bims-mitmed 2026-07-19 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–07–19
twelve papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Exogenous Mitochondrial Transfer in Differentiating Brown Adipocytes and AGPAT2-Deficient Preadipocytes.
The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis.
Mitochondrial morphology and mtDNA content in fibroblasts from patients with different types of mucopolysaccharidosis.
Dopaminergic neurons preferentially accumulate mtDNA rearrangements.
Why do astronauts' bodies waste away? Space-station study points to mitochondria.
Next generation AAV-F capsid gene therapy rescues disease pathology in a model of pyruvate dehydrogenase complex deficiency.
Inhibition of mitochondrial complex I impedes zygotic genome activation via PDH-histone modification retrograde signaling.
Mitofusin-2 in ventral striatal D1 neurons regulates effort-based motivation through sex-specific mitochondrial-synaptic reprogramming.
In Utero Molecular-Targeted Drug Therapies: Translational Principles, Pharmacologic Considerations, and Emerging Clinical Applications.
Urolithin A enhances mitochondrial biogenesis-related markers and maximal respiratory capacity during C2C12 differentiation.
Somatic pathogenic mitochondrial DNA mutations independently predict worse prognosis in hepatocellular carcinoma.
Generation of a Patient-Derived Inducible Pluripotent Stem Cell Model for Studying the YARS2-Related Genetic Disease.

J Vis Exp. 2026 Jun 26.

Exogenous Mitochondrial Transfer in Differentiating Brown Adipocytes and AGPAT2-Deficient Preadipocytes.

Antonio Moreno, Claudia Parra-Ruiz, Francisca Stolzenbach, Víctor Cortés.

Mitochondria are key signaling hubs; however, whether mitochondrial mass expansion is mechanistically required for differentiation remains an open question. AGPAT2 catalyzes the conversion of lysophosphatidic acid into phosphatidic acid, and its deficiency leads to adipose tissue deficiency and impaired adipogenesis associated with reduced mitochondrial mass. The impact of mitochondrial mass expansion on adipogenesis was assessed by transferring exogenous mitochondria into differentiating brown adipocytes. Whether mitochondrial transfer could rescue the impaired adipogenesis of AGPAT2-deficient cells was also investigated. Human and murine mitochondria were successfully transferred and incorporated into the endogenous mitochondrial network of differentiating mouse preadipocytes and persisted throughout brown adipogenesis. Adipogenic differentiation was required for the retention of transferred mitochondria. Mitochondrial transfer did not modify the expression of molecular markers of mature brown adipocytes or lipid droplet content, although it affected the relative distribution of lipid droplet size in a species-dependent manner. In Agpat2-/- preadipocytes, mitochondrial transfer failed to rescue adipogenesis, indicating that mitochondrial mass expansion alone is insufficient to reverse the mechanisms leading to lipodystrophy in this model. These results indicate that, although exogenous human and murine mitochondria can be incorporated into the mitochondrial network of differentiating adipocytes, they do not directly influence the adipogenic program.

DOI: https://doi.org/10.3791/71223
Int J Mol Sci. 2026 Jul 01. pii: 5931. [Epub ahead of print]27(13):

The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis.

Anastasia Kolotova, Alexandr Shestopalov, Sergey Kutsev.

  Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases-caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation-and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes-including volume reduction and cristae loss-represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber's hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers-such as lipid peroxidation products, decreased GPX4, and iron deposition-rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition-using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers-together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis-ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases.

Keywords:  apoptosis; ferroptosis; iron metabolism; lipid peroxidation; mitochondria; mitochondrial diseases; molecular crosstalk; oxidative stress; regulated cell death; tissue specificity

DOI:  https://doi.org/10.3390/ijms27135931
Acta Biochim Pol. 2026 ;73 16345

Mitochondrial morphology and mtDNA content in fibroblasts from patients with different types of mucopolysaccharidosis.

Klaudia Walczak, Lidia Gaffke, Karolina Pierzynowska, Natalia Sowa-Rogozińska, Ewa Piotrowska.

