage progression, and displayed overt differences in specific brain regions across postnatal development. Our findings show that these disruptions in all categories occur specifically within the subventricular zone and corpus callosum prior to the age when these mice experience neurodegeneration. Given that LS is considered a neurodegenerative disease, we propose that there are neurodevelopmental signatures predating classic diagnosis in LS.

Keywords:  Corpus Callosum; Leigh Syndrome; Neural Stem Cells; Postnatal Neurogenesis; Subventricular Zone

DOI:  https://doi.org/10.1038/s44321-025-00367-4
Nat Commun. 2025 Dec 21.

Targeted antisense oligonucleotide treatment rescues developmental alterations in spinal muscular atrophy organoids.

Irene Faravelli, Paola Rinchetti, Monica Tambalo, Illia Simutin, Lisa Mapelli, Sara Mancinelli, Matteo Miotto, Mafalda Rizzuti, Andrea D'Angelo, Chiara Cordiglieri, Giulia Forotti, Clelia Peano, Paolo Kunderfranco, Luca Calandriello, Giacomo P Comi, Elvezia Paraboschi, Eleonora Pali, Francesca Beatrice, Egidio D'Angelo, Serge Przedborski, Monica Nizzardo, Simona Lodato, Stefania Corti.

Spinal muscular atrophy (SMA) is a severe neurological disease caused by mutations in the SMN1 gene, characterized by early onset and degeneration of lower motor neurons. Understanding early neurodevelopmental defects in SMA is crucial for optimizing therapeutic interventions. Using spinal cord and cerebral organoids generated from multiple SMA type 1 male donors, we revealed widespread disease mechanisms beyond motor neuron degeneration. Single-cell transcriptomics uncovered pervasive alterations across neural populations, from progenitors to neurons, demonstrating SMN-dependent dysregulation of neuronal differentiation programs. Multi-electrode array (MEA) analysis identified consistent hyperexcitability in both spinal and brain organoids, establishing altered electrical properties as a central nervous system-wide feature of pathogenesis. Early administration of an optimized antisense oligonucleotide (ASO) that increased SMN levels rescued morphological and functional deficits in spinal cord organoids across different genetic backgrounds. Importantly, this early intervention precisely corrected aberrant splicing in here identified SMN1 targets enriched at critical nodes of neuronal differentiation. Our findings demonstrate that early developmental defects are core features of SMA pathogenesis that can be prevented by timely therapeutic intervention, providing insights for optimizing treatment strategies.

DOI: https://doi.org/10.1038/s41467-025-67725-1
Cell Rep. 2025 Dec 18. pii: S2211-1247(25)01499-8. [Epub ahead of print]45(1): 116727

Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.

Lilia Colina-Tenorio, Patrick Horten, Enzo Scifo, Susanne E Horvath, Rhena F U Klar, Chantal Priesnitz, Fabian den Brave, Martin van der Laan, Thomas Becker, Kuo Song, Heike Rampelt.

  Mitochondrial cytochrome c oxidase, complex IV (CIV) of the respiratory chain, is assembled in a modular fashion from mitochondrial as well as nuclear-encoded subunits, guided by numerous assembly factors. This intricate process is further complicated by the characteristic architecture of the inner mitochondrial membrane. The mitochondrial contact site and cristae organizing system (MICOS) maintains the stability of crista junctions that connect the cristae, the site of mitochondrial respiration, with the inner boundary membrane, where newly imported respiratory subunits first arrive. Here, we report that MICOS facilitates specific assembly steps of CIV and associates with intermediates of the Cox1 and Cox3 modules. Moreover, MICOS recruits a variety of assembly factors even in the absence of ongoing CIV biogenesis, directly or via the mitochondrial multifunctional assembly (MIMAS). Our results establish MICOS as an important agent in efficient respiratory chain assembly that promotes CIV biogenesis within the compartmentalized inner membrane architecture.

Keywords:  CP: Cell biology; CP: Metabolism; MICOS; MIMAS; Mic60; cristae; cytochrome c oxidase; mitochondria; protein assembly; respiratory chain

DOI:  https://doi.org/10.1016/j.celrep.2025.116727
Neurodegener Dis Manag. 2025 Dec 25. 1-12

Neuropathology of Friedreich ataxia and its links to metabolic pathways.

Elizabeth Mercado-Ayón, Michael P Lazaropoulos, Yesica Mercado-Ayón, David R Lynch.

  Frataxin is an evolutionarily conserved mitochondrial protein essential for energy metabolism. Biallelic GAA repeat expansions in the FXN gene reduce frataxin expression, causing Friedreich's ataxia. Frataxin deficiency impairs key mitochondrial metabolic enzymes, leading to widespread mitochondrial dysfunction with disrupted glucose and fatty acid oxidation. Although systemic mitochondrial dysfunction affects multiple organ systems, neurological deficits are the only feature uniformly observed in all FRDA patients. This review highlights recent insights into the neuropathology of FRDA, emphasizing the detailed developmental timing of neuroanatomical changes. It also focuses on selective mitochondrial metabolic pathways, including fatty acid metabolism, ceramide synthesis, and ketogenesis, which may underlie neuron-specific vulnerability and serve as potential targets for pharmacological or dietary intervention. The possibility of non-traditional interventions based on metabolic features of FRDA offers hope for ameliorating the severity of FRDA.

Keywords:  Frataxin; Friedreich ataxia; fatty acids; metabolism; mitochondrion; neuroanatomy

DOI:  https://doi.org/10.1080/17582024.2025.2607957
J Transl Med. 2025 Dec 23. 23(1): 1415

Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.

Lei Lyu, Beibei Qie, Yanjie He, Feilong Chen, Bao Liu.

  Mitochondria function as the primary energy hubs of cells and possess semi-autonomous genetic characteristic. Mutations in mitochondrial DNA (mtDNA) frequently lead to severe illness and even premature death. The rapid advancement of gene therapy offers promising potential for correcting such disorders. This review first aims to delineate the mechanisms of gene therapy strategies applicable to mitochondrial diseases, including the allotopic expression of mtDNA in the nucleus, mitochondrial-targeted nuclease cleavage, and mtDNA-targeted base editing. It also discusses in detail the clinical efficacy of mtDNA allotopic expression and the preclinical progress of other strategies. Furthermore, the unique physiological features of mitochondria, such as heteroplasmy and independent molecular transport mechanisms, pose distinct challenges for the clinical implementation of mitochondrial gene therapy strategies. Accordingly, this review elaborates on the current limitations of each approach. Finally, it highlights potential optimization directions to address these challenges, emphasizing that understanding heteroplasmy dynamics and their corresponding phenotypes, ensuring the safe delivery and tissue-specific expression of therapeutic elements, and maintaining long-term therapeutic specificity and efficiency are essential for the clinical translation of mitochondrial gene therapy.

Keywords:  Allotopic expression; Base editing; Mitochondrial DNA; Mitochondrial disorders; Nuclease

DOI:  https://doi.org/10.1186/s12967-025-07420-3
Mol Ther. 2025 Dec 24. pii: S1525-0016(25)01064-0. [Epub ahead of print]

Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.

Sandra R Bacman, Wendy Shoop, C Spencer Henley-Beasley, Rhese Thompson, Jose Domingo Barrera-Paez, Lise-Michelle Theard, Monica Rodriguez-Silva, Cassandra Gorsuch, Elisabeth R Barton, Carlos T Moraes.

Mitochondrial myopathies are often caused by heteroplasmic mutations in the mitochondrial DNA (mtDNA). In muscle, biochemical, pathological, and clinical impairments are observed only when the ratios of mutant/wild-type mtDNA are high. Because reductions in mutant mtDNA loads are essentially permanent, we reasoned that transient expression of a therapeutic mitochondrial nuclease could be sufficient to permanently alter heteroplasmy. We expressed a mitochondrial targeted gene editing nuclease (mitoARCUS) via intramuscular injection of lipid nanoparticle (LNP)/mRNA complexes in a mouse model of mtDNA disease (m.5024C>T in the mt-tRNAAla gene). Transient expression of mitoARCUS in the tibialis anterior (TA) led to a robust decrease in mtDNA mutation load which was maintained up to forty-two weeks after injection. A molecular marker of the mitochondrial defect in this model, namely low levels of mt-tRNAAla, were markedly improved in treated muscles. Muscle force assessment in situ after repeated stimulation showed that fatigability was improved in the treated TA. Finally, we showed that multi-muscle injections can alter mtDNA heteroplasmy essentially in whole limbs. These results demonstrate that transient expression of mitoARCUS via LNP/mRNA intramuscular injections have long-lasting positive effects in muscles afflicted with mitochondrial myopathy.

DOI: https://doi.org/10.1016/j.ymthe.2025.12.041
Front Neurol. 2025 ;16 1657852

Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.

Gülhan Karakaya Molla, Özlem Ünal Uzun, Hanım Babazade Agakisili, Emine Genç, Zümrüt Arslan Gülten, Tarık Yıldırım, Aydan Sezgin Ersoy, Belkıs Ak, Aliye Gülbahçe, Sevil Yıldız, Nafiye Emel Çakar, Meryem Karaca, Tanyel Zübarioğlu, Burcu Öztürk Hişmi, Şahin Erdöl, Hasan Önal, Bülent Kara, Gülden Fatma Gökçay.

