bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–06–14
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial disease: mechanisms, signalling, and therapeutic opportunities.
  2. Mitochondrial complex I deficiency-associated diseases and models.
  3. Effects of an indole chemical, mitochonic acid 5, in a mouse model of mitochondrial disease onset.
  4. Expanding the landscape of tRNA pathogenic variants in mitochondrial DNA.
  5. Generation and characterization of the hiPSC line CSSi023-A (16154) from a patient with ADOA caused by an OPA1 variant.
  6. DRP1 and MID49 co-diffusion scans mitochondria for fission.
  7. FXN protomutations are the source of pathogenic expanded GAA alleles in Friedreich ataxia and explain its unequal population distribution.
  8. Testicular origin of epigenetic inheritance independent of sperm mitochondrial DNA and epididymal exposure.
  9. Mitochondrial capsules mitigate mitochondrial dysfunction.
  10. Placental nicotinamide adenine dinucleotide modulates the timing of labor.
  11. Mitochondria-ER contacts function as an iron supply hub.
  12. Mitochondria tethered to the nucleus secure its energy supply.
  13. Electron transport chain complex I and mitochondrial fusion regulate ROS for differentiation in Drosophila neural stem cells.
  14. Expression of four mitochondrial tRNAs from only two loci.
  15. Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
  16. Engineered Tan-CDs@AS-IV Nanosystem Orchestrates Mitochondrial Biogenesis and Intercellular Transfer to Restore Endothelial Function via PGC-1α and Cx43 Signaling Pathways.
  17. A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
  18. The placental metabolic clock.
  19. Proteomics-based insights into mammalian oocyte and early embryo development.
  20. Single-Cell Imaging of Mitochondrial Metabolism and Remodeling in C2C12 Murine Skeletal Muscle Cells upon Differentiation.
  21. Programmable delivery of mitochondria to specific cell types.
  22. Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.
  23. TTC19 and FMNL2 gene variants in a pediatric case of mitochondrial disorder with renal tubular acidosis.
  24. Omega-3 fatty acid supplementation improves skeletal muscle mitochondrial function in a model of Barth syndrome.
  1. Free Radic Biol Med. 2026 Jun 06. pii: S0891-5849(26)00857-9. [Epub ahead of print]253 749-769
    Mitochondrial disease: mechanisms, signalling, and therapeutic opportunities.
    Samantha Corrà, Luke Young, Anthony L Moore, Carlo Viscomi.
      Mitochondria are central hubs of cellular metabolism and signalling, and their dysfunction underlies a broad spectrum of human diseases, including rare mitochondrial disorders as well as common neurodegenerative and metabolic conditions. Mitochondrial diseases are genetically heterogeneous disorders caused by mutations in nuclear or mitochondrial DNA that impair oxidative phosphorylation (OXPHOS), resulting in reduced ATP production and cellular energy failure. Despite a shared bioenergetic defect, these diseases display marked clinical variability, and the mechanisms underlying this heterogeneity remain poorly understood. At present, no curative therapies are available, although several metabolic and experimental approaches have shown promise in preclinical models. Mitochondrial dysfunction is commonly associated with altered redox homeostasis and increased production of reactive oxygen species (ROS), which can damage mitochondrial components, including mitochondrial DNA, and further impair respiratory chain function. At the same time, ROS also act as context-dependent signalling molecules, with effects that vary according to concentration, localization, and cell type complicating their interpretation in disease mechanisms and therapy development. In this review, we summarize current concepts in mitochondrial disease pathophysiology focusing on unresolved questions that limit mechanistic understanding and clinical translation. We critically evaluate the role of ROS in disease progression and signalling, discuss how the alternative oxidase (AOX) has emerged as a valuable experimental tool to dissect ROS-related mechanisms and reveal unexpected aspects of mitochondrial dysfunction and disease variability.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.013
  2. Cell Mol Life Sci. 2026 Jun 10. pii: 249. [Epub ahead of print]83(1):
    Mitochondrial complex I deficiency-associated diseases and models.