  Mucopolysaccharidosis (MPS) is a group of inherited metabolic diseases, characterized by defects in the degradation of glycosaminoglycans and their accumulation in lysosomes. However, various secondary cellular changes also contribute to the pathomechanism of MPS. Previous studies have reached contradictory conclusions about the changes in mitochondria in MPS, from increased numbers of mitochondria to impaired activities of some mitochondrial respiratory chain enzymes to no changes in mitochondrial respiration. In this preliminary, hypothesis-generating study, mitochondrial network morphology and mitochondrial DNA (mtDNA) abundance were investigated in fibroblasts derived from patients suffering from diverse MPS types. Fluorescence microscopy and real-time PCR were used to estimate these parameters, respectively. No significant changes in the mitochondrial network morphology were detected in MPS fibroblasts relative to control cells. Decreased levels of mtDNA relative to nuclear DNA levels were evident in some (I, II, IIIA, IIID, and VI) but not all MPS types compared to control fibroblasts. The results of this study suggest that there are some, although perhaps not dramatic, impairments of mitochondrial functions in some MPS types; however, they do not provide direct evidence of mitochondrial dysfunction. Therefore, these findings should be interpreted as descriptive and exploratory, highlighting the need for further functional and mechanistic studies.

Keywords:  MPS; fluorescence microscopy; mitochondria; mitochondrial DNA; mucopolysaccharidosis

DOI:  https://doi.org/10.3389/abp.2026.16345
Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2601897123

Dopaminergic neurons preferentially accumulate mtDNA rearrangements.

Tania Arguello, Christian D Alcalde Pretel, Nadee Nissanka, Derek Van Booven, Milena Pinto, Monica Rodriguez-Silva, Lise-Michelle Theard, Anthony J Griswold, Carlos T Moraes.

  High levels of mitochondrial DNA (mtDNA) deletions have been described in the substantia nigra. However, the mechanisms involved are poorly understood. We found that transient expression of a mitochondrial targeted restriction endonuclease (mitoPstI) in mice leads to an accumulation of mtDNA rearrangements that involve both the PstI cleavage sites and unrelated specific regions of the mtDNA, including the MTERF1 binding site and the edge of the D-loop. This pattern of rearrangements after double-strand breaks supports the presence of recombination hotspots in the mtDNA. Transient expression of mitoPstI in dopaminergic neurons led to further accumulation of mtDNA rearrangements in dopaminergic neurons after expression was suppressed, a pattern that was not observed in glutamatergic neurons. This accumulation was also blunted when a mtDNA replisome factor was absent, suggesting that robust mtDNA replication is required for the accumulation of preexisting mtDNA rearrangements in dopaminergic neurons over time.

Keywords:  Parkinson’s disease; deletions; dopaminergic; double strand break; mtDNA

DOI:  https://doi.org/10.1073/pnas.2601897123
Nature. 2026 Jul 16.

Why do astronauts' bodies waste away? Space-station study points to mitochondria.

Miryam Naddaf.



Keywords:  Cell biology; Metabolism

DOI:  https://doi.org/10.1038/d41586-026-02089-0
Mol Ther Adv. 2026 Sep 10. 34(3): 201781

Next generation AAV-F capsid gene therapy rescues disease pathology in a model of pyruvate dehydrogenase complex deficiency.

Anna Keegan, Özge Çetin, Ellie M Chilcott, Juan Antinao Diaz, Simon Eaton, Simon N Waddington, John R Counsell, Shamima Rahman, Rajvinder Karda.

  Pyruvate dehydrogenase complex deficiency (PDHD) is a severe mitochondrial disorder most frequently caused by pathogenic variants in PDHA1, leading to neurodevelopmental delay and early mortality, thus necessitating brain-targeted interventions. Using a brain-specific Pdha1 knockout mouse model, we compared intracerebroventricular delivery of AAV9 capsid and a recently described synthetic neurotropic AAV-F capsid, both expressing human PDHA1 coding sequence driven by a constitutive CAG promoter. Newborn mice received titer-matched AAV9, AAV-F, or AAV9 at 10-fold higher dose. Low-dose AAV-F and high-dose AAV9 significantly improved survival and restored PDH enzyme activity, metabolite profiles, and brain histopathology to near wild-type levels. However, mice treated by postnatal day 100 (P100) showed impaired motor function. Importantly, AAV-F achieved broad CNS transduction with minimal liver expression, thus outperforming low-dose AAV9. These results support the therapeutic potential of AAV-based gene therapy for PDHD and highlight AAV-F as a promising capsid for efficient, CNS-specific delivery.