   Introduction: Stroke-like episodes (SLE) are defined as events characterized by the sudden onset of neurological symptoms with clinical manifestations similar to those of a stroke. However, they are distinguished by the presence of radiological lesions that do not conform to single vascular territory. MELAS syndrome, which is characterized by metabolic encephalopathy, lactic acidosis, and SLE, has been identified as the first genetically defined and most widely known mitochondrial cause of SLE. It has been demonstrated that SLE may occur in the course of a variety of mitochondrial diseases, including those that are the result of nuclear DNA mutations.
Objective: In this retrospective, multicenter, observational cohort study, we sought to determine the clinical, radiological, EEG, and genetic characteristics of patients with mitochondrial gene mutations presenting with SLE and the frequency and treatment of SLE.
Methods: Thirty-four patients with a genetically diagnosed mitochondrial disease from 9 paediatric metabolic disease centres in the Marmara Region of Turkey were included in the study, of whom 13 pateints had SLEs. Demographic characteristics, symptoms, clinical features, cranial MRI, EEG findings, and genetic characteristics were evaluated.
Conclusion: In this study, stroke-like episodes in genetically defined mitochondrial disorders were most frequently observed in MELAS and POLG mutations, and rarely in CoQ10 deficiency, Leigh syndrome cases. Cranial MRI findings are often frontotemporal in location and inconsistent with vascular distribution, and focal epileptiform activity on EEG are diagnostically significant. In MELAS, clinical improvement was observed in patients when L-arginine was initiated in the acute period. The findings emphasise that SLE should be evaluated in the differential diagnosis of sudden onset neurological symptoms in mitochondrial diseases.

Keywords:  CoQ10 deficiency; MELAS; POLG mutations; mitochondrial diseases; stroke-like episodes

DOI:  https://doi.org/10.3389/fneur.2025.1657852
J Child Neurol. 2025 Dec 23. 8830738251404115

From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.

Sofia Corbaz, Daniela Alejandra Pibernus, Mariana Amina Loos, María Mercedes Pérez, María Celeste Buompadre, Francisco Martín García, María Paula Rodriguez, Carlos Rugilo, Marisa Armeno, Go Hun Seo, Rin Khang, Cristina Noemi Alonso, Hilda Verónica Aráoz.

  Pyruvate dehydrogenase complex (PDC) deficiency is a rare mitochondrial disorder characterized by impaired oxidative metabolism, predominantly due to pathogenic variants in the PDHA1 gene. We present the clinical, biochemical, radiologic, and molecular characterization of 4 Argentine pediatric patients with PDHA1-related PDC deficiency, including a novel missense variant, c.260T>C p.(Ile87Thr). Clinical presentations ranged from severe neonatal encephalopathy with central apneas to a more slowly progressive neurodegenerative course in childhood. All patients exhibited lactic acidosis and structural brain abnormalities, with 3 fulfilling criteria for Leigh syndrome. Molecular studies identified 4 missense variants located in conserved regions of the E1α subunit. In silico analysis of the novel p.(Ile87Thr) variant suggested impaired thiamine pyrophosphate binding. All patients received thiamine and a ketogenic diet, with favorable outcomes in seizure control, neurodevelopment, and metabolic stability. Our findings expand the clinical and molecular spectrum of PDHA1-related PDC deficiency and underscore the importance of early diagnosis and targeted metabolic therapy. Furthermore, we report a previously undescribed radiologic pattern in one patient and propose potential structural implications of the novel variant based on protein modeling.

Keywords:  Ketogenic diet; Leigh syndrome; PDHA1; mitochondrial disease; pyruvate dehydrogenase deficiency

DOI:  https://doi.org/10.1177/08830738251404115
Hum Mol Genet. 2025 Dec 23. pii: ddaf190. [Epub ahead of print]

Unrecognized high prevalence of expanded composite repeats in Friedreich ataxia.

Morgan C Devore, Christina Lam, Graham Wiley, Courtney C Park, David R Lynch, Sanjay I Bidichandani.

  Many diseases are caused by pathogenic expansion of microsatellite repeats. Longread sequencing allows evaluation of the content of such expanded repeats. Friedreich ataxia patients are typically homozygous for an expanded GAA repeat in intron 1 of the FXN gene. Longread whole genome sequencing identified expanded composite alleles, consisting of substantial tracks of tandem GGA triplets within the expanded GAA repeat. In a prospective series of 112 unrelated patients, we found that approximately 20% of people with Friedreich ataxia have at least one such expanded composite allele. Other minor sequence interruptions in the expanded GAA repeat were detected in a further 10% of patients. Most expanded composite alleles revealed by longread genome sequencing are not detectable by standard PCR-based testing, and have therefore remained hidden despite their relatively high prevalence. This results in erroneous genotyping of patients and heterozygous carriers. We describe an optimized workflow to detect these expanded composite alleles, which permitted accurate genotyping and heterozygous carrier identification. A recurrent proximal FXN gene deletion caused by Alu-mediated non-homologous recombination was identified in an additional 2% of patients. These findings redefine the spectrum of pathogenic alleles in Friedreich ataxia, and demonstrate that expanded alleles containing substantial non-GAA interruptions are prevalent and pathogenic.

Keywords:   Alu-mediated recombination; Friedreich ataxia; composite repeat; genotyping errors; proximal FXN deletion

DOI:  https://doi.org/10.1093/hmg/ddaf190
Eur J Hum Genet. 2025 Dec 27.

A systematic analysis of mitochondrial aminoacyl tRNA synthetase variants in a rare disease cohort.

Thiloka E Ratnaike, M Eren Kule, Ida Paramonov, Leslie Matalonga, Kiran Polavarapu, Catarina Olimpio, Rita Horváth.

Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a group of proteins encoded by nuclear DNA that play a crucial role in mitochondrial protein synthesis. Mitochondrial diseases caused by mt-aaRS variants are phenotypically heterogenous but often present with significant neurological features such as childhood-onset encephalopathy and seizures. As such, these conditions are a diagnostic challenge. We present an approach that systematically quantifies phenotypic similarity of individuals with an mt-aaRS variant to published cases, to aid variant interpretation, in RD-Connect-a large Europe-wide rare disease cohort. Across 98 individuals with a mt-aaRS gene of interest, we prioritised 38 individuals with 63 variants following bioinformatic and manual analyses. We additionally reviewed Exomiser prioritisation using a pre-defined gene list for neurological disorders within the RD-Connect Genome-Phenome Analysis Platform (GPAP). We were able to generate likely diagnoses in 11 individuals and VUS findings in 13 individuals, following careful phenotype similarity analysis using a phenotype-genotype dataset generated from 234 published individuals. Four of these 24 individuals did not have an Exomiser-ranked gene variant in the GPAP. Therefore, this approach, using individual-level curated phenotype-genotype data to support variant interpretation, can highlight potentially significant variants that may not be captured by current pipelines. This workflow can be replicated in other heterogeneous rare diseases to support clinical practice.

DOI: https://doi.org/10.1038/s41431-025-01990-y
Am J Physiol Renal Physiol. 2025 Dec 22.

Dynamic and differential renal cortical cell-specific mitochondrial metabolism in response to fasting.

Kyle Feola, Andrea Henning Venable, Mina Rasouli, Julie Do, Tatyana Broomfield, Claire Llamas, Dana Straus, Joshua C Russell, Prashant Mishra, Behzad Najafian, Sarah C Huen.

  The metabolic health of the kidney is directly correlated to the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel the diverse functions of the kidney is limited by the kidney's structural and functional heterogeneity, especially in key metabolic organelles like the mitochondria. As the kidney contains many different cell types, we sought to determine the intra-renal mitochondrial heterogeneity that contributes to cell-specific metabolism. To interrogate this, we utilized a recently developed mitochondrial tagging technique, MITO-Tag, to isolate kidney cell-type specific mitochondria. Here, we investigated mitochondrial functional capacities and the metabolomes of the early and late proximal tubule (PT) and the distal convoluted tubule (DCT). The conditional MITO-Tag transgene was combined with Slc34a1-CreERT2, Ggt1-Cre, or Pvalb-Cre transgenes to generate mouse models capable of cell-specific isolation of hemagglutinin (HA)-tagged mitochondria from the early PT, late PT, or the DCT, respectively. Functional assays measuring mitochondrial respiratory and fatty acid oxidation (FAO) capacities and metabolomics were performed on anti-HA immunoprecipitated mitochondria from kidneys of ad libitum fed and 24-hour fasted male mice. The renal MITO-Tag models targeting the early PT, late PT, and DCT revealed differential mitochondrial respiratory and FAO capacities which dynamically changed during fasting conditions. The renal MITO-Tag model captured differential mitochondrial metabolism and functional capacities across the early PT, late PT, and DCT at baseline and in response to fasting.

Keywords:  cellular metabolic heterogeneity; kidney; metabolism; mitochondria; tubular epithelium

DOI:  https://doi.org/10.1152/ajprenal.00235.2025
Mol Brain. 2025 Dec 25.

Human midbrain organoids reveal the characteristics of axonal mitochondria specific to dopaminergic neurons.

Akihiko Nishijima, Mutsumi Yokota, Soichiro Kakuta, Akihiro Yamaguchi, Kei-Ichi Ishikawa, Hideyuki Okano, Wado Akamatsu, Nobutaka Hattori, Masato Koike.

  Mitochondrial dysfunction and abnormalities in mitochondrial quality control contribute to the development of neurodegenerative diseases. Parkinson's disease is a neurodegenerative disease that causes motor problems mainly due to the loss of dopaminergic neurons in the substantia nigra pars compacta. Axonal mitochondria in neurons reportedly differ in properties and morphologies from mitochondria in somata or dendrites. However, the function and morphology of axonal mitochondria in human dopaminergic neurons remain poorly understood. To define the function and morphology of axonal mitochondria in human dopaminergic neurons, we newly generated tyrosine hydroxylase (TH) reporter (TH-GFP) induced pluripotent stem cell (iPSC) lines from one control and one PRKN-mutant patient iPSC lines and differentiated these iPSC lines into dopaminergic neurons in two-dimensional monolayer cultures or three-dimensional midbrain organoids. Immunostainings with antibodies against axonal and dendritic markers showed that axons could be better distinguished from dendrites of dopaminergic neurons in the peripheral area of three-dimensional midbrain organoids than in two-dimensional monolayers. Live-cell imaging and correlative light-electron microscopy in peripheral areas of midbrain organoids derived from control TH-GFP iPSCs demonstrated that axonal mitochondria in dopaminergic neurons had lower membrane potential and were shorter in length than those in non-dopaminergic neurons. Although the mitochondrial membrane potential did not significantly differ between dopaminergic and non-dopaminergic neurons derived from PRKN-mutant patient lines, these differences tended to be similar to those in control lines. These results were also largely consistent with those of our previous study on somatic mitochondria. The findings of the present study indicate that midbrain organoids are an effective tool to distinguish axonal from dendritic mitochondria in dopaminergic neurons. This may facilitate the analysis of axonal mitochondria to provide further insights into the mechanisms of dopaminergic neuron degeneration in patients with Parkinson's disease.