    Lena Jentsch, Natascia Ventura.
      Mitochondrial complex I is the first and largest enzyme of the mitochondrial respiratory chain and thus plays a crucial role in cellular energy metabolism. Defects in the mitochondrial respiratory chain, and in particular CI deficiency, are the primary cause of human mitochondrial associated diseases, which most often presents as severe neurometabolic disorders with fatal outcome. Up to this date the diagnosis and treatment of CI deficiency-associated diseases is challenging, only limited symptomatic therapies exist and no cures are available. This review aims at summarizing current knowledge on the genetic basis of CI deficiency-associated diseases and available experimental disease models. Most common human disorders caused by CI deficiency range from Leigh syndrome to MELAS and LHON, all characterized by genetic and symptomatic heterogeneity. So far, in vivo studies on non-mammalian organisms and mouse models, as well as in vitro studies on patient derived fibroblasts, cybrids and human-induced pluripotent stem cells have mainly facilitated the research of CI deficiency. These model systems provide insights on molecular mechanisms in mitochondrial disease and approaches for potential therapeutic intervention strategies. However, current research is limited by translational relevance of existing disease models, varying degrees of heteroplasmy and tissue specific effects characteristic of mitochondrial diseases, so that basic disease mechanisms still remain poorly understood. To overcome these challenges there is an urgent need for in vivo and in vitro human relevant models to aid the development of effective therapeutic interventions and potential cures of CI deficiency-associated diseases.
    Keywords:  Mammalian cell models; Mitochondrial complex I; Mitochondriopathies; Model organisms
    DOI:  https://doi.org/10.1007/s00018-026-06169-2
  3. Sci Rep. 2026 Jun 10.
    Effects of an indole chemical, mitochonic acid 5, in a mouse model of mitochondrial disease onset.
    Emi Ogasawara, Haruna Tani, Chitose Suzuki, Yuji Owada, Masaki Ogata, Naotada Ishihara, Takaaki Abe, Kazuto Nakada.
      This study tested the effects of mitochonic acid 5 (MA-5) using a mouse model of mitochondrial disease onset (mito-mice∆), with disease resulting from the accumulation of pathogenic mitochondrial DNA harboring a large deletion (∆mtDNA). Administration of MA-5 to mito-mice∆ inhibited the progression of clinical symptoms, such as low body weight and lactic acidosis. In the kidneys, MA-5 protected against mitochondrial respiration defects and subsequent renal failure, even when ∆mtDNA accumulated to > 80%. In the heart, MA-5 also resolved the mitochondrial respiration defects. Our findings suggested that administration of MA-5 would be effective in delaying the progression of some mitochondrial diseases caused by mutant mtDNA and especially in mitochondrial-mediated renal failure.
    Keywords:  Mitochondria; Mitochondrial DNA (mtDNA); Mitochondrial diseases; Mitochonic acid 5 (MA-5); Mouse model; Respiratory chain
    DOI:  https://doi.org/10.1038/s41598-026-57342-3
  4. Brain Commun. 2026 ;8(3): fcag178
    Expanding the landscape of tRNA pathogenic variants in mitochondrial DNA.
    Salvatore Loris Siragusa, Santino Blando, Claudio Fiorini, Alberto Pietro Pasti, Danara Ormanbekova, Francesco Casadei, Luca Morandi, Elena Pegoraro, Rocco Liguori, Valerio Carelli, Chiara La Morgia, Leonardo Caporali, Maria Lucia Valentino.
      We present a comprehensive molecular and histopathological characterization of nine patients with mitochondrial myopathy, predominantly manifesting progressive external ophthalmoplegia (PEO), associated with heteroplasmic variants in mitochondrial tRNA genes (mt-tRNA). Among the ten variants identified, four were novel and previously unreported in MITOMAP. Using laser capture microdissection and deep next-generation sequencing, we quantified heteroplasmy at the single-muscle-fibre level, demonstrating that cytochrome c oxidase (COX)-deficient fibres consistently reached near-homoplasmic mutant loads, whereas COX-positive fibres remained heteroplasmic with lower variant fractions. These findings firmly support the pathogenic role of all variants. Furthermore, digital droplet PCR revealed an increased mitochondrial DNA (mtDNA) content in COX-deficient fibres, indicating compensatory mitochondrial biogenesis. Of particular note, one patient harboured two novel heteroplasmic variants, m.10009G > A and m.15961G > A, for which long-read sequencing identified mitogenomes carrying both variants also in cis, suggesting the occurrence of mtDNA recombination in human tissue. By applying refined American College of Medical Genetics and Genomics (ACMG) criteria specific for mt-tRNA, we reclassified several variants as pathogenic or likely pathogenic, including three previously deemed of uncertain significance. Overall, our integrative approach-combining single-fibre molecular dissection, mtDNA quantification, and long-read sequencing-broadens the mutational spectrum of pathogenic mt-tRNA variants, highlights the diagnostic value of single-fibre analyses in confirming pathogenicity, and provides new insights into mitochondrial genome dynamics and compensatory responses in mitochondrial disease.
    Keywords:  mitochondrial DNA; mitochondrial myopathy; mt-tRNA variant; mtDNA recombination; single muscle fibre microdissection
    DOI:  https://doi.org/10.1093/braincomms/fcag178
  5. Stem Cell Res. 2026 Jun 01. pii: S1873-5061(26)00118-2. [Epub ahead of print]94 104022
    Generation and characterization of the hiPSC line CSSi023-A (16154) from a patient with ADOA caused by an OPA1 variant.
    Angela Maria Giada Giovenale, Ilaria Ferrone, Silvia Tomaselli, Elisa Maria Turco, Martina Mazzoni, Barbara Torres, Paola Zanfardino, Edvige Vulcano, Daniela Ferrari, Devid Damiani, Filippo M Santorelli, Alessandro De Luca, Maria Pennuto, Angelo Luigi Vescovi, Vittoria Petruzzella, Jessica Diana Rosati.
      Autosomal Dominant Optic Atrophy plus syndrome (ADOA, OMIM #125250) is a mitochondrial optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs), leading to worsening visual impairment. The disease is caused by pathogenic variants in the Optic Atrophy 1 (OPA1) gene, a member of the guanosine triphosphatase (GTPase) family that plays a central role in mitochondrial fusion and fission, mitophagy regulation, and mitochondrial DNA (mtDNA) maintenance. To model this disorder, we generated and characterized a human induced pluripotent stem cell (hiPSC) line from primary fibroblasts obtained from a patient affected by ADOA syndrome.
    DOI:  https://doi.org/10.1016/j.scr.2026.104022
  6. Nat Cell Biol. 2026 Jun 11.
    DRP1 and MID49 co-diffusion scans mitochondria for fission.
    Cristiana Zollo, David Gomez Suarez, Elmira Parvindokht Bararpour, Andreas Jenner, Pratima Verma, Jan Koch, Sabine Wilhelm, Christian Jüngst, Lukas Faber, Faye White, Ana J García-Sáez.
      DRP1 is a dynamin-related large GTPase responsible for mitochondrial fission, which ensures proper mitochondrial distribution, morphology and quality control. Despite its relevance, the mechanism of mitochondrial division, especially regarding the dynamic regulation of DRP1, remains elusive. Here we report that DRP1 oligomers diffuse in helical-like trajectories along mitochondria, browsing the organelle surface and stalling at preconstricted fission sites, in what we call 'mito-scanner' motion. Molecular dynamics simulations support a geometry-mediated diffusion mechanism emerging from surface confinement. Perturbation of DRP1 motility results in elongated mitochondria, underscoring the functional importance of DRP1 scanning dynamics in mitochondrial division. We also show that DRP1 dynamics on mitochondria are differentially regulated by interactions with its adaptors, where co-diffusion of MID49/MID51 with DRP1 promotes its motility. Our findings support a model in which receptor-regulated mitochondrial surveillance by DRP1 enables balanced organelle division, with potential implications for targeting this process in disease.