Keywords:  AAV-F; adeno-associated virus; clincal translation and pyruvate dehydrogenase deficiency; gene supplementation; neonatal gene therapy; preclinical

DOI:  https://doi.org/10.1016/j.omta.2026.201781
Biochem Biophys Res Commun. 2026 Jul 14. pii: S0006-291X(26)01060-0. [Epub ahead of print]830 154296

Inhibition of mitochondrial complex I impedes zygotic genome activation via PDH-histone modification retrograde signaling.

Guang-Xin Pan, Xiao-Yan Shi, Li-Quan Zhou, Yuan-Yuan Li.

  Rotenone (RTN), an insecticide that functions through inhibiting mitochondrial electron transport chain complex I, has been demonstrated to impair reproductive health in mammals. Nevertheless, its impact on the process of preimplantation development remains to be elucidated. In this study, the toxic effects of RTN on mouse preimplantation embryo development were determined by exposure to different concentrations of RTN. RTN exposure resulted in developmental arrest of mouse preimplantation embryos in a dose-dependent manner. Mechanistically, RTN treatment induced mitochondrial dysfunction, elevated ROS levels, severe DNA damage and developmental arrest at the 2-cell stage. Furthermore, RTN treatment resulted in the failure of nuclear localization of the mitochondrial TCA cycle enzyme, pyruvate dehydrogenase (PDH), and abnormalities in histone modifications. This, in turn, led to impaired zygotic genome activation and development beyond the 2-cell stage. In addition, dichloroacetic acid enhanced the nuclear localization of PDH in 2-cell embryo, thereby augmenting TCA flux and promoting preimplantation development. In conclusion, RTN has the potential to exert cytotoxic effects on mammalian reproduction, and electron transport chain complex I inhibitors should be used with caution when applied to the treatment of reproductive diseases. Furthermore, this study enhances our comprehension of the interplay between mitochondrial metabolism and epigenetic regulation in early embryos.

Keywords:  ROS; Rotenone; TCA cycle; Zygotic genome activation; preimplantation

DOI:  https://doi.org/10.1016/j.bbrc.2026.154296
Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2601657123

Mitofusin-2 in ventral striatal D1 neurons regulates effort-based motivation through sex-specific mitochondrial-synaptic reprogramming.

Alessandro Chioino, Dogukan H Ulgen, Olivia Zanoletti, Isabelle Guillot de Suduiraut, Ashley M Maynard, Elisenda Sanz, Albert Quintana, Simone Astori, Carmen Sandi.

  Effort-based motivation varies widely across individuals and affects well-being, yet the molecular and neuronal mechanisms that set motivational capacity remain incompletely understood. Mitochondrial function is emerging as a critical regulator of behavior, and mitofusin-2 (MFN2) is a key mediator of mitochondrial fusion and endoplasmic reticulum-mitochondria coupling. Here, we asked how downregulation of Mfn2 in dopamine receptor type-1-expressing medium spiny neurons (D1-MSNs) contributes to effort-based motivation and stress coping in male and female mice by integrating electrophysiology, neuronal and synaptic morphology, immunohistochemistry, mitochondrial readouts, RNA in situ hybridization, RiboTag, and behavioral analyses. MFN2 deficiency resulted in fragmented dendritic mitochondria and remodeled synaptic inputs in ventral striatal D1-MSNs, with no cellular impact in dorsomedial striatal D1-MSNs. Although MFN2 deficiency elicited sex-dependent synaptic and structural alterations, both sexes showed reduced recruitment of accumbal D1-MSNs during motivated behavior and impaired effort-based motivation and stress coping. Translatome profiling revealed shared depletion of mitochondrial pathways in both sexes, with more pronounced suppression of oxidative phosphorylation and TCA cycle programs in males. Strikingly, only males also exhibited coordinated downregulation of ribosomal programs together with enrichment of synaptic pathways, with high representation of genes regulating glutamate receptor cycling and PSD remodeling, providing a mechanistic framework for the observed synaptic alterations. Pathway-level network inference further supported coupling among mitochondrial, translational, and synaptic programs in males. These findings identify MFN2-dependent mitochondrial integrity in ventral striatal D1-MSNs as a critical determinant of motivational capacity and reveal sex-specific molecular and cellular responses through which mitochondrial dysfunction converges on similar motivational deficits.

