Mitochondrion[JOURNAL]
Sun
200 papers
Quantitative proteomic profiling of neural cells-specific metabolic reprogramming in response to mitochondrial dysfunction using iMPAQT2.
Tani A, Yagi M, Horiuchi N … +5 more , Nagata K, Tanaka T, Kittaka H, Igami K, Uchiumi T
Mitochondrion · 2026 Sep · PMID 42140371 · Publisher ↗
Age-related mitochondrial dysfunction is increasingly recognized as a key contributor to neurodegenerative disease pathogenesis. In the central nervous system, neurons, oligodendrocytes, and astrocytes which derived from...
Age-related mitochondrial dysfunction is increasingly recognized as a key contributor to neurodegenerative disease pathogenesis. In the central nervous system, neurons, oligodendrocytes, and astrocytes which derived from neural stem cells, fulfill distinct metabolic and functional roles. However, the specific vulnerabilities of these cell types to mitochondrial impairment remain unclear. In this study, we employed the iMPAQT2 proteomics platform to systematically compare the metabolic profiles of neurons, oligodendrocytes, and astrocytes, and to elucidate the molecular consequences of mitochondrial dysfunction induced by chloramphenicol and oligomycin. Our findings indicate that neurons and oligodendrocytes primarily rely on oxidative phosphorylation (OXPHOS) for ATP production, whereas astrocytes predominantly utilize glycolysis. It is noteworthy that oligodendrocytes exhibited enriched pathways for cholesterol synthesis, fatty acid degradation, and heme catabolism-processes that are critical for myelin maintenance. Treatment with the mitochondrial function inhibitors chloramphenicol or oligomycin reduced the expression of OXPHOS enzymes in all cell types. This reduction was particularly pronounced in oligodendrocytes for glycolysis, cholesterol synthesis, heme degradation, and fatty acid degradation. These results suggest that oligodendrocytes are particularly vulnerable to mitochondrial dysfunction, which may play a pivotal role in the pathogenesis of age-related neurodegenerative disorders.
Predicting recurrence risk of Leigh syndrome using prenatal mtDNA heteroplasmy assessment.
Shishimorova M, Ma H, Koski A … +14 more , Dyken CV, Gutierrez NM, Frana D, Li Y, Eyberg D, Tevkin S, Hayama T, Kang E, Amato P, Havlin K, Goodier C, Newman R, Shields S, Mitalipov S
Mitochondrion · 2026 Sep · PMID 42134429 · Publisher ↗
Predicting recurrence risk for mitochondrial DNA (mtDNA) disorders is challenging because heteroplasmy levels can shift during development. We examined whether prenatal heteroplasmy measurements predict postnatal outcome...
Predicting recurrence risk for mitochondrial DNA (mtDNA) disorders is challenging because heteroplasmy levels can shift during development. We examined whether prenatal heteroplasmy measurements predict postnatal outcomes for the pathogenic m.13513G > A variant associated with Leigh syndrome. In a longitudinal family-based study involving three naturally conceived pregnancies, mtDNA heteroplasmy was assessed by chorionic villus sampling at 10-12 weeks of gestation and, when available, amniocentesis at 16 weeks, with follow-up in neonatal and postnatal tissues. Prenatal heteroplasmy levels below ∼30% were associated with unaffected outcomes, whereas an affected sibling exhibited near-homoplasmic variant loads in critical organs. These findings suggest prenatal heteroplasmy assessment may inform recurrence risk for the mtDNA m.13513G > A disorder.
Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.
Sugiura A, Nakamura K, McBride HM … +1 more , Okazaki Y
Mitochondrion · 2026 Sep · PMID 42128214 · Publisher ↗
Mitochondrial-derived vesicles (MDVs) mediate selective trafficking of mitochondrial proteins and lipids to other organelles and contribute to organelle communication and mitochondrial quality control. While MDVs that de...
Mitochondrial-derived vesicles (MDVs) mediate selective trafficking of mitochondrial proteins and lipids to other organelles and contribute to organelle communication and mitochondrial quality control. While MDVs that deliver mitochondrial cargo to lysosomes have been extensively studied, the diversity of MDV pathways linking mitochondria to peroxisomes remains poorly understood. In particular, it is unclear how MDV pathways targeting peroxisomes relate to those delivering cargo to lysosomes, and whether cargos targeted to pre-existing peroxisomes utilize the same vesicular intermediates that participate in de novo peroxisome biogenesis. Here we examined MAPL trafficking using a peroxisome reconstitution system in PEX3-deficient fibroblasts. We found that MAPL is excluded from PEX3-positive pre-peroxisomal vesicles and instead is delivered to pre-existing peroxisomes, indicating that MAPL trafficking occurs through a pathway distinct from vesicles that initiate peroxisome formation. Structure-function analysis further revealed that a C-terminal amphipathic helix within MAPL is required for efficient targeting to peroxisomes. SNX9 depletion impaired both MAPL delivery to pre-existing peroxisomes and stress-induced lysosomal MDV pathways, whereas VPS35 depletion selectively reduced MAPL delivery without affecting lysosomal MDV pathways. In contrast, Parkin depletion impaired lysosomal MDV pathways but did not influence MAPL trafficking. Together, these findings demonstrate that mitochondria generate multiple classes of MDVs that are sorted into mechanistically distinct trafficking routes linking mitochondria with peroxisomes and lysosomes.
Mitochondrial DNA analysis in a cohort of stillbirths with brainstem and cardiac conduction system abnormalities.
Lecca M, Mele N, Leonardi P … +2 more , Ottaviani G, Errichiello E
Mitochondrion · 2026 Jul · PMID 41935656 · Publisher ↗
Stillbirth (SB) accounts for over 60% of perinatal deaths in high-income countries, with a significant portion of cases remaining unexplained following thorough anatomopathological investigation. Mitochondrial DNA (mtDNA...
Stillbirth (SB) accounts for over 60% of perinatal deaths in high-income countries, with a significant portion of cases remaining unexplained following thorough anatomopathological investigation. Mitochondrial DNA (mtDNA) alterations were analyzed in 42 SB cases with brainstem and cardiac conduction system (CCS) anomalies and in 32 control fetuses without these anomalies. DNA extracted from brainstem tissues was analyzed in both groups. In addition, unaffected tissues from the SB cases were examined for intra-individual comparison. The analysis included mtDNA sequencing, haplogroup determination, copy number (CN) quantification, and evaluation of displacement loop (D-loop) instability and methylation. Across the entire SB cohort, a total of 158 variants were identified, with a significant enrichment of variants observed in cases without CCS anomalies (p = 0.024). Affected brainstem tissues exhibited significantly higher mtDNA-CN compared with both control brainstem tissues (p < 0.0001) and unaffected tissues (p = 0.005), with levels higher in mild lesions than in severe lesions (p = 0.02). D-loop instability was identified in 37% of cases, and D-loop methylation levels were consistently higher in affected brainstem tissues compared with both control brainstem tissues (p < 0.0001) and unaffected tissues (p = 0.0001). These findings support mitochondrial dysfunction as a key contributor to fetal demise and mtDNA-CN as a potential biomarker for SB.
Overexpression of miR-455-3p enhances mitophagy, synaptic and mitochondrial proteins in Alzheimer's disease.
Pradeepkiran JA, Bandaru M, Islam MA … +4 more , Kshirsagar S, Alvir RV, Mukherjee U, Reddy PH
Mitochondrion · 2026 Jul · PMID 41932415 · Publisher ↗
MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression, neural development and plasticity in Alzheimer's disease (AD). Our lab recently discovered molecular links between miR-45...
MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression, neural development and plasticity in Alzheimer's disease (AD). Our lab recently discovered molecular links between miR-455-3p and AD. miR-455-3p is known to regulate APP expression, thereby influencing amyloid beta (Aβ) generation. Using pronuclear injection and CRISPR/Cas9 technologies, we created miR-455-3p transgenic (TG) and knockout (KO) mice. Remarkably, the miR-455-3p TG mice displayed an extended lifespan (by approximately 5 months) compared to wild-type (WT) mice, whereas miR-455-3p KO mice had a reduced lifespan (by 4 months). Behaviorally, miR-455-3p TG mice outperformed cognitive tasks such as the Morris water maze and Y-maze, indicating improved spatial memory and learning. To explore miR-455-3p's role in AD progression, we crossed miR-455-3p TG and miR-455-3p KO mice with the humanized amyloid beta knock-in (hAbKI) mouse model, which mimics late-onset AD features. The resulting experimental groups included WT, miR-455-3p TG, miR-455-3p KO, hAbKI, miR-455-3p TG X hAbKI, and miR-455-3p KO X hAbKI. In the current study, we investigated mitochondrial dynamics, mitochondrial biogenesis, mitophagy and synaptic proteins in all six groups of 12-month-old male and female mice. We focused on examining the expression of, mitophagy regulators (PINK1, Parkin), and synaptic markers (PSD95, Synaptophysin), mitochondrial biogenesis regulators (PGC1α, NRF1, TFAM) and dynamic proteins (DRP1, FIS1, Mfn1/2, OPA1) in the cortex of 12-month-old animals using western blot and immunofluorescence analyses. We also studied spine density in hippocampal sections for the mice groups in a Golgi-cox staining assay. We found miR-455-3p overexpression enhances mitophagy, mitochondrial biogenesis, dynamics proteins and spine density, in hAbKI mice. Depleted miR-455-3p exacerbates mitochondrial defects, defective mitophagy and synaptic loss in hAbKI mice. Our findings highlight miR-455-3p as a promising therapeutic target that modulates multiple pathological pathways in AD. This is the first genetic crossing study of miR-455-3p TG/KO mice with late onset AD, hAbKI mice.
Integrated molecular and clinical profiling of primary mitochondrial oxidative phosphorylation disorders in an Indian cohort: Insights from genetics, neuroimaging, and machine learning.
Banerjee S, Mondal R, Deb S … +11 more , Shome G, Chakraborty S, Saha C, Pandit A, Sen G, Bhattacharya S, Sen P, Bhattacharya NP, Roy J, Chowdhury A, Benito-León J
Mitochondrion · 2026 Jul · PMID 41850596 · Publisher ↗
Primary mitochondrial disorders are clinically and genetically heterogeneous and remain underdiagnosed in resource-limited settings. We performed a retrospective observational study (March 2016- January 2024) at a tertia...
Primary mitochondrial disorders are clinically and genetically heterogeneous and remain underdiagnosed in resource-limited settings. We performed a retrospective observational study (March 2016- January 2024) at a tertiary neurology center in Eastern India to characterize the clinical, biochemical, neuroimaging, electrophysiological, and molecular features of suspected mitochondrial disease and to explore interpretable machine-learning approaches for syndromic stratification. Forty-eight patients from 42 unrelated families were classified as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS; n = 17), chronic progressive external ophthalmoplegia (CPEO; n = 14), Leber hereditary optic neuropathy (LHON; n = 10), or Leigh syndrome (n = 7). Mean age at presentation was 23.9 years (range: 9 months-60 years), with a slight male predominance. Neuroimaging was abnormal in 23/48 (47.9%) and showed syndrome-concordant patterns, including stroke-like cortical lesions in MELAS and symmetric basal ganglia involvement in Leigh syndrome; brain magnetic resonance imaging was typically normal in CPEO. Elevated blood and/or cerebrospinal fluid lactate was common, and electroencephalographic abnormalities were concentrated in MELAS and Leigh syndrome. Targeted molecular testing in a subset identified pathogenic mtDNA variants consistent with phenotype, including MT-TL1 variants in MELAS, m.11778G>A in MT-ND4 in LHON, and m.8993T>G in MT-ATP6 in Leigh syndrome; no mtDNA deletions were detected in tested CPEO cases. Decision tree and random forest models highlighted clinically intuitive discriminators (e.g., visual loss, external ophthalmoplegia/ptosis, and seizure phenotype), supporting their potential role as transparent triage tools for targeted molecular evaluation. This cohort provides the first detailed characterization of mitochondrial syndromes in Eastern India and supports a pragmatic diagnostic framework integrating bedside phenotyping, targeted assays, and interpretable machine learning.
Impact of compound heterozygous SDHA variants on mitochondrial function in pediatric with neurological disease.
Garrido-Moraga R, Serrano-Lorenzo P, Esteban-Amo MJ … +7 more , Bellusci M, de la Fuente MÁ, Arenas J, González-Quintana A, Ugalde C, Simarro M, Martín MA
Mitochondrion · 2026 Jul · PMID 41833598 · Publisher ↗
This study examines two rare compound heterozygous missense variants in the SDHA gene, c.1535G > A (p.R512Q) and c.1753C > T (p.R585W), identified in a pediatric patient presenting with neurological manifestations, inclu...
This study examines two rare compound heterozygous missense variants in the SDHA gene, c.1535G > A (p.R512Q) and c.1753C > T (p.R585W), identified in a pediatric patient presenting with neurological manifestations, including epilepsy, developmental delay, and optic atrophy. The SDHA gene encodes a key component of succinate dehydrogenase (SDH), an essential enzyme complex at the intersection of two fundamental metabolic pathways: the Krebs cycle, and the mitochondrial respiratory chain (MRC). Patient-derived fibroblasts were used to evaluate the impact of the mutations on SDH activity and MRC assembly and function. The analysis revealed significant decreases in SDH activity and subunit levels, as well as impaired assembly. Additionally, complex I (CI) activity and CI-containing supercomplexes formation were also impaired, indicating more widespread mitochondrial dysfunction. Unexpectedly, basal and maximal respiration rates remained unchanged, though spare respiratory capacity was significantly reduced. These findings demonstrate the deleterious effects of the c.1535G > A and c.1753C > T variants, which had previously been associated with primary mitochondrial disorder (PMD) and tumors but had not been functionally validated until now.