    DOI:  https://doi.org/10.1038/s41556-026-01986-w
  7. Hum Mol Genet. 2026 Jun 09. pii: ddag046. [Epub ahead of print]35(11):
    FXN protomutations are the source of pathogenic expanded GAA alleles in Friedreich ataxia and explain its unequal population distribution.
    Morgan C Devore, Christina Lam, Emily Xiao, Jeremy Devore, Kassandra R C McCain, Graham Wiley, Courtney C Park, David R Lynch, Sanjay I Bidichandani.
      Friedreich ataxia (FRDA) is a recessive condition that is typically caused by inheriting an expanded GAA repeat (usually > 500 triplets) in the FXN gene from both parents who are heterozygous carriers of the expanded (E) allele. E alleles, which are evolutionarily derived from non-pathogenic long normal (LN) alleles (≥12 triplets), occasionally arise de novo via intergenerational expansion of premutation alleles (34-60 triplets). However, why FRDA susceptibility is limited to Eurasians, and how the prevalence of E alleles is sustained in susceptible populations are incompletely understood. Sequencing of the FXN locus revealed two major subclasses of E alleles, which have originated from a subset of Eurasian LN alleles, termed protomutations. Haplotype identity, the observed size continuum of protomutation-premutation-E alleles, and evidence of intergenerational instability in a protomutation allele, together support a dynamic relationship wherein protomutations can transition to premutation and E alleles. Consistent with the exclusive prevalence of FRDA in Eurasia, protomutations are absent in sub-Saharan Africa, where E alleles did not develop despite a relatively high prevalence of LN alleles. However, genetic admixture has introduced a slight risk of FRDA in African Americans. Analysis of ancient DNAs revealed that protomutations have existed in Europe and Western Asia for thousands of years, with evidence of spread to Europe via early Neolithic farmers. These data indicate that FXN protomutations serve as a reservoir for the generation of premutation and E alleles, and for millennia have sustained the geographically-defined population distribution of FRDA.
    Keywords:  Friedreich ataxia; Protomutation; ancient DNA; population susceptibility; repeat expansion
    DOI:  https://doi.org/10.1093/hmg/ddag046
  8. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2611096123
    Testicular origin of epigenetic inheritance independent of sperm mitochondrial DNA and epididymal exposure.
    Zhuqing Wang, Yasuhiro Yamauchi, Sheng Chen, Huili Zheng, Monika A Ward, Wei Yan.
      Paternal epigenetic inheritance remains mechanistically unresolved. Recent studies propose that environmental exposures induce mitochondrial DNA (mtDNA)-dependent transcription in sperm during epididymal transit, altering small RNA content and offspring phenotypes. Here, we show that mature murine sperm are effectively devoid of mtDNA, precluding mtDNA-dependent transcription, and that sperm-borne mitochondrial RNAs originate during spermatogenesis. Testicular sperm transmitted diet-induced metabolic traits as efficiently as, and in most cohorts more efficiently than, epididymal sperm. These findings establish testicular inheritance independent of sperm mtDNA transcription and epididymal exposure.
    Keywords:  epigenetic inheritance; mitochondrial DNA; small RNA; sperm epigenome
    DOI:  https://doi.org/10.1073/pnas.2611096123
  9. Nat Genet. 2026 Jun;58(6): 1200
    Mitochondrial capsules mitigate mitochondrial dysfunction.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-026-02651-6
  10. Science. 2026 Jun 11. 392(6803): 1194-1199
    Placental nicotinamide adenine dinucleotide modulates the timing of labor.
    Erin J Ciampa, Luana M Machado, Kathy J Lee, Amanda J Clark, Kyle Q Vu, Nawal A Khan, Sarah Kispert, Samantha Armstrong, Yunping Li, Ginger L Milne, Ashley Solmonson, S Ananth Karumanchi, Samir M Parikh.
