bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–03–22
twenty-one papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson's disease models.
  2. MFF budding from mitochondria regulates melanosome size and maturation.
  3. Masked mitochondria slip into cells to treat disease in mice.
  4. Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.
  5. Structures of respiratory supercomplexes and ATP synthase oligomers in mammalian mitochondrial inner membrane.
  6. Disturbed mitochondrial maturation in cardiolipin remodeling-deficient cardiomyocytes.
  7. MitoTracker transfers from astrocytes to neurons independently of mitochondria.
  8. Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.
  9. Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
  10. Progressive cognitive impairment and ventricular tachycardia in a boy with biallelic POLG variants and a de novo RYR2 variation.
  11. Skeletal muscle metabolism in health and disease: Mechanisms, interventions, and clinical perspectives.
  12. In vivo base editing reverses a neurodevelopmental disorder.
  13. Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
  14. Quantitative imaging of mitochondrial redox conditions at the single-organelle level.
  15. Extracellular matrix signals promote actin-dependent mitochondrial elongation and activity.
  16. Placental dysregulation of mitochondrial morphology and dynamics as a hallmark of maternal age-related adaptation.
  17. Pregnancy precipitates metabolic imbalance and accelerates death in an animal model of mitochondrial cardiomyopathy.
  18. Bisphenol-A impairs hippocampal neurogenesis by disrupting Kinesin-1-dependent mitochondrial trafficