Mitochondrion[JOURNAL]
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200 papers
miR-205-5p accelerates lung fibroblast senescence in IPF patients via mediation of mitochondrial dynamics.
Wei R, Shen Y, Guo B … +2 more , Wang S, Han Q
Mitochondrion · 2026 Jun · PMID 42365869 · Publisher ↗
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that occurs primarily in the elderly. Although senescence of lung fibroblasts (LFs) contributes to IPF development, the potential mechanisms und...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that occurs primarily in the elderly. Although senescence of lung fibroblasts (LFs) contributes to IPF development, the potential mechanisms underlying LF senescence are not fully understood. This study aimed to delineate the role and underlying mechanisms of miR-205-5p in regulating LF senescence in patients with IPF. The LFs from IPF patients (IPF-LFs) and age-matched controls (Control-LFs) were isolated and cultured. Senescence of LFs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. Mitochondrial morphology of LFs was evaluated by MitoTracker staining and transmission electron microscope. The expression of miR-205-5p was examined by RT-PCR. Compared with Control-LFs, IPF-LFs exhibited increased cellular senescence with higher expression of SA-β-gal, p21 and p16 as well as decreased proliferative capacity. Importantly, IPF-LFs had decreased mitochondrial fission, evidenced by elongated mitochondria and downregulation of mitochondrial fission regulator 1-like protein (MTFR1L). The expression of miR-205-5p was much higher in IPF-LFs than Control-LFs. Notably, upregulation of miR-205-5p in Control-LFs led to increased cellular senescence, whereas downregulation rescued IPF-LF senescence. Mechanistically, miR-205-5p downregulated mitochondrial fission in LFs via MTFR1L, leading to mitochondrial dysfunction and cellular senescence. Taken together, our study illustrated that miR-205-5p serves as a critical regulator of cellular senescence of LFs isolated from IPF patients via mediation of mitochondrial dynamics.
A neuronal model of mtDNA disease reveals an ineffective reprogramming of the electron transfer chain during neuronal maturation.
Bell ST, Acín-Pérez R, Ghouri I … +3 more , Meyrick J, Lightowlers R, Russell O
Mitochondrion · 2026 Jun · PMID 42364888 · Publisher ↗
Large-scale mitochondrial DNA (mtDNA) deletions can result in deficiency of oxidative phosphorylation and subsequent mitochondrial dysfunction, ultimately leading to mitochondrial disease. To investigate effective treatm...
Large-scale mitochondrial DNA (mtDNA) deletions can result in deficiency of oxidative phosphorylation and subsequent mitochondrial dysfunction, ultimately leading to mitochondrial disease. To investigate effective treatments, we report a characterised heteroplasmic iPSC-derived neuronal model with a single, large scale ∼6 kb mtDNA deletion. While mtDNA heteroplasmy remains stable during iNGN2-induced neuronal differentiation from iPSCs, the presence of this mtDNA deletion results in an upregulation of mtDNA copy number and compensatory adaptation of oxidative phosphorylation (OXPHOS) machinery. Despite this increase, mitochondrial dysfunction and reduced oxygen consumption is prevalent. Furthermore, as differentiated neurons mature over time, mitochondrial supercomplexes and isolated complex II diminish, suggesting an increase of severity of the mitochondrial dysfunction. In summary, this study provides insight into a novel compensatory mechanism during iPSC differentiation to bypass mitochondrial dysfunction, and how this response exacerbates dysfunction during culture of mature neurons.
ATPIF1, the rheostat in mitochondrial bioenergetics and dysfunction in diseases.
Huang J, Xue C, Li H … +2 more , Wu Y, Wei Q
Mitochondrion · 2026 Jun · PMID 42364887 · Publisher ↗
ATP synthase inhibitory factor 1 (ATPIF1) is a critical regulator of the activity of F1F0-ATPase, a central enzyme in mitochondrial ATP production. Accumulating evidence highlights ATPIF1 as a master modulator of mitocho...