Mitochondrial dysfunction and mitochondrial unfolded protein response (UPR): unravelling their roles in autism spectrum disorder pathogenesis.
Jeejo M, Mathew M, Mohanakumar KP … +1 more , Rajamma U
Mitochondrion · 2026 Jul · PMID 41833597 · Publisher ↗
Autism spectrum disorders (ASD) is a complex neurodevelopmental condition characterized by a gamut of impairments in social interaction, communication, and behaviour. Emerging evidence implicates mitochondrial dysfunctio...
Autism spectrum disorders (ASD) is a complex neurodevelopmental condition characterized by a gamut of impairments in social interaction, communication, and behaviour. Emerging evidence implicates mitochondrial dysfunction, manifested through disruptions in ATP synthesis, mitochondrial DNA (mtDNA) mutations, and heightened oxidative stress, as a significant contributor to the pathophysiology of ASD. Notably, individuals with ASD demonstrate a higher prevalence of mitochondrial disorders compared to the general population, suggesting a potential pathogenic link. However, the relationship between mitochondrial dysfunction and ASD is heterogeneous and varies among individuals, reflecting the disorder's intrinsic complexity. Recent interest in the Mitochondrial Unfolded Protein Response (UPR), which is activated in response to mitochondrial stress and misfolded proteins, underscores its critical role in maintaining mitochondrial integrity. Yet, its specific implications in ASD have been insufficiently investigated. This review aims to consolidate the current literature on UPR-related biomarkers in the context of ASD, elucidating how disruptions in this pathway may exacerbate mitochondrial dysfunction and contribute to ASD pathogenesis. In this narrative review, based on our literature search from academic databases such as PubMed, Scopus, Web of Science, and Google Scholar, and also grey literature, we present a conceptual framework to enhance our understanding of ASD pathophysiology that integrates mitochondrial stress, UPR activation, and neurodevelopmental outcomes. This review aims to expand the existing knowledge of mitochondrial contributions to ASD and identify new research dimensions to explore the mechanisms underlying UPR deregulation in ASD pathophysiology, thereby highlighting the potential therapeutic directions for targeting mitochondria-mediated UPR dysfunction in ASD.
Quantitative imaging of mitochondrial redox conditions at the single-organelle level.
Pöschel S, Müller M
Mitochondrion · 2026 Jul · PMID 41833596 · Publisher ↗
Mitochondria are morphologically and functionally heterogeneous and dynamically adapt to the current metabolic status of their hosting cell. Moreover, they are prominent sources but also sensitive targets of redox modula...
Mitochondria are morphologically and functionally heterogeneous and dynamically adapt to the current metabolic status of their hosting cell. Moreover, they are prominent sources but also sensitive targets of redox modulation and oxidative stress. Such subcellular ROS/redox signals are considered pivotal aspects in health and disease. Yet, their deciphering requires advanced optical tools. Here we took advantage of transgenic redox-indicator mice expressing a mitochondria-targeted reduction/oxidation-sensitive green fluorescent protein (roGFPm) in excitatory projection neurons. By excitation-ratiometric two-photon microscopy we quantified in acute brain slices the redox conditions of individual mitochondria. After developing adequate redox sensor calibrations and solving laser-mediated bleaching issues, we finally chose caudoputamen, which showed the most promising mitochondrial arrangement for our imaging approach. Confirming the reliability of single-mitochondria redox imaging, we characterized the interplay of redox state and mitochondrial morphology. In general, roGFPm was more oxidized in spherical than in filamentous mitochondria. Acute hypoxia reverted mitochondria to a more roundish shape and evoked a reducing shift. Furthermore, the fraction of spherical mitochondria increased with aging. Around postnatal day (pd)350, a significantly higher fraction of roundish mitochondria was present in females than in males. In addition, from pd150 on, female mice showed lower degrees of roGFPm oxidation than males. Both findings might be linked to estrogen levels, which decrease in female mice with reproductive senescence around pd350. In view of the pivotal role of mitochondria for cellular wellbeing and their involvement in various neuropathologies, the established single-organelle redox-imaging approach will foster further detailed studies.
Late-onset TK2 deficiency in adults: Long-term clinical outcomes of deoxynucleoside therapy.
Durmus H, Gedikbaşı A, Ceylaner S … +4 more , Çakar A, Mergen S, Kıyan E, Parman YG
Mitochondrion · 2026 Jul · PMID 41771327 · Publisher ↗
OBJECTIVE: To evaluate the long-term efficacy and safety of deoxynucleoside therapy in adult patients with late-onset thymidine kinase 2 deficiency (TK2d). BACKGROUND: TK2d is a mitochondrial myopathy causing progressive...