      Labor is mediated proximately by prostaglandin signaling within gestational tissues and must be tightly regulated for birth to occur after appropriate fetal development. Metabolic changes accompanying gestational aging have been postulated as a determinant of birth timing, but specific nutrients, sensors, and messengers remain obscure. We report that placental nicotinamide adenine dinucleotide (NAD+) dynamically tunes gestational length. Depletion of placental NAD+ in mice provoked labor onset, mediated by the role of NAD+ as a cofactor for 15-hydroxy prostaglandin dehydrogenase, an enzyme responsible for suppressing prostaglandin accumulation. Augmentation of placental NAD+ prolonged gestation at baseline and in a model of preterm labor. These findings suggest a central role for metabolic exhaustion in provoking labor and reveal potential therapeutic avenues for preterm labor and the optimization of labor induction.
    DOI:  https://doi.org/10.1126/science.adz1624
  11. Nat Cell Biol. 2026 Jun 10.
    Mitochondria-ER contacts function as an iron supply hub.
    Hijiri Oshio, Isshin Shiiba, Naoki Ito, Naozumi Okada, Fuya Yamaguchi, Yuto Ishikawa, Shun Nagashima, Yuuta Fujikawa, Keitaro Umezawa, Yuri Miura, Misaki Shimizu, Yoshiro Saito, Tomoyuki Yamaguchi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.
    DOI:  https://doi.org/10.1038/s41556-026-01974-0
  12. Nature. 2026 Jun;654(8119): 605-606
    Mitochondria tethered to the nucleus secure its energy supply.
    Philippa Clarke, Sophie Trefely.
      
    Keywords:  Cell biology; Developmental biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-01587-5
  13. Stem Cell Reports. 2026 Jun 11. pii: S2213-6711(26)00162-1. [Epub ahead of print] 102951
    Electron transport chain complex I and mitochondrial fusion regulate ROS for differentiation in Drosophila neural stem cells.
    Rahul Kumar Verma, Atharva Bhingare, Dnyanesh Dubal, Richa Rikhy.
      Mitochondrial fusion and electron transport chain complex I are each essential for differentiation in Drosophila neuroblasts, but the mechanism by which they interact to mediate differentiation is unknown. We found that complex I subunit depletion did not affect type II neuroblast numbers but reduced their proliferation and decreased their lineage cells. Complex I depletion decreased the mitochondrial membrane potential and cristae numbers, increased fragmentation and ROS, and inhibited Notch signaling in lineage cells. Similarly, antioxidant enzyme depletion increased ROS and reduced lineage cells. Both complex I and antioxidant proteins promoted the G1/S transition and nuclear cyclin E levels. Additional mitochondrial fusion via Drp1 mutants restored ROS levels, proliferation, and differentiation defects in complex I and antioxidant protein-depleted neuroblasts. Overexpression of antioxidant proteins and an increase in Notch signaling alleviated ROS and the complex I depletion-driven defect in neuroblast proliferation and differentiation. Complex I and mitochondrial fusion together restrict ROS to support neuroblast proliferation and differentiation.
    Keywords:  Drosophila; Drp1; Notch; complex I; differentiation; mitochondria; mitochondrial fragmentation; mitochondrial fusion; neural stem cells; neuroblasts
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102951
  14. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2534946123
    Expression of four mitochondrial tRNAs from only two loci.
    Jessica M Warren, Kasavajhala V S K Prasad, Anistynn M Mendez, Stephanie Temnyk, John P McCutcheon.