ATP synthase inhibitory factor 1 (ATPIF1) is a critical regulator of the activity of F1F0-ATPase, a central enzyme in mitochondrial ATP production. Accumulating evidence highlights ATPIF1 as a master modulator of mitochondrial morphology, function, cellular metabolism, and stress responses in diverse physiological and pathological conditions. In this review, we first provide a brief overview of mitochondrial structure and ATP production. We then focus on the cellular and molecular mechanisms of mitochondrial bioenergetics regulated by ATPIF1 and emphasize the role of ATPIF1 in energy preservation, mitophagy and redox balance. Furthermore, we comprehensively summarize recent advances about the pathological function of ATPIF1 in various mitochondrial dysfunction related diseases, including ischemia/reperfusion injury, aging, cancer, sepsis and chronic inflammation, and neurodegenerative disorders. ATP1IF1, the mitochondrial rheostat, emerges as a novel therapeutic target to combat mitochondrial dysfunction across multiple organ systems.
Spatholobi caulis and Epicatechin amplify erythropoiesis through mitochondrial translocation of AKT and enhanced oxidative phosphorylation.
Chien TJ, Huang QW, Chuang PH … +13 more , Wu CY, Lee MC, Hsu YN, Su YL, Chen SW, Wu YX, Chen MH, Kuo C, Han XY, Yang HY, Chang HY, Chang CH, Chang YI
Mitochondrion · 2026 Jun · PMID 42364886 · Publisher ↗
Erythroid differentiation requires a metabolic shift to oxidative phosphorylation (OXPHOS). We investigated the effects of Spatholobi Caulis (SC) and its active flavonoid, epicatechin (EC), on erythropoiesis. Both SC and...
Erythroid differentiation requires a metabolic shift to oxidative phosphorylation (OXPHOS). We investigated the effects of Spatholobi Caulis (SC) and its active flavonoid, epicatechin (EC), on erythropoiesis. Both SC and EC significantly amplified erythroid differentiation in vitro and in vivo. Mechanistically, SC and EC further triggered differentiation-induced AKT activation and its mitochondrial translocation, leading to upregulation of mitochondrial DNA-encoded respiratory chain genes and enhanced OXPHOS capacity. Notably, this functional enhancement occurred without changes in mitochondrial mass or mtDNA copy number, indicating a biogenesis-independent mechanism. Both PI3K/AKT signaling and intact OXPHOS function were essential, as pharmacological inhibition of either pathway abolished SC's pro-erythropoietic activity. Our findings establish an AKT-mitochondrial axis that couples proliferative signaling to bioenergetics, offering a therapeutic strategy for anemias involving mitochondrial dysfunction.
DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.
Geng M, Wang D, Kavoosi S … +2 more , Kaufman BA, Sondheimer N
Mitochondrion · 2026 Jun · PMID 42364885 · Publisher ↗
Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase proc...
Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.
Energy beats: Daily and circadian rhythms in mitochondrial biology.
Ceccato N, Damulewicz M, Mazzotta GM
Mitochondrion · 2026 Jun · PMID 42364884 · Publisher ↗
Circadian rhythms orchestrate a wide array of behavioral and physiological functions, coordinating cellular and organismal processes on an approximately 24-h cycle through an intrinsic timekeeping system. Among the many...
Circadian rhythms orchestrate a wide array of behavioral and physiological functions, coordinating cellular and organismal processes on an approximately 24-h cycle through an intrinsic timekeeping system. Among the many processes subject to this temporal regulation, mitochondrial function has emerged as a critical and dynamic target of circadian control. Mitochondria, far from being static organelles, undergo continuous morphological remodeling through cycles of fusion and fission, collectively termed mitochondrial dynamics, that are essential for maintaining metabolic homeostasis, energy production, and cellular quality control. Disruptions in circadian rhythmicity, such as those arising from sleep disturbances or irregular feeding patterns, have been associated with impaired glucose tolerance, insulin resistance, and increased risk of metabolic syndrome, diabetes, and cardiovascular disease. Emerging evidence suggests that the circadian clock and mitochondrial dynamics are engaged in a bidirectional interplay, whereby clock-controlled gene expression shapes mitochondrial morphology and function, while mitochondrial metabolic states in turn feedback to influence circadian timing. This review explores the evolutionary origins of mitochondrial rhythmicity, synthesizes current evidence on how the circadian clock regulates mitochondrial dynamics, and examines the physiological and pathological implications of their interconnection. A particular focus is placed on how disruptions in this circadian-mitochondrial axis may contribute to the development of common diseases, including neurodegenerative disorders, metabolic diseases, and cancer, highlighting novel avenues for chronobiologically informed therapeutic strategies.