OBJECTIVE: To evaluate the long-term efficacy and safety of deoxynucleoside therapy in adult patients with late-onset thymidine kinase 2 deficiency (TK2d). BACKGROUND: TK2d is a mitochondrial myopathy causing progressive weakness, respiratory insufficiency, and early mortality. While nucleoside supplementation benefits pediatric cases, evidence in adults remains limited. METHODS: Six genetically confirmed adults with TK2d were treated under compassionate-use protocols in Turkey, receiving escalating doses of oral or PEG-administered Doxecitine and Doxribtimine up to 800 mg/kg/day. Functional and clinical outcomes included the 6-minute walk test (6MWT), Hammersmith Functional Motor Scale Expanded (HFMSE), forced vital capacity (FVC), Fatigue Severity Scale (FSS), and body mass index (BMI). RESULTS: Over a median follow-up of 24 (range 6-36) months, therapy was associated with sustained functional and respiratory improvements. Mean 6MWT increased from 152 m at baseline to 468 m at 24 months and exceeded 600 m in patients with 36-month data. The mean HFMSE increased from 20.5 at baseline to 24.5 at 3 months, 29 at 6 months. Patients with the longest follow-up reached a mean HFMSE of 58 at 36 months. FVC, which had declined before treatment, stabilized or improved in all patients (mean increase from 36% to 55.6% at 36 months). The youngest patient achieved near-normal respiratory function. Fatigue severity decreased by ∼ 30%, and BMI improved notably in underweight individuals. Treatment was generally well tolerated; transient liver enzyme elevations and mild gastrointestinal side effects resolved spontaneously. CONCLUSIONS: Deoxynucleoside therapy appears effective and well tolerated in adults with TK2d, producing sustained functional and respiratory gains. Early treatment initiation is crucial to maximize benefit; though partial improvements may occur even in advanced disease.
Patient-derived TWNK variants recapitulate multisystem Perrault syndrome pathology in a mouse model.
Wang W, Dong X, Cao CY … +2 more , Li HB, Lv YF
Mitochondrion · 2026 May · PMID 41765062 · Publisher ↗
Perrault syndrome (PS) is a rare autosomal-recessive disorder characterized by bilateral sensorineural hearing loss, ovarian dysgenesis in females, and variable neurological impairment. Pathogenic variants in TWNK, encod...
Perrault syndrome (PS) is a rare autosomal-recessive disorder characterized by bilateral sensorineural hearing loss, ovarian dysgenesis in females, and variable neurological impairment. Pathogenic variants in TWNK, encoding the mitochondrial helicase Twinkle, disrupt mtDNA maintenance and underlie a subset of PS cases. Here, we generated the first mouse models carrying patient-specific TWNK missense mutations c.814G > A (p.Ala272Thr) and c.1166C > T (p.Ala389Val), both in homozygosity and compound heterozygosity, using CRISPR/Cas9 editing. Mutant mice exhibit profound hearing loss, locomotor hypoactivity, and axonal peripheral neuropathy, while overall growth remains normal. Molecular assays reveal a significant reduction in mtDNA copy number and ATP content in muscle and brain, accompanied by impaired respiratory-chain function. These phenotypes faithfully recapitulate core features of human PS, establishing a genetically precise in vivo platform to dissect disease mechanisms and to evaluate targeted therapies for mitochondrial dysfunction and sensorineural hearing loss.
From variant interpretation to structural discovery: A new Zinc-binding domain in PARS2.
Hoebeke C, Engel C, Berat CM … +14 more , Milh M, Chaussenot A, Boddaert N, Chabrol B, Saadi SA, Fragaki K, Pereira S, Lepelley A, Bannwarth S, Navarro LR, Paquis-Flucklinger V, Schiff M, Sissler M, Rouzier C
Mitochondrion · 2026 May · PMID 41720228 · Publisher ↗
Aminoacyl-tRNA synthetases (aaRSs) are multi-domain enzymes that, in addition to their catalytic and tRNA-anticodon-binding domains, may include clade-specific extra regions conferring unique properties. These extra doma...