Keywords:  mitochondria; motivation; ventral striatum

DOI:  https://doi.org/10.1073/pnas.2601657123
J Clin Med. 2026 Jun 25. pii: 4960. [Epub ahead of print]15(13):

In Utero Molecular-Targeted Drug Therapies: Translational Principles, Pharmacologic Considerations, and Emerging Clinical Applications.

Akihiro Hasegawa, Ehsan Rojhani, Ahmed Hashem Fathallah, Rodrigo Ruano, Alireza Abdollah Shamshirsaz.

  Advances in fetal diagnosis and molecular medicine have opened new opportunities for in utero molecular-targeted drug therapy, shifting fetal treatment from purely procedural interventions toward pharmacologic strategies that address disease mechanisms before irreversible organ damage occurs. In this review, we highlight recent advances in in utero drug therapy, focusing on molecular-targeted approaches with emerging clinical or trial-level evidence. Early clinical experience and ongoing trials have demonstrated the feasibility of achieving therapeutically relevant fetal drug exposure, although the strength of evidence varies considerably across therapeutic classes. However, significant challenges remain, including optimization of fetal drug delivery, characterization of fetal pharmacokinetics and pharmacodynamics, long-term safety assessment, and ethical considerations. The current evidence base ranges from single case reports to ongoing Phase 3 clinical trials, underscoring both the promise of prenatal molecular therapeutics and the need for further prospective evaluation. Continued integration of fetal imaging, genomics, ethics and pharmacology will be essential to advance safe and effective prenatal precision therapies.

Keywords:  fetal therapy; in utero therapy; molecular-targeted therapy; precision medicine; prenatal pharmacotherapy; review

DOI:  https://doi.org/10.3390/jcm15134960
Front Cell Dev Biol. 2026 ;14 1854844

Urolithin A enhances mitochondrial biogenesis-related markers and maximal respiratory capacity during C2C12 differentiation.

Ronald Vargas-Foitzick, Diego Irribarra-Tapia, Mayalen Valero-Breton, Elisa Balboa.

   Introduction: Skeletal muscle differentiation in the C2C12 myoblast model requires extensive mitochondrial remodeling to meet rising bioenergetic demands through coordinated changes in biogenesis, dynamics, and respiratory adaptation. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins, improves mitochondrial health, but its role in late-stage myogenic differentiation remains unclear.
Methods: C2C12 myotubes were treated with UA (2 μM) for 72 h during late-stage differentiation (days 3-6). Mitochondrial signaling, respiratory capacity, myogenic morphology, and ultrastructure were assessed by Western blot, high-resolution respirometry, hematoxylin-eosin staining, and transmission electron microscopy.
Results: UA was non-cytotoxic and increased AMPKα phosphorylation and PGC-1α expression, whereas TOM20, MFN2, and OPA1 were unchanged. Mitophagy/autophagy-related markers (p-ULK1, p62, BNIP3L/NIX, LC3-II/I) were not altered, indicating no detectable changes in steady-state autophagy under the conditions tested. UA selectively increased OXPHOS Complex I and II abundance and enhanced maximal uncoupled respiration, and was associated with increased myotube diameter and myogenic marker abundance. No overt ultrastructural differences were observed by electron microscopy.
Discussion: These findings suggest that UA promotes mitochondrial functional adaptation during myogenic differentiation, with accompanying changes in myogenic phenotype, without clear evidence of altered steady-state mitophagy/autophagy markers or mitochondrial morphology.

Keywords:  C2C12 myotubes; maximal respiration; myogenic differentiation; oxphos; urolithin A

DOI:  https://doi.org/10.3389/fcell.2026.1854844
Sci Rep. 2026 Jul 13.