Restoration of mitochondrial dynamics and synaptic function by mitophagy enhancers in a tauopathy cell model.
Kshirsagar S, Reddy AP, Reddy PH
Mitochondrion · 2026 Jun · PMID 42276536 · Publisher ↗
OBJECTIVES: To evaluate whether mitophagy enhancers-including urolithin A, actinonin, tomatidine, and nicotinamide riboside-can counteract mitochondrial dysfunction and synaptic damage induced by phosphorylated Tau in Al...
OBJECTIVES: To evaluate whether mitophagy enhancers-including urolithin A, actinonin, tomatidine, and nicotinamide riboside-can counteract mitochondrial dysfunction and synaptic damage induced by phosphorylated Tau in Alzheimer's disease. METHODS: We Used immortalized mouse hippocampal primary HT22 neurons expressing mutant Tau (mTau-HT22). We treated cells with mitophagy enhancers and measured gene and protein levels of mitochondrial dynamics, biogenesis, mitophagy, synaptic markers, assessed cell viability, mitochondrial respiration, and examined mitochondrial morphology via transmission electron microscopy. RESULTS: Compared to controls, mTau-HT22 cells exhibited increased mitochondrial fission and reduced fusion, diminished mitochondrial biogenesis, impaired mitophagy and synaptic gene expression, reduced cell survival, lower respiration, and fragmented mitochondria. Treatment with all mitophagy-enhancing compounds improved mitochondrial dynamics-, biogenesis-, and mitophagy-related marker expression together with mitochondrial functional outcomes, with urolithin A showing the strongest effects. Notably, a combined treatment of urolithin A with EGCG further enhanced respiratory function beyond single-agent treatments. CONCLUSIONS: Mitophagy enhancers, particularly urolithin A alone or in combination with EGCG, restore mitochondrial and synaptic health in Tau-induced toxicity models. These findings position mitophagy enhancement as a potential therapeutic approach requiring further validation in Alzheimer's disease.
Oxidative stress and inflammatory signaling in hypertensive stroke: mechanistic integration in vascular and neurovascular dysfunction.
Gao Z, Li J, Wang L … +1 more , Jiang D
Mitochondrion · 2026 Jun · PMID 42270001 · Publisher ↗
Hypertensive stroke emerges through complex interactions between oxidative stress, inflammatory signaling, vascular remodeling, and neurovascular dysfunction; however, the mechanisms coordinating these processes across v...
Hypertensive stroke emerges through complex interactions between oxidative stress, inflammatory signaling, vascular remodeling, and neurovascular dysfunction; however, the mechanisms coordinating these processes across vascular and neurovascular compartments remain incompletely resolved. This review integrates current mechanistic evidence to clarify how compartment-specific redox imbalance interfaces with inflammatory signaling to drive endothelial dysfunction, extracellular matrix remodeling, arterial stiffening, microvascular rarefaction, and neurovascular unit instability. Reactive oxygen species (ROS) derived from NADPH oxidases and mitochondrial electron transport systems act as spatially restricted signaling mediators that influence key regulatory pathways, including PI3K/Akt, NF-κB, and Nrf2. NOX2-associated ROS signaling appears to contribute predominantly to endothelial inflammatory amplification, nitric oxide depletion, leukocyte recruitment, and blood-brain barrier destabilization, whereas NOX4-related activity is more strongly linked to vascular stiffening, extracellular matrix reorganization, and chronic fibrotic remodeling. Inflammatory signaling evolves through pulsatile and region-specific activation patterns rather than uniform progression, while incomplete antioxidant compensation sustains persistent low-grade oxidative and inflammatory signaling. The neurovascular unit emerges as a major convergence site where endothelial dysfunction, glial activation, mitochondrial instability, and neuronal metabolic vulnerability progressively interact under chronic stress conditions. Despite substantial mechanistic progress, major translational limitations remain, including insufficient spatial and temporal resolution of current biomarker strategies and limited integration of compartment-specific signaling dynamics. Future progress will likely depend on spatially resolved analytical platforms, standardized mechanistic frameworks, and integrative systems-level models capable of linking localized molecular signaling with clinically interpretable vascular outcomes in hypertensive stroke.
TTC19 and FMNL2 gene variants in a pediatric case of mitochondrial disorder with renal tubular acidosis.
Jacob P, Deepha S, Hassan AV … +8 more , Rao S, Santhoshkumar R, Vasudeva K, Kapahtia S, Sharma M, Nandeesh BN, Nagappa M, Govindaraj P
Mitochondrion · 2026 Jun · PMID 42250897 · Publisher ↗
Mitochondrial complex III deficiency caused by pathogenic variants in TTC19 is a heterogeneous disorder typically presenting with progressive neurological involvement in late childhood. Early-onset of disease with predom...
Mitochondrial complex III deficiency caused by pathogenic variants in TTC19 is a heterogeneous disorder typically presenting with progressive neurological involvement in late childhood. Early-onset of disease with predominant renal manifestations are uncommon and may complicate diagnosis. We report a child presenting with developmental delay, failure to thrive, lactic acidosis, and distal renal tubular acidosis (dRTA), raising suspicion of an underlying mitochondrial disorder. Whole exome sequencing (WES) analysis identified a homozygous intron-exon boundary deletion of 31 bp (c.463-19_474del) in TTC19 predicted to disrupt splicing, with functional evidence demonstrating aberrant transcript formation, reduced gene expression, and mitochondrial dysfunction in patient-derived fibroblasts. Based on the biochemical findings, re-analysis of exome data revealed a novel homozygous canonical splice-site variant (c.783-1G>A) in FMNL2. The splicing assay showed the skipping of exon 9, and reduced expression in the fibroblasts. This case expands the clinical spectrum of TTC19-related mitochondrial complex III deficiency with early-onset renal tubular acidosis. While TTC19 is the most plausible primary disease-causing gene, the functional disruption of FMNL2 suggests a potential contributory role or association with the renal phenotype. Hence, these findings highlight the importance of genomic re-analysis along with functional studies in resolving complex multisystem disorders.
Heart failure and mitochondrial dynamics: Role of intracellular angiotensin and emerging therapeutics.
Panchbhai P, Mehadwan SS, Chaturvedi G … +8 more , Dubey N, Singh P, Parakh N, Baitha U, Prakash V, Narang R, Agrawal DK, Yadav HN
Mitochondrion · 2026 Jun · PMID 42242610 · Publisher ↗
Heart failure (HF) remains a leading cause of morbidity and mortality worldwide despite significant advances in neurohumoral therapies targeting the renin-angiotensin-aldosterone (RAAS). Although RAAS inhibition improves...
Heart failure (HF) remains a leading cause of morbidity and mortality worldwide despite significant advances in neurohumoral therapies targeting the renin-angiotensin-aldosterone (RAAS). Although RAAS inhibition improves survival and limits adverse cardiac remodelling in failing hearts, mitochondrial dynamic dysfunction persists in a larger proportion of treated patients, indicating an intracellular signalling mechanism that sustains the pathological remodelling in these patients. Emerging evidence shows a shift toward a fission-dominant mitochondrial phenotype, acting as a critical feature of a failing heart. Angiotensin II (Ang II), beyond its classical endocrine actions, activates a network of calcium- and redox-dependent intracellular signalling pathways that converge on the mitochondrial fission machinery. Many of these components are incompletely inhibited by the conventional RAAS blockade, providing a mechanistic basis for RAAS escape and persistent mitochondrial dysfunction. This review highlights the mechanism underlying the temporal stabilization of fission-dominant mitochondrial phenotype, and discusses the opportunity to target mitochondrial dynamics as a complementary therapeutic strategy. Reframing angiotensin signalling through the lens of mitochondrial dysregulated dynamics may help overcome the limitations of current heart failure therapies.
Mitochondrial C3aR and endoplasmic reticulum C5aR orchestrate calcium imbalance during oxidative stress in retinal pigment epithelial cells.
Ishii M, Rohrer B
Mitochondrion · 2026 Jun · PMID 42242609 · Publisher ↗
Although C3a and C5a are classically recognized as extracellular anaphylatoxins, we previously identified mitochondrial C3a receptors (mt-C3aR) in stressed RPE cells, where its activation enhanced Ca uptake and inhibited...