      Transfer RNAs (tRNAs) are among the few genes retained in animal mitochondrial genomes after more than a billion years of gene loss. These ancient bacterial vestiges are often structurally aberrant and less stable than their bacterial or cytosolic tRNA counterparts. In some lineages, mitochondrial tRNAs (mt-tRNAs) have become so truncated that the loss of one or both arms has expanded our understanding of what constitutes a functional tRNA. Here, we report another radical departure from canonical tRNA gene architecture: two overlapping tRNAs produced from opposite strands of the same locus. These "mirror" tRNA pairs eliminate the need to retain separate loci for all tRNA genes, as a single locus can produce tRNAs to decode two different amino acids. We show that these mirror tRNAs are aminoacylated and demonstrate their presence in mitoribosomes. Furthermore, mirror tRNAs display strand-specific patterns of nucleotide modification and RNA editing, reflecting specific posttranscriptional maturation that depends on transcriptional orientation. This demonstration of functional, bidirectional tRNA expression reveals an unexpected strategy by which mitochondrial genomes maintain a complete set of tRNAs in the face of unrelenting gene loss. The presence of mirror tRNAs has broad implications for the evolution of tRNA-interacting enzymes, mitochondrial biology, and even the origins of the protein synthesis machinery itself.
    Keywords:  bidirectional transcription; mitochondrial genome evolution; mitochondrial tRNAs
    DOI:  https://doi.org/10.1073/pnas.2534946123
  15. Nat Commun. 2026 Jun 12.
    Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
    Angelica E Lang, Chris Stein, Roger Schultz, Catherine M Drerup.
      To maintain a functional mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because most mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires communication between mitochondria and the nucleus. This can be a challenge in a large, compartmentalized cell like a neuron in which a significant portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with nuclear expression of mitochondrial genes. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.
    DOI:  https://doi.org/10.1038/s41467-026-74127-4
  16. Nanomaterials (Basel). 2026 Jun 04. pii: 698. [Epub ahead of print]16(11):
    Engineered Tan-CDs@AS-IV Nanosystem Orchestrates Mitochondrial Biogenesis and Intercellular Transfer to Restore Endothelial Function via PGC-1α and Cx43 Signaling Pathways.
    Haoran Wang, Xiaoyu Wang, Shuo Liu, Chunzhao Liu.
      Ischemic diseases are characterized by the functional collapse of endothelial cells (ECs) triggered by insufficient tissue perfusion. Given that mitochondria serve as the metabolic hub of ECs, their homeostatic imbalance, which is manifested by adenosine triphosphate (ATP) depletion, reactive oxygen species (ROS) bursts, and mitochondrial permeability transition pore opening, serves as the initiating factor driving impaired angiogenesis and tissue necrosis. In this study, we engineered an integrated nanosystem (Tan-CDs@AS-IV) by transforming Tanshinone into antioxidant carbon dots to encapsulate Astragaloside IV, achieving multi-level synergistic regulation of mitochondrial function. Our results demonstrate that Tan-CDs@AS-IV possesses superior structural stability and cellular internalization capabilities, significantly enhancing the migration and tubulogenesis of ECs under ischemic stress. Mechanistically, Tan-CDs@AS-IV effectively scavenges mitochondrial ROS and restores membrane potential and ATP production. Crucially, the nanosystem orchestrates mitochondrial biogenesis via peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) upregulation while simultaneously facilitating intercellular mitochondrial transfer through Connexin 43 (Cx43)-mediated gap junctions. This synergistic "endogenous amplification and intercellular replenishment" model establishes a robust mitochondrial quality control relay. By reconstructing cellular energy homeostasis, this study provides a novel nanoengineering strategy for the targeted therapy of ischemic diseases.
    Keywords:  PGC-1α/Cx43 signaling; carbon dot-based nanosystem; endothelial function; intercellular mitochondrial transfer; mitochondrial biogenesis
    DOI:  https://doi.org/10.3390/nano16110698
  17. Nat Commun. 2026 Jun 10.
    A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
    Sarin Segev-Nakar, Itay Koren.
      Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.
    DOI:  https://doi.org/10.1038/s41467-026-74117-6
  18. Science. 2026 Jun 11. 392(6803): 1128-1129
    The placental metabolic clock.