Keywords:  Axonal mitochondria; Dopaminergic neurons; Electron microscopy; Live-cell imaging; Midbrain organoids

DOI:  https://doi.org/10.1186/s13041-025-01268-w
Cell Death Dis. 2025 Dec 26.

Model organisms in POLG-related disorders: insights from yeast to multicellular systems.

Raquel Brañas Casas, Giovanni Risato, Alessandro Zuppardo, Carlo Viscomi, Francesco Argenton, Mara Doimo, Nicola Facchinello, Natascia Tiso.

Mitochondrial genetic diseases are complex disorders that impair cellular energy production, leading to diverse clinical manifestations across multiple organ systems. These diseases arise from mutations in either mitochondrial DNA or nuclear DNA. Among nuclear DNA-related cases, mutations in POLG and POLG2, which encode subunits of mitochondrial DNA polymerase γ, are particularly significant, causing conditions such as Alpers-Huttenlocher syndrome and progressive external ophthalmoplegia. Model organisms have been instrumental in elucidating POLG-related disease mechanisms and advancing therapeutic strategies. Saccharomyces cerevisiae (budding yeast) provided insights into fundamental mitochondrial functions, while Caenorhabditis elegans (roundworm) helped explore POLG's roles in multicellular organisms. Drosophila melanogaster (fruit fly) has been pivotal in studying neurological aspects, and Mus musculus (mouse) models contributed to understanding systemic effects in mammals. Recently, Danio rerio (zebrafish) has emerged as a promising vertebrate model for drug screening, due to its optical transparency and genetic tractability. Each model system offers unique advantages, collectively bridging the gap between basic research and clinical applications. This review will examine in vivo models used in POLG disorder research, highlighting their contributions to understanding disease mechanisms and therapeutic advancements.

DOI: https://doi.org/10.1038/s41419-025-08366-6
Am J Med Genet A. 2025 Dec 23.

A Novel Variant in the TAMM41-Associated Mitochondrial Myopathy.

Cristiane Araujo Martins Moreno, Clara Camelo Gontijo, Alulin Tacio Quadros Santos Monteiro Fonseca, Rita Horvath, David Schlesinger, Edmar Zanoteli.

Pathogenic variants in TAMM41 were recently linked to mitochondrial myopathy, presenting with neonatal hypotonia, generalized weakness, developmental delay, ptosis, and ophthalmoparesis. Here, we present a long-term follow-up of an additional case, a Brazilian patient harboring a novel TAMM41 variant in compound heterozygosity with a previously described pathogenic variant. Patient exhibited mild developmental delay, acquired independent gait, but subsequently developed motor regression and weakness associated with recurrent infections, severe axial involvement, and marked restrictive pulmonary dysfunction. Muscle biopsy revealed decreased COX and SDH staining, which may serve as an important diagnostic clue for this condition. This case expanded the genetic spectrum of TAMM41-related mitochondrial myopathy and provided a brief review of disorders associated with reduced SDH staining.

DOI: https://doi.org/10.1002/ajmga.70034
Front Med. 2025 Dec 26.

Sequential development of three syndromes in a patient with m.3243A>G mutation: a case report.

Guoling Zeng, Rongpei Liu, Xiaotian Li, Zhaoqi Lv, Lei Cui, Xiong Zhang, Jianyong Wang.

  Mitochondrial disorders are highly heterogeneous and can manifest as a spectrum of clinically heterogeneous disorders that affect multiple organ systems. Herein, we report a Chinese female patient carrying mitochondrial DNA m.3243A>G mutation who sequentially experienced myoclonic epilepsy with ragged red fibers, mitochondrial neurogastrointestinal encephalomyopathy, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. This report expands the current understanding of phenotypic heterogeneity in mitochondrial disorders.

Keywords:  m.3243A>G; mitochondrial disorders; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); myoclonic epilepsy with ragged red fibers (MERRF)

DOI:  https://doi.org/10.1007/s11684-025-1186-7
Nat Commun. 2025 Dec 23.

Leveraging engineered mitochondria through intercellular communication network for accelerated transport and delivery.

Yiwei Peng, Datong Gao, Yiliang Yang, Yitian Du, Zhenzhen Yang, Jiajia Li, Meng Lin, Yanxia Zhou, Xinru Li, Xianrong Qi.