Although C3a and C5a are classically recognized as extracellular anaphylatoxins, we previously identified mitochondrial C3a receptors (mt-C3aR) in stressed RPE cells, where its activation enhanced Ca uptake and inhibited oxidative phosphorylation (OXPHOS). Here, we demonstrate a second intracellular anaphylatoxin receptor, C5aR, localized to the endoplasmic reticulum (ER) by confocal and immuno-electron microscopy. ER-C5aR activation increased SERCA-dependent Ca uptake and, together with mt-C3aR, facilitated ER-to-mitochondria Ca transfer at mitochondria-endoplasmic reticulum contact sites (MERCS). Moreover, oxidative stress induced Gα16 redistribution, enabling its interaction with ER-C5aR. These findings reveal a novel mechanism by which intracellular anaphylatoxin receptors shape Ca homeostasis and cellular stress responses.
Mitochondrial dysfunction in muscle cells induced by snoring vibrations.
Stål P, El-Habta R, Qian YC … +5 more , Zhu S, Williams C, Mateus A, Gilthorpe JD, Shah F
Mitochondrion · 2026 Jun · PMID 42235782 · Publisher ↗
Snoring-related vibrations have been proposed as a pathogenic factor contributing to upper airway muscle dysfunction in patients with obstructive sleep apnea (OSA). To investigate whether exposure to snoring vibration is...
Snoring-related vibrations have been proposed as a pathogenic factor contributing to upper airway muscle dysfunction in patients with obstructive sleep apnea (OSA). To investigate whether exposure to snoring vibration is linked to muscle weakness, we used an in vitro vibration model to examine its effects on mitochondrial homeostasis in L6 muscle cells at 8, 12, 24, and 48 h. The findings were then compared with mitochondrial alterations in the upper airway muscles from snorers and patients with OSA. Proteomic analysis of L6 myoblasts revealed extensive remodeling of the mitochondrial proteome at 8 h, affecting pathways involved in oxidative phosphorylation, protein import, ribosome biogenesis, and RNA processing. Respiratory chain remodeling was subunit-specific, with increased abundance of selected components of Complexes I, IV, and V, including NDUFS4, COX5A, and ATP5PD. However, reductions in spliceosome-associated factors, such as SRSF2 and DDX46, along with alterations in mitochondrial ribosomal proteins, indicated impaired RNA processing and protein synthesis. Furthermore, both proteomic and transcriptomic analyses revealed activation of a mechanosensing-mechanotransduction axis, with early upregulation of integrin subunits and mechanosensitive ion channels, followed by transient activation of focal adhesion signaling. Despite transcriptional upregulation of selected Complex IV subunits Cox5a and Cox6a2, this response was accompanied by accumulation of unspliced pre-mRNA, indicating impaired RNA processing efficiency and a decoupling between transcript and protein levels. Real-time Seahorse assay revealed a collapse of mitochondrial respiration and glycolytic reserve at 8 h. Although mitochondrial oxygen consumption recovered after 48 h, the ability to dynamically upregulate glycolysis remained impaired. In patients, muscle capillarization was impaired, COX activity was reduced, and mitochondrial organization was disrupted. Moreover, transcription of Complex IV subunits COX5A and COX6A2 was, as in vibrated L6 cells, upregulated, suggesting a mismatch between transcript levels and protein expression. We conclude that snoring-induced vibrations are an unrecognized stressor that disrupts mitochondrial homeostasis in muscle by impairing RNA processing, protein synthesis, and mechanotransduction-driven mitochondrial remodeling, leading to transcript-protein uncoupling and likely muscle dysfunction.
Mitochondrial donation and human reproduction: Clinical, ethical and legal aspects.
Piergentili R, Vergallo GM, Marinelli E … +5 more , Pelagatti E, Sechi S, Furnari ML, Gullo G, Zaami S
Mitochondrion · 2026 Jun · PMID 42235781 · Publisher ↗
Women carriers of a disease caused by changes in mitochondrial DNA (mtDNA) seeking to achieve motherhood, currently have three options: (i) prenatal testing, via CVS or amniocentesis for women aiming to conceive naturall...
Women carriers of a disease caused by changes in mitochondrial DNA (mtDNA) seeking to achieve motherhood, currently have three options: (i) prenatal testing, via CVS or amniocentesis for women aiming to conceive naturally and test the health of the fetus during development; (ii) preimplantation genetic testing (PGT), which allows for the selection of embryos without mtDNA mutations or with the lowest possible chance of pathogenic mtDNA presence, and (iii) egg donation. The United Kingdom and Australia have approved two methods for replacing mutant mtDNA: maternal spindle transfer (MST) and pronuclear transfer (PNT). In MST, the maternal nuclear DNA is transferred from the patient's oocyte into an enucleated donor oocyte from which the maternal spindle has been removed. The reconstituted egg would then be fertilized by the intended father's sperm and the newly formed embryo implanted in the intended mother. In PNT, first mother's eggs are fertilized using the intended father's sperm, then the pronuclei of the embryo are transferred to a recipient embryo, from which the pronuclei have been removed. This paper will illustrate the basis of mtDNA-related diseases and the approaches to minimize transmission to offspring. Then, it will focus on the main ethical and legal/regulatory complexities as to various types of nuclear transfer to prevent mtDNA diseases, the risks to the child and future generations, and the issues related to germline changing. Our conclusion is that the two main methods developed to replace pathogenic mtDNA variants are morally approvable because they afford the newborn child quality of life.
Role of oxidative stress in the susceptibility to mitophagy of the skin fibroblasts and iPSC-derived neurons of patients with MERRF syndrome.
Wu YT, Tay HY, Liao HH … +2 more , Yang JT, Wei YH
Mitochondrion · 2026 May · PMID 42162776 · Publisher ↗
Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is mainly caused by the m.8344A>G mutation and mitochondrial dysfunction, but the pathogenesis remains unclear. In this study, we demonstrated that carbonyl cyan...
Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is mainly caused by the m.8344A>G mutation and mitochondrial dysfunction, but the pathogenesis remains unclear. In this study, we demonstrated that carbonyl cyanide m-chlorophenyl hydrazine (CCCP) induced PINK1-mediated mitophagy and accelerated mitochondrial turnover in the skin fibroblasts of MERRF patients. We found that CCCP led to more pronounced increase of PINK1 accumulation, activation of LC3B II and degradation of Mfn1, Mfn2, OSCP and OPA1 cleavage in MERRF skin fibroblasts as compared with normal skin fibroblasts. Moreover, N-acetylcysteine suppressed PINK1 accumulation and ubiquitin phosphorylation, and thus impaired clearance of damaged mitochondria. This inhibitory effect was validated in MERRF patient iPSC-derived neurons harboring the m.8344A>G mutation, which displayed mitochondrial dysfunction, ROS overproduction and impaired electrophysiological function of mature neurons. These findings suggest that oxidative stress plays a crucial role in the susceptibility to mitophagy of skin fibroblasts and iPSC-derived neurons of MERRF patients and that restoring proper mitophagic flux is a potential therapeutic approach.
Challenging mtDNA tRNA variant guidelines: Emphasizing single-cell analysis through four novel variants.
Prosper C, Zereg E, Chaussenot A … +14 more , Bannwarth S, Lannes B, Streichenberger N, Kaphan E, Nadaj-Pakleza A, Villa L, Sacconi S, Masingue M, Birgy E, Francou B, Ait-El-Mkadem Saadi S, Fragaki K, Paquis-Flucklinger V, Rouzier C
Mitochondrion · 2026 Sep · PMID 42150647 · Publisher ↗
The broad clinical and genetic heterogeneity of mitochondrial diseases makes diagnosis challenging. Accurate characterization of novel variants is crucial to reduce diagnostic uncertainty, guide treatment, and enable rel...
The broad clinical and genetic heterogeneity of mitochondrial diseases makes diagnosis challenging. Accurate characterization of novel variants is crucial to reduce diagnostic uncertainty, guide treatment, and enable reliable genetic counseling. In this study, we validated a single-cell NGS-based analysis approach by comparison with conventional PCR-RFLP and applied it to five mtDNA variants identified in patients evaluated at our national reference center for mitochondrial disorders (CALISSON). Variant interpretation was assessed using multiple frameworks, including Yarham's scoring, Wong's specifications, and the ClinGen guidelines. We report four novel variants (m.9998 T > C in MT-TG, m.7530A > G in MT-TD, and m.4271G > C and m.4305A > G in MT-TI), including three for which single-fiber analysis provided strong evidence supporting pathogenicity. However, these functional results alone were not sufficient to enable reclassification under the current ClinGen framework. These findings highlight differences between the various scoring systems and illustrate the limitations of current recommendations in fully integrating functional evidence and tissue segregation data. We therefore suggest that adjusted weighting of existing criteria may improve variant classification. Nevertheless, classification frameworks must preserve reproducibility across laboratories, and the criteria proposed here should be considered preliminary points for reflection requiring further validation in larger cohorts, as well as the establishment of standardized criteria for functional studies, including single-fiber analyses.