    Kiyoshi Yoshioka, Shin-Ichiro Imai.
      NAD+ depletion triggers a countdown to birth in mice.
    DOI:  https://doi.org/10.1126/science.aei4119
  19. Nat Cell Biol. 2026 Jun 11.
    Proteomics-based insights into mammalian oocyte and early embryo development.
    Sifan Rong, Zhuocheng Liu, Wencheng Zhu, Liangshan Mu.
      Advances in proteomics are transforming our understanding of mammalian oocyte maturation and preimplantation embryo development. These resources and their findings provide unprecedented insights into the molecular underpinnings of developmental competence. Here we summarize the ongoing development of proteomic methodologies and highlight the stage-specific reprogramming events of the proteome in both humans and mice, underscoring the unique utility of proteomics in deciphering oocyte maturation and early embryonic development. Furthermore, we discuss the clinical implications of these findings, highlighting the translational potential of proteomics in understanding reproductive ageing, improving oocyte quality, and refining the outcomes of assisted reproductive technology.
    DOI:  https://doi.org/10.1038/s41556-026-01993-x
  20. Int J Mol Sci. 2026 May 22. pii: 4689. [Epub ahead of print]27(11):
    Single-Cell Imaging of Mitochondrial Metabolism and Remodeling in C2C12 Murine Skeletal Muscle Cells upon Differentiation.
    Rozhin Penjweini, Alessandra Pasut, Branden Roarke, Katie A Link, Dan L Sackett, Jay R Knutson.
      As primary sites for oxygen consumption and energy production via oxidative phosphorylation (OXPHOS), mitochondria play a central role in the regulation of bioenergetics and generation of key metabolic intermediates for myogenic cell growth. Common methods to study mitochondria and their metabolism typically rely on population-level analyses, which can mask potential differences in individual cells. In this study, we used various imaging approaches to investigate the interplay between intracellular oxygenation, mitochondrial metabolism and dynamics in a model of myogenic differentiation. Fluorescence imaging of intracellular oxygen revealed that myogenic differentiation is accompanied by progressive shifts in intracellular oxygenation that depend upon and reflect changes in mitochondrial metabolism (i.e., higher oxygen consumption and adenosine triphosphate (ATP) production). By measuring intracellular oxygenation, we showed that mitochondrial metabolism reduces oxygen availability in the cytosol and the nucleus. Real-time redox imaging at the single-cell level further highlighted substantial metabolic heterogeneity and a shift toward OXPHOS as differentiation progressed. Morphological analyses revealed that during myogenic differentiation, mitochondria increase in size while becoming less mobile and overlapping less with microtubules. Overall, this study illustrates the value of combining complementary imaging approaches to provide a comprehensive single-cell perspective on mitochondrial metabolism, remodeling and spatial organization during myogenesis.
    Keywords:  mitochondrial metabolism; mitochondrial morphology and dynamics; single-cell imaging
    DOI:  https://doi.org/10.3390/ijms27114689
  21. Nat Rev Mol Cell Biol. 2026 Jun 09.
    Programmable delivery of mitochondria to specific cell types.
    Temurkhan Ayupov.
      
    DOI:  https://doi.org/10.1038/s41580-026-00986-w
  22. Biochim Biophys Acta Mol Cell Res. 2026 Jun 09. pii: S0167-4889(26)00069-8. [Epub ahead of print] 120171
    Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.
    Ahram Ahn, Seungwoo Hong, Michele Brischigliaro, Flavia Fontanesi, Antoni Barrientos.