Aminoacyl-tRNA synthetases (aaRSs) are multi-domain enzymes that, in addition to their catalytic and tRNA-anticodon-binding domains, may include clade-specific extra regions conferring unique properties. These extra domains are poorly characterized in mitochondrial aaRSs (ARS2), complicating genetic diagnosis. ARS2 enzymes are essential for mitochondrial translation, broadly expressed, and pathogenic variants in any domain can cause varied neurological disorders. Here, we show how diagnosis challenge leads to a fundamental discovery. PARS2 deficiency, caused by pathogenic variantsin the nuclear gene encoding mitochondrial prolyl-tRNA synthetase (ProRS), was reported in few patients. Here, we describe two unrelated patients with epileptic encephalopathy who carry biallelic PARS2 variants including one novel variant predicted as "likely benign" due to poor interspecies conservation of the impacted region.First, through thorough phenotypic evaluation, we confirmed that both patients' clinical features match those of a cohort of 22 patients previously reported with PARS2 deficiency. Next, using comparative protein-structure modeling and a detailed clade-specific analysis of sequence conservation, we discovered that this variant actually falls within a previously unrecognized zinc-binding domain (ZBD), structurally similar to the well-characterized and essential ZBD found in cytosolic ProRS. Our findings underscore the limitations of existing tools for predicting the pathogenicity of ARS2 variants and demonstrate the value of integrating structural modeling with evolutionary conservation analysis. In conclusion, this work not only reveals a critical ZBD in PARS2, offering new insights into its structural and functional properties but also expands the genotypic spectrum of PARS2-related disorders and provides a comprehensive description of the associated phenotypes.
Phenotypic description and functional characterization of the mitochondrial disease associated with the SFXN4 gene.
Courtois S, Angelini C, Preud'homme J … +10 more , Le Quang M, Dumon E, Dulucq S, Aladjidi N, Kannengiesser C, Barat P, Naudion S, Espil C, Martin-Negrier ML, Trimouille A
Mitochondrion · 2026 May · PMID 41713566 · Publisher ↗
Sideroflexin 4 (SFXN4) is a transmembrane protein located in the inner membrane of the mitochondria. SFXN4 is also thought to be involved in the formation of iron-sulphur centres. Deleterious bi-allelic variants of the S...
Sideroflexin 4 (SFXN4) is a transmembrane protein located in the inner membrane of the mitochondria. SFXN4 is also thought to be involved in the formation of iron-sulphur centres. Deleterious bi-allelic variants of the SFXN4 gene have been reported in only 3 patients, with a phenotype including intellectual disability and macrocytic anaemia. We describe here a patient carrying pathogenic variants of SFXN4, associated with a non-anaemic sideroblastic macrocytosis and a complex I deficiency.
URMD-Seq: A high-throughput method for scalable detection of ultra-rare mutations in the human mitochondrial genome.
Li ZES, Dunn R, Caloren LC … +4 more , Ziada AS, Chapman H, Gadawska I, Côté HCF
Mitochondrion · 2026 May · PMID 41687757 · Publisher ↗
The study of mitochondrial genetics has long been limited to polymorphisms and high frequency mutations owing in part to technical and technological limitations in reliably detecting and quantifying rare somatic mutation...
The study of mitochondrial genetics has long been limited to polymorphisms and high frequency mutations owing in part to technical and technological limitations in reliably detecting and quantifying rare somatic mutations. Over the past decade or so, the study of rare somatic mitochondrial DNA (mtDNA) variants has expanded and continues to garner increasing interest in a wide range of research fields. Here, we describe Ultra-Rare Mutation Detection-Sequencing (URMD-Seq), a high-throughput method that combines unique molecular identifier (UMI)-based library preparation and Next Generation Sequencing (NGS) for the accurate and scalable detection of ultra-rare mutations in the mtDNA control region. Our method exploits degenerate primers to label individual mtDNA molecules. This is followed by several purification, quantification and amplification steps, to obtain high quality amplicons for sequencing on the Illumina MiSeq platform. Our approach enables the use of total genomic DNA extract as starting point for the assay, overcoming the need for organelle isolation and/or mtDNA enrichment, hence broadening the type of specimen that can be studied, while offering cost and time benefits. The assay described herein has been demonstrated to reliably measure variants present at on average 0.09%, but as low as 0.03%, variant allele frequency in a variety of tissues, including fresh and frozen biobanked specimens. Using this protocol, library preparation of 300 specimens can be completed by a single individual with general nucleic acid handling experience in approximately 20 days. Given its flexibility and scalability, URMD-Seq is particularly well suited for epidemiological studies using a large number of specimens.
Dysregulated iron homeostasis Drives mitochondrial Injury and ferroptosis susceptibility in MELAS fibroblasts.
Lin YH, Wang XW, Li YA … +6 more , Chen TY, Lian WS, Wang FS, Lan MY, Liou CW, Lin TK
Mitochondrion · 2026 May · PMID 41687756 · Publisher ↗
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, caused by mtDNA mutations, disrupts mitochondrial function and triggers oxidative stress. This study explores ferroptosis playi...