Somatic pathogenic mitochondrial DNA mutations independently predict worse prognosis in hepatocellular carcinoma.

Camelia Alexandra Coada, Monica De Luise, Rosanna Clima, Stefano Miglietta, Marcella Attimonelli, Veronica De Sanctis, Roberto Bertorelli, Chiara Valentini, Paolo Cavallerio, Federico Manuel Giorgi, Catia Giovannini, Ivana Kurelac, Luisa Iommarini, Laura Gramantieri, Anna Maria Porcelli, Fabio Piscaglia, Giuseppe Gasparre.

  Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide, but its cancerization and progression mechanisms are still poorly understood. Mitochondrial DNA (mtDNA) mutations have been involved in tumor progression by influencing metabolic rewiring and plasticity. In this work, we aimed to investigate the contribution of mtDNA mutations to the pathogenesis and prognosis of HCC. Whole exome sequencing data from the TCGA-LIHC project were used to reconstruct the mitochondrial genomes. Discovered variants were classified using the HmtVar pathogenicity scoring system and the ACMG/AMP standard guidelines. The validation of results was performed on a separate in-house cohort of selected HCC cases from our hospital. Pathogenic mtDNA mutations were present in 33.6% of patients. GSEA revealed pathogenic mtDNA mutations mainly targeting the reactive oxygen species (ROS) pathway, suggesting an increased ROS production in these tumors which may contribute to the survival, proliferation and metastatization capacity. Survival analysis revealed a significant decrease in the overall survival of patients harboring pathogenic mtDNA variants (p = 0.01). A similar trend was observed in the validation cohort. Overall, we showed that somatic mtDNA mutations occur in a significant proportion of HCC cases, expectedly acting as modifiers on the ROS pathway, and that their occurrence confers a worse prognosis.

Keywords:  Hepatocellular carcinoma; Mitochondria; Prognosis; Reactive oxygen species

DOI:  https://doi.org/10.1038/s41598-026-61381-1
Int J Stem Cells. 2026 Jul 13.

Generation of a Patient-Derived Inducible Pluripotent Stem Cell Model for Studying the YARS2-Related Genetic Disease.

Chenbo Zeng, Andrew Gray, Rebecca Ganetzky, Ya-Ming Hou, Lorraine Iacovitti.

  The YARS2 variant, harboring the compound heterozygous pathogenic mutations F185L/E264del, was identified in the gene for mitochondrial tyrosyl-tRNA synthetase in a proband that suffered a neonatal phenotype. To facilitate studies to better understand the severity of the mutations, we created a patient-derived inducible pluripotent stem cell (iPSC) model. We first derived iPSCs from fibroblasts of the patient Q1818, which contain two mutations, c.553T＞ C (p.F185L) and c.792_794delAGA (p.E264del) in the YARS2 gene. We then generated three isogenic control iPSC lines with one or both mutations corrected by using CRISPR-Cas9 technology. The correction of mutations in YARS2 was confirmed by Sanger sequencing. The stemness of iPSC lines was demonstrated by the expression of stem cell markers in the iPSCs, as determined using qPCR, immunostaining, and trilineage differentiation. Moreover, three positive clones of each iPSC line were extensively characterized, confirming that they originated from Q1818 fibroblasts, had normal karyotypes, and did not contain off-targets in the YARS2 coding sequence; genome wide off target effects were not a major concern. Subsequently, Q1818 iPSCs and the three isogenic control iPSCs were differentiated into clinically relevant motor neurons. In addition, we demonstrated that the patient fibroblasts and the derived iPSCs are heterozygous for either c. 553T＞C or c.792_794delAGA, and that the two mutations are located on different alleles of the YARS2 gene, providing critical information for studying the mutation-associated disease. In conclusion, we have generated a set of four iPSC lines, which can be used as a model to study a clinically severe case of YARS2 disease.

Keywords:  CRISPR-Cas9; Inducible pluripotent stem cell; Isogenic cells; Tyrosyl-tRNA synthetase 2

DOI:  https://doi.org/10.15283/ijsc25101