      Mammalian mitochondrial gene expression operates within an unusually compact genomic architecture in which most regulatory information must be encoded within or immediately adjacent to protein-coding sequences. In this context, mitochondrial mRNAs function not merely as templates for translation but as structured molecules whose folding landscape contributes to multiple stages of gene expression. Recent advances in chemical probing, mutational profiling, and mitoribosome profiling have begun to disclose the human mitochondrial mRNA structurome in its native organellar context, revealing a transcriptome that is broadly accessible yet punctuated by localized structural elements and alternative conformational states. These studies indicate that RNA structure contributes to translation initiation on leaderless transcripts, elongation kinetics, translational coupling across bicistronic junctions, and dynamic remodeling during membrane protein synthesis. They also highlight the role of RNA-binding proteins, including LRPPRC-SLIRP and related factors, in maintaining a translation-competent folding environment. In this review, we discuss the structural organization of mitochondrial mRNAs, the experimental approaches that enabled its analysis, and emerging mechanistic links between RNA folding, translational regulation, and respiratory chain biogenesis. We further discuss how alterations in mt-mRNA structure may represent an underappreciated determinant of mitochondrial disease and consider implications for future diagnostic and therapeutic strategies.
    Keywords:  Bicistronic transcripts; Mitochondrial RNA folding; Mitochondrial RNA processing; Mitochondrial RNA structurome; Mitochondrial gene expression; Mitochondrial translation
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120171
  23. Mitochondrion. 2026 Jun 06. pii: S1567-7249(26)00073-5. [Epub ahead of print]91 102183
    TTC19 and FMNL2 gene variants in a pediatric case of mitochondrial disorder with renal tubular acidosis.
    Prince Jacob, Sekar Deepha, Akhila Vasanth Hassan, Shilpa Rao, Rashmi Santhoshkumar, Kanika Vasudeva, Siddharth Kapahtia, Meenakshi Sharma, Bevinahalli Nanjegowda Nandeesh, Madhu Nagappa, Periyasamy Govindaraj.
      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.
    Keywords:  Complex III; FMNL2; Mitochondrial disorder; Renal tubular acidosis; TTC19
    DOI:  https://doi.org/10.1016/j.mito.2026.102183
  24. JCI Insight. 2026 Jun 09. pii: e196134. [Epub ahead of print]
    Omega-3 fatty acid supplementation improves skeletal muscle mitochondrial function in a model of Barth syndrome.
    Katharina B Kuentzel, Ana Vranešević, Samuel Aj Trammell, Fabian Finger, Jesper F Havelund, Yvette L Schooneveldt, Ivan Bradić, Nicoline R Andersen, Anna S Hassing, Katja T Michler, Martin R Larsen, Zachary Gerhart-Hines, Steven M Claypool, Jonas T Treebak, Andreas M Fritzen, Matthew P Gillum, Steen Larsen, Nils Færgeman, Trisha J Grevengoed.
      The composition of mitochondrial membrane lipids is crucial to cellular respiration, as seen in Barth syndrome (BTHS), a rare disease affecting skeletal muscle, heart, and neutrophils. In BTHS, mutations in the tafazzin (TAZ) gene reduce remodeling of the mitochondrial phospholipid, cardiolipin, causing mitochondrial dysfunction in skeletal muscle and heart. Here, we investigated effects of altering polyunsaturated fatty acid content in cardiolipin using preclinical models of BTHS. In vitro, the absence of TAZ did not impair omega-3 fatty acid incorporation into cardiolipin and resulted in increased turnover of these acyl chains. To examine this in a functional model, we generated a muscle-specific knockout mouse of TAZ (TAZ MKO), which recapitulated the human phenotype in skeletal muscle. Supplementing the diet of TAZ MKO with fish-oil-derived omega-3 fatty acids prevented lean mass loss, improved mitochondrial respiration, altered mitochondrial structure, and revealed moderate improvements in the stress response. Surprisingly, no diet-induced changes to cardiolipin species were observed in the TAZ MKO, but other phospholipids were altered by both genotype and diet, revealing complex regulation and potential compensation. Overall, this work provides evidence that omega-3 fatty acid supplementation is beneficial in muscle lacking TAZ to improve quality of life when added to current BTHS treatments.
    Keywords:  Lipidomics; Metabolism; Mitochondria; Muscle biology
    DOI:  https://doi.org/10.1172/jci.insight.196134
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