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, caused by mtDNA mutations, disrupts mitochondrial function and triggers oxidative stress. This study explores ferroptosis playing a key role in cell death in MELAS patient-derived fibroblasts harboring low (MELAS) or high (MELAS) heteroplasmy levels, subjected to rotenone-induced mitochondrial stress (a Complex I inhibitor). Rotenone crucially curtailed cell viability in MELAS fibroblasts relative to normal human dermal fibroblasts (NHDF), alongside elevated cellular/mitochondrial reactive oxygen species (ROS), lipid peroxidation, stable SOD1, and mildly diminished SOD2 in MELAS cells. Rotenone induced selective Fe accumulation in MELAS cells, while MELAS showed exacerbated Fe elevation both at baseline and rotenone-treated conditions. Ferroptosis susceptibility was evident in rotenone-treated MELAS via suppressed glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter (xCT); ferroptosis suppressor FSP1 was downregulated across MELAS subtypes versus NHDF. Iron homeostasis was dysregulated, with compensatory transferrin receptor (TFRC) and divalent metal transporter 1 (DMT1) reductions in MELAS cells. Non-toxic deferoxamine (DFO; 1-100 μM) pretreatment reversed cell survival, attenuated mitochondrial fragmentation, and restored elongated morphology in the stressed MELAS fibroblasts. These data establish the imbalance of Fe and mitochondrial damages are central amplifier of MELAS pathology, positioning iron chelation as a viable therapeutic to mitigate oxidative harm and safeguard cellular viability.
TNF-α-mediated down-regulation of mitochondrial transcription factors: Rescue by Angiotensin-(1-7) peptide.
Natarajan B, Vijayakumar A, Iyer DR … +6 more , Venkatraman J, Arige V, Khan AA, Barthwal MK, Kontos C, Mahapatra NR
Mitochondrion · 2026 May · PMID 41687755 · Publisher ↗
Manifesting initially as a physiological adaptation to pressure/volume overload, cardiac hypertrophy helps to maintain normal cardiac output via optimal mitochondrial function. However, chronic hypertension leads to path...
Manifesting initially as a physiological adaptation to pressure/volume overload, cardiac hypertrophy helps to maintain normal cardiac output via optimal mitochondrial function. However, chronic hypertension leads to pathological cardiac hypertrophy that is characterized by compromised cardiac output and mitochondrial dysfunction. Against this backdrop, we sought to delineate the molecular mechanisms underlying the regulation of mitochondrial transcription factors (mTFs; viz. Tfam, Tfb1m and Tfb2m which play a pivotal role in maintaining mitochondrial homeostasis) in cardiomyocytes. We show that the expression of mtTFs is repressed in the left ventricle of spontaneously hypertensive rats (SHR) as compared to normotensive Wistar Kyoto rats (WKY). In line with these findings, TNF-ɑ diminished the expression of mtTFs in H9c2 cardiomyoblasts. Ang-(1-7), an anti-inflammatory and anti-hypertensive peptide, reversed these effects of TNF-ɑ in vitro. We show that PGC-1ɑ-YY1 transcriptional complex acts as a molecular switch to modulate the expression of mtTFs. While TNF-ɑ prevents the formation of PGC-1ɑ-YY1 complex and promotes transcriptional repression of mtTFs mediated by YY1, Ang-(1-7) restores the complex formation, causing transcriptional activation of mtTFs. Thus, Ang-(1-7) emerges as an important regulator of cardiac mitochondrial biogenesis under inflammatory conditions.
Unmasking NLRX1: Exploring the broadening biological landscape of a mysterious mitochondrial sensor.
Bag J, Banerjee S, Banerjee S … +2 more , Ashok Kumar SK, De S
Mitochondrion · 2026 May · PMID 41679578 · Publisher ↗
The nucleotide-binding oligomerization domain-like receptor (NLR) family is an important family of cytoplasmic pathogen recognition receptors involved in innate immune defense. Among them, NLR family member X1 (NLRX1) st...
The nucleotide-binding oligomerization domain-like receptor (NLR) family is an important family of cytoplasmic pathogen recognition receptors involved in innate immune defense. Among them, NLR family member X1 (NLRX1) stands out with its specific N-terminal targeting sequence that targets it to mitochondria and thereby couples immune regulation with mitochondrial function. Recent findings point to NLRX1 as an important negative regulator of inflammation and also a modulator of mitochondrial metabolism and autophagy. Recent research has amplified our knowledge of the multifunctional biological functions of NLRX1, which involve it in the pathogenesis and development of several inflammatory, autoimmune, metabolic, and cancerous disorders. Despite significant progress, the specific molecular mechanisms involved in NLRX1-regulated cellular homeostasis are still not fully elucidated. In this review, we compile and critically review the recent data on NLRX1, highlighting its molecular interactions, signaling pathways, and disease-modulating functional relevance. Integrating findings from recent experimental and clinical research, this review attempts to discern the general biological significance of NLRX1 as well as its promise as an emerging therapeutic target in the new era of advanced research.