Inspired by the non-transmembrane transfer of mitochondria in cell-to-cell communications, herein, we report an original exploration to accelerate mitochondrial intercellular transport, and its application to exogenous cargo delivery. We discover that deliberate PINK1-targeted mitophagy downregulation elevates mitochondrial transit capacity via multifaceted drivers-morphological adaptation, metabolic reprogramming, and respiratory enhancement. Capitalizing on this, we engineer high-speed mitochondrial vehicles for photosensitizer hitchhiking, with spatiotemporal tracking elucidating its dynamic intercellular transit and physiological impacts. Through mitochondria's communication network-tunneling nanotubes (TNTs), the mitochondria-photosensitizer cotransporter achieves reinforced intercellular delivery, thereby inducing deep tumor penetration and enhanced photodynamic killing. Our work establishes a transformative mitochondria-hitchhiking platform for overcoming biological barriers in drug delivery and provides mechanistic insights into manipulating intercellular organelle transport for therapeutic applications.

DOI: https://doi.org/10.1038/s41467-025-67837-8
Sci Rep. 2025 Dec 23.

A role for Fis1 in dendritic development.

Klaudia Strucinska, Parker Kneis, Travis Pennington, Katarzyna Cizio, Patrycja Szybowska, Abigail Morgan, Joshua Weertman, Tommy L Lewis.

Mitochondrial ATP production and calcium handling are critical for metabolic regulation and neurotransmission. Thus, the formation and maintenance of the mitochondrial network is a critical component of neuronal health. Cortical pyramidal neurons contain compartment-specific mitochondrial morphologies that result from distinct axonal and dendritic mitochondrial fission and fusion profiles. We previously revealed that axonal mitochondria are maintained at a small size as a result of high axonal mitochondrial fission factor (Mff) activity. However, loss of Mff activity had little effect on cortical dendritic mitochondria, raising the question of how fission/fusion balance is controlled in the dendrites. Therefore, we sought to investigate the role of another fission factor, fission 1 (Fis1), on mitochondrial morphology, dynamics and function in cortical neurons. We knocked down Fis1 in cortical neurons both in primary culture and in vivo, and unexpectedly found that Fis1 depletion decreased mitochondrial length in the dendrites, without affecting mitochondrial size in the axon. Further, loss of Fis1 activity resulted in both increased mitochondrial motility and dynamics in the dendrites. These results argue Fis1 exhibits dendrite selectivity and plays a more complex role in neuronal mitochondrial dynamics than previously reported. Functionally, Fis1 loss resulted in reduced mitochondrial membrane potential, increased sensitivity to complex III blockade, and decreased mitochondrial calcium uptake during neuronal activity. The altered mitochondrial network culminated in elevated resting calcium levels that increased dendritic branching but reduced spine density. We conclude that Fis1 activity regulates mitochondrial morphological and functional features that influence dendritic tree arborization and connectivity.

DOI: https://doi.org/10.1038/s41598-025-33557-8
Mol Neurobiol. 2025 Dec 27. 63(1): 329

Deciphering the PGC-1α-TFAM Axis in Parkinson's Disease (PD) - A Mechanism Approach Targeting Therapeutics for PD.

Mahalaxmi Iyer, Masako Kinoshita, Dibbanti HariKrishna Reddy, Harysh Winster Suresh Babu, Vikas Lakhanpal, Mukesh Kumar Yadav, Jayalakshmi Krishnan, Vignesh Palanivel, Salmanul Faris, Khushboo Chauhan, Balachandar Vellingiri.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in dopamine depletion and impaired motor function. Growing evidence implicates mitochondrial dysfunction as a central driver of PD pathogenesis with many PD-associated genes and proteins localized are localized near mitochondria and they also have major functions in proper functioning of mitochondria. Among mitochondrial regulators, the transcriptional co-activator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) orchestrates oxidative stress response, mitochondrial biogenesis and inflammatory pathways whereas mitochondrial transcription factor A (TFAM) is essential for maintaining mitochondrial DNA (mtDNA) integrity and copy number variations. Dysregulation of TFAM contributes to mtDNA stress mediated oxidative stress and neurodegeneration whereas experimental studies demonstrate that TFAM overexpression or enzyme replacement enhances neuronal survival and functions. Therefore, in this review we have highlighted the PGC-1α-TFAM regulatory axis as a central hub linking mitochondrial dysfunction, neuroinflammation and oxidative stress in PD. We further discuss therapeutic opportunities aimed at modulating PGC-1α and TFAM to restore mitochondrial homeostasis, underscoring their potential as promising yet underexplored targets for slowing or halting PD progression.

Keywords:  Mitochondria; PGC-1α; Parkinson’s Disease; TFAM; Therapeutics

DOI:  https://doi.org/10.1007/s12035-025-05611-z
Cell Death Discov. 2025 Dec 24.

Targeting mitochondrial autophagy for anti-aging.

Wenjun Shan, Yuling Liu, Ruying Tang, Longfei Lin, Hui Li, Hongjun Yang.

Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1). During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.

DOI: https://doi.org/10.1038/s41420-025-02913-y
Cell Death Discov. 2025 Dec 20.

Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.

Ping Zhang, Peng Huang, Qiongye Dong, Juan Luo, Guanghui Cui, Xin Guo, Minghua Li, Xia Long, Hongyu Zhang, Wei V Zheng, Peng Cui.

Parkinson's disease (PD) is a challenging neurodegenerative disorder. Recently, therapy of neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) has emerged as a significant advancement in regenerative medicine. Melatonin (MT), acting as a mitochondrial targeting hormone, exhibits neuroprotective properties in neurodegenerative diseases and modulates stem cell differentiation through mitochondrial dynamics. However, the precise mechanism by which MT influences dopaminergic (DA) neuronal differentiation in hiPSCs through regulating mitochondrial dynamics remains unclear. In this study, we developed and optimized a technical protocol for the in vitro functional neuronal differentiation of hiPSCs. Our findings demonstrate that MT enhances the differentiation potential of hiPSCs toward neuroectoderm and significantly improves the efficiency of NSCs differentiation into DA neurons by more than three times within hiPSCs. Using the specific MT receptor inhibitor, Luzindole, we confirmed its inhibitory effect on MT-mediated promotion of neural differentiation. Mechanistically, we propose that MT enhances functional DA neuron differentiation from hiPSCs by activating mitochondrial dynamics-mediated WNT/β-catenin signaling pathways. Additionally, we elucidated the critical role of mitofusin2 (MFN2) in enhancing the directed differentiation of DA neurons from hiPSCs. In vivo studies validated the efficacy of MT-treated hiPSC-derived DA progenitor cells in regenerating tyrosine hydroxylase (TH)-positive DA neurons and improving motor function in a MPTP-induced mouse model of Parkinson's disease. In conclusion, this study highlights the potential clinical relevance of MT-enhanced differentiation of hiPSCs into DA neurons, offering promising implications for the treatment of PD.Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.

DOI: https://doi.org/10.1038/s41420-025-02906-x
Mol Biol Cell. 2025 Dec 24. mbcE25040188

A new subset of mitochondrial-derived vesicles perform inter-mitochondrial communications.

Priyanka Adla, Vani Bshivakumar, Dheeraj Pathak, Ushodaya Mattam, Prasad Tammineni, Thanuja Krishnamoorthy, Naresh B V Sepuri.

Mitochondria have a fascinating array of tools in their armory for maintaining cellular homeostasis, of which the formation of Mitochondrial-Derived Vesicles (MDVs) is the least energy-intensive. MDVs have become the 'go-to' vesicles for mitochondria to perform functions such as ferrying damaged mitochondrial proteins to lysosomes and regulating peroxisomal morphology. In a corollary to the increasing number of MDV functions, the discovery of MDV subsets has also increased. However, all the known MDV communications have been from mitochondria to other organelles. Using purified mitochondria from rat liver, we show that MDVs can be generated in vitro, and proteomic analyses reveal that liver MDVs are enriched in metabolic proteins mirroring the liver's metabolic hub status. Intriguingly, live cell imaging studies in HepG2 cells reveal a new subset of MDVs that are TOMM70+ve but TOMM20-ve. This subset of MDVs harbors metabolic enzymes, such as ALDH7A1, an aldehyde dehydrogenase. Remarkably, this class of MDVs facilitates communication between mitochondria, revealing a previously unknown communication channel. [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-04-0188
Epigenomics. 2025 Dec 23. 1-18

Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.

Phyo W Win, Julia Nguyen, Elly H Shin, Tyler S Nagano, Brent Selimi, Katie Hong, Anahita M Meybodi, Bradley P Yates, Emma V Burke, David E Carter, Gregory A Newby, Charles Newcomb, Dan E Arking, Christina A Castellani.

   AIMS: Mitochondrial DNA copy number (mtDNA-CN) is associated with several age-related chronic diseases and is a predictor of all-cause mortality. Here, we examine site-specific differential nuclear DNA (nDNA) methylation and differential gene expression resulting from in vitro reduction of mtDNA-CN to uncover shared genes and biological pathways mediating the effect of mtDNA-CN on disease.
MATERIALS AND METHODS: Epigenome and transcriptome profiles were generated for three independent human embryonic kidney (HEK293T) cell lines harboring a mitochondrial transcription factor A (TFAM) knockout generated via CRISPR-Cas9, and matched control lines.
RESULTS: We identified 2924 differentially methylated sites, 67 differentially methylated regions, and 102 differentially expressed genes associated with mtDNA-CN. Integrated analysis uncovered 24 Gene-CpG pairs. GABAA receptor genes and related pathways, the neuroactive ligand signaling pathway, ABCD1/2 gene activity, and cell signaling processes were overrepresented, providing insight into the underlying biological mechanisms facilitating these associations. We also report evidence implicating chromatin state regulatory mechanisms as modulators of mtDNA-CN effect on gene expression.
CONCLUSIONS: We demonstrate that mitochondrial DNA variation signals to the nuclear DNA epigenome and transcriptome and may lead to nuclear remodeling relevant to development, aging, and complex disease.