Electron microscopy visualization of cell-free mitochondrial DNA-associated vesicular structures in human plasma, serum, and saliva.
Volos A, Franklin SG, Michelson J … +3 more , Rausser S, Brestoff JR, Picard M
Mitochondrion · 2026 May · PMID 42144122 · Publisher ↗
Human biofluids contain cell-free mitochondrial DNA (cf-mtDNA) and extracellular mitochondria (ex-Mito), creating the challenge of defining their origins, destinations, mechanisms of regulation, and biological purpose(s)...
Human biofluids contain cell-free mitochondrial DNA (cf-mtDNA) and extracellular mitochondria (ex-Mito), creating the challenge of defining their origins, destinations, mechanisms of regulation, and biological purpose(s). To expand our understanding of vesicular structures across human biofluids, we present a descriptive electron microscopy analysis of circulating particles from cf-mtDNA-enriched plasma (citrate, heparin, and EDTA), serum (red and gold top), and saliva collected from ten healthy participants (5 females, 5 males, mean age 44.9 years). Ex-mito and extracellular vesicles (EVs) were isolated by centrifugation followed by size-exclusion chromatography, imaged by transmission electron microscopy, and morphometrically analyzed. In parallel, cf-mtDNA was quantified in each biofluid to confirm enrichment. The resulting catalog of the most common circulating particles in plasma, serum, and saliva show that circulating double-membrane extracellular particles are present across human biofluids, along with EVs and other particle types. Combining imaging with cf-mtDNA quantification, we show that individuals with higher plasma cf-mtDNA concentrations tend to contain more double-membrane, ex-Mito-like particles. These preliminary and largely qualitative results do not directly demonstrate but are consistent with the concept of mitochondria transfer and/or signaling between cells and tissues. The image inventory provided here expands our knowledge of cell-free mitochondrial biology and provides a resource to inform biofluid selection and technical considerations in future studies quantifying ex-Mito and cf-mtDNA.
mA-Mediated epitranscriptomic control of mitochondrial dysfunction in neurodegeneration.
Jauhari A
Mitochondrion · 2026 Sep · PMID 42140375 · Publisher ↗
Mitochondrial dysfunction is a common pathology of neurodegenerative diseases, which contributes to neuronal vulnerability via excessive oxidative stress, impaired bioenergetics, and dysregulated apoptosis. Emerging stud...
Mitochondrial dysfunction is a common pathology of neurodegenerative diseases, which contributes to neuronal vulnerability via excessive oxidative stress, impaired bioenergetics, and dysregulated apoptosis. Emerging studies highlighted the critical role of epitranscriptomic RNA modifications, particularly N-methyladenosine (mA), in mitochondrial gene expression regulation and cellular stress responses. mA modifications are installed by methyltransferases ("writers," METTL3/METTL14), recognized by reader proteins (YTH domain family proteins, IGF2BPs), and removed by demethylases ("erasers," FTO, ALKBH5), collectively orchestrating mRNA splicing, localization, stability, and translation. Recent evidence demonstrates that mA modifications modulate both nuclear-encoded and mitochondrially encoded transcripts and regulate key mitochondrial processes, including fission/fusion dynamics, oxidative phosphorylation, mitophagy, and apoptosis. Dysregulation of mA machinery disrupts mitochondrial homeostasis, exacerbates oxidative stress and neuroinflammation, and promotes neuronal loss. Importantly, pharmacological or genetic modulation of mA regulators can restore mitochondrial function, inhibit caspase activation, and dampen pro-inflammatory signaling, underscoring their therapeutic potential. This review consolidates current insights into mitochondrial epitranscriptomics, emphasizing how mA modifications act as central regulators of mitochondrial stress responses and neurodegeneration.
Discovery of FRAG-i: a small molecule inhibitor of Drp1 that modulates mitochondrial fission.
Ateşoğlu Ş, Çataltepe SN, Bardakcı E … +6 more , Aldogan EH, Yorgancioglu Budak G, Bektaş M, Akçakaya H, Baday S, Yöntem FD
Mitochondrion · 2026 Sep · PMID 42140374 · Publisher ↗
Mitochondrial dynamics, regulated by the balance of fission and fusion, are essential for cellular homeostasis, and their disruption-particularly via excessive Drp1-dependent fission-contributes to cancer and other patho...
Mitochondrial dynamics, regulated by the balance of fission and fusion, are essential for cellular homeostasis, and their disruption-particularly via excessive Drp1-dependent fission-contributes to cancer and other pathologies. Current Drp1 inhibitors lack specificity or exhibit off-target toxicity, highlighting the need for safer alternatives. Here, we identify FRAG-i, a small-molecule Drp1 inhibitor discovered through multi-stage virtual screening and molecular dynamics refinement of a 3.5-million-compound library. FRAG-i binds the Drp1 GTPase domain with high affinity (Kd = 732.4 ± 4.2 nM) and increases Drp1 thermal stability in recombinant and cellular assays. Functionally, FRAG-i selectively suppresses mitochondrial fission in A549 lung carcinoma cells while sparing the fused networks of non-cancerous BEAS-2B epithelial cells. FRAG-i preserves mitochondrial membrane potential, ATP levels, and redox balance without cytotoxicity, and modulates Drp1, MiD49, and Mfn2 expression in a context-dependent manner. These results establish FRAG-i as a selective, non-toxic Drp1 inhibitor with potential for further therapeutic development.
A century of studies on mitochondrial cytochrome c oxidase.
Pedroza-Dávila U, Camacho-Villasana Y, González-Halphen D … +1 more , Perez-Martinez X
Mitochondrion · 2026 May · PMID 42140373 · Publisher ↗
Cytochrome c oxidase (CcO, complex IV) is the last component of the respiratory chain, catalyzing the reduction of oxygen to water and the translocation of protons to the inner membrane space. In 1925, David Keilin publi...
Cytochrome c oxidase (CcO, complex IV) is the last component of the respiratory chain, catalyzing the reduction of oxygen to water and the translocation of protons to the inner membrane space. In 1925, David Keilin published his work on the rediscovery of cytochromes, including types a and a. The same year, Otto Warburg published part of his work on the "respiratory ferment". Both articles are fundamental to bioenergetics and the mitochondrial field. Since its discovery, CcO has been the subject of study in hundreds of laboratories across the world, but there are still many interrogates to be answered. To commemorate the 100 anniversary of the publication of these two seminal works, this review examines various aspects of the history of CcO (complex IV) and the challenges yet to be resolved of this enzyme.
Insights into mitochondrial-mediated immune responses in Galleria mellonella: A model for fungal pathogenesis and redox regulation.
Kaczmarek A, Boguś MI
Mitochondrion · 2026 Sep · PMID 42140372 · Publisher ↗
Innate immunity's integration of redox signaling in pathogen defense is a key area in host-pathogen biology. Using Galleria mellonella infected with the fungus Conidiobolus coronatus, we reveal mitochondrial redox-mediat...
Innate immunity's integration of redox signaling in pathogen defense is a key area in host-pathogen biology. Using Galleria mellonella infected with the fungus Conidiobolus coronatus, we reveal mitochondrial redox-mediated immune responses. Fluorescence microscopy, flow cytometry, and spectrofluorimetry uncovered a rapid, hemocyte-specific oxidative burst marked by elevated reactive oxygen and nitrogen species, with distinct compartmentalization between cells and hemolymph. This redox surge coincided with G0/G1 cell cycle arrest, indicating stress checkpoint activation. Despite oxidative and nitrosative stress, caspase-5-like activity was unaltered, suggesting pyroptosis is not the primary immune response. ROS localization and increased hydrogen peroxide levels point to organelle-centered signaling. Additionally, increased acetyltransferase activity reflects an adaptive detoxification response linked to phase II metabolism. These results position G. mellonella as a valuable model to study mitochondrial redox-immune interplay and provide novel insights into conserved fungal defense mechanisms.
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