Short telomeres in mitochondrial DNA depletion disorders.
Dille Y, Rampakakis E, Aubert G … +7 more , Dassi C, Mannherz W, Berrahmoune S, Srour M, Buhas D, Agarwal S, Myers KA
Mitochondrion · 2026 May · PMID 41679577 · Publisher ↗
Mitochondrial DNA (mtDNA) depletion disorders (MDDs) are rare, genetically diverse conditions marked by a significant reduction in mtDNA, primarily affecting energy-demanding tissues such as muscle, liver, and brain, som...
Mitochondrial DNA (mtDNA) depletion disorders (MDDs) are rare, genetically diverse conditions marked by a significant reduction in mtDNA, primarily affecting energy-demanding tissues such as muscle, liver, and brain, sometimes leading to catastrophic multisystem failure. In a cohort of patients with MDDs, we measured telomere length in lymphocytes, granulocytes, T cells, and B cells, and compared to healthy controls. Telomere length was shorter overall in patients with MDDs, with the most significant differences observed in granulocytes. The observation that mtDNA depletion is associated with shorter telomeres may provide insight into MDD pathophysiology. Telomere length may have potential as a biomarker in mitochondrial disease, but further study is needed.
Probability of Mitochondrial DNA heteroplasmy in different tissues from European populations.
Cuesta-Aguirre DR, Onieva A, Aluja MP … +1 more , Santos C
Mitochondrion · 2026 May · PMID 41628679 · Publisher ↗
Mitochondrial DNA (mtDNA) heteroplasmy complicates genetic analyses due to its variability across individuals and tissues. We analyzed over 400 Spanish blood samples and integrated published Massively Parallel Sequencing...
Mitochondrial DNA (mtDNA) heteroplasmy complicates genetic analyses due to its variability across individuals and tissues. We analyzed over 400 Spanish blood samples and integrated published Massively Parallel Sequencing (MPS) data from ten additional European tissues. Heteroplasmy was tissue-specific, with skeletal muscle, kidney, and liver showing the highest levels, while the intestines, skin, and cerebellum had the lowest. Blood uniquely displayed more heteroplasmies in coding than non-coding regions. Several conserved positions not previously described as hotspots showed high frequencies. These results establish the first comprehensive tissue-specific heteroplasmic profile of the complete mitochondrial genome in a European population, improving the interpretation of mtDNA variation in forensic and biomedical contexts.
Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.
Jee E, Medha M, Baek H … +2 more , Kim J, Kim Y
Mitochondrion · 2026 May · PMID 41628678 · Publisher ↗
Friedreich's ataxia (FRDA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein essential for iron-sulfur cluster assembly and iron homeostasis. In addition to neurological symptoms, cardiac dysfun...
Friedreich's ataxia (FRDA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein essential for iron-sulfur cluster assembly and iron homeostasis. In addition to neurological symptoms, cardiac dysfunction is common and represents a major cause of premature death in FRDA. Although iron overload has been suggested as a major player for FRDA-related cardiomyopathy, its underlying mechanisms remain unclear. Using heart-specific frataxin deficient mice, we observed that FRDA-related cardiac hypertrophy is accompanied by mitochondrial iron overload. Transmission electron microscopy (TEM) revealed iron aggregates within cardiac mitochondria, whose ultrastructure was severely altered. Along with the iron deposits and structural abnormalities, mitochondrial respiration was markedly impaired in FRDA hearts, despite the absence of increased oxidative stress. Notably, although dysfunctional mitochondria accumulate in parallel with enhanced mitochondrial biogenesis, the clearance of damaged or dysfunctional mitochondria (i.e., mitophagy) is disrupted, as evidenced by excessive accumulation of p62 and Parkin proteins. The lysosomal system, which plays a central role for mitochondrial turnover, appears to be dysregulated via the mTOR-TFEB axis. Hyperactivation mTOR inhibits lysosomal biogenesis and function, although lysosomal content remains unchanged. Collectively, our study provides mechanistic insight into the role of mitochondrial iron aggregates in the pathogenesis of FRDA-related cardiomyopathy and suggests a potential contribution of lysosomal dysfunction to impaired mitochondrial quality control in the context of cardiac frataxin deficiency.
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