Keywords:  Mitochondria; epigenome; mitochondrial DNA; mitochondrial DNA copy number; transcriptome

DOI:  https://doi.org/10.1080/17501911.2025.2603883
Autophagy. 2025 Dec 26.

Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.

Ang Li, Shu-Qin Cao, Evandro F Fang, Huanxing Su.

  Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in EMBO Molecular Medicine demonstrates that PINK1-PRKN-dependent mitophagy is markedly impaired in ALS motor neurons. Through high-content drug screening, we identified a potent mitophagy agonist isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba that stabilizes the PINK1-TOMM complex on the outer mitochondrial membrane, enhances PINK1-PRKN-dependent mitophagy, and ameliorates motor neuron degeneration in ALS-like Caenorhabditis elegans, mouse models, and induced pluripotent stem cell-derived motor neurons. Consequently, ISO is able to alleviate ALS-associated phenotypes. In this commentary, we contextualize these findings broadly to discuss whether pharmacologically induced mitophagy can act as an effective therapeutic strategy, distinct from current clinical approaches, for the development of ALS-targeted treatments.

Keywords:  ALS; PINK1-Parkin; isoginkgetin; mitophagy; motor neurons

DOI:  https://doi.org/10.1080/15548627.2025.2610450
bioRxiv. 2025 Dec 11. pii: 2025.12.08.693036. [Epub ahead of print]

Integration of artificial intelligence and high-content screening enabled identification of drugs for long-term treatment of cerebral cavernous malformation disease.

Eduardo Frias-Anaya, Helios Gallego-Gutierrez, Cassandra Bui, Janeth Ochoa Birrueta, Jeffrey Steinberg, Ingrid Reynolds Niesman, Brendan Gongol, Brina Nguyen, Aaryaman Sawhney, Zaida Mizushima, Nyle Connolly, Bethan Kilpatrick, Issam A Awad, Hemal H Patel, JoAnn Trejo, Jeremiah D Momper, Andrea Taddei, Miguel Alejandro Lopez-Ramirez.

Background: Adults and children with cerebral cavernous malformations (CCMs) are at risk of experiencing lifelong complications such as hemorrhagic strokes, neurological deficits, and epileptic seizures. These complications can severely reduce quality of life. At present, there is no safe or effective therapeutic option for the long-term treatment of CCMs.
Methods: Using advanced artificial intelligence (AI) and machine learning models, powered by the Benevolent Platform™, we aimed to identify therapeutic drug targets for CCM pathology (e.g., CCM1, CCM2, CCM3). An AI integrative approach utilized various data types from biomedical entities, including diseases, genes, tissues, and biological mechanisms, together with CCM transcriptomic experimental data. High-throughput drug screening of AI-selected FDA-approved medications, analyses of mitochondrial morphology, and studies on pharmacokinetics, pharmacodynamics, and toxicology were conducted in CCM animal models to identify drugs that could potentially be repurposed for the long-term treatment of CCM disease.
Results: AI predicted the AMPK (AMP-activated protein kinase) and mTOR (mammalian target of rapamycin) pathways as potential therapeutic targets that contribute to CCM pathology. High-content screening validation revealed that the FDA-approved drug metformin, which acts as an AMPK agonist and mTOR inhibitor, can reverse changes in cell-cell junction organization and increase KLF4 expression, a marker for CCM, in human CCM endothelial cells in cultured assays. In addition, pharmacodynamic markers of metformin were observed in CCM mouse models ( Slco1c1-iCreERT2;Krit1 fl/fl ;Pten fl/wt and Slco1c1-iCreERT2;Pdcd10 fl/fl ) including reduced S6 kinase or ribosomal protein phosphorylation, a marker of decrease mTOR signaling, and increased AMPK phosphorylation, a marker of AMPK activation, that corresponded to reduced lesion burden. Pharmacokinetic and toxicological studies in CCM animal models showed that that metformin penetrates the brain and long-term administration has a favorable safety profile. We also demonstrated that brain endothelial cells in chronic CCM mouse models exhibit increased levels of the inflammatory marker VCAM-1, which is associated with altered mitochondrial phenotypes, as observed by immunofluorescence, MITO-tagging, and electron microscopy analysis. Additionally, we discovered that metformin and a potent AMPK activator, PF-06409577, can reverse mitochondrial phenotypic changes in brain endothelial cells and reduce the elevation of VCAM-1 expression associated with chronic CCM disease. Therefore, metformin can provide cytoprotection and may reverse the CCM endothelial phenotype by activating AMPK.
Conclusions: Predictions using AI technology and high-throughput drug screening, combined with pharmacokinetic, pharmacodynamic, and toxicological studies in CCM animal models, identified metformin as a promising drug candidate for repurposing for the long-term treatment of CCM disease. We propose that metformin enhances metabolic adaptation to brain vascular malformations by activating AMPK, which helps reverse mitochondrial fragmentation in brain endothelial cells.
Graphical abstract:

DOI: https://doi.org/10.64898/2025.12.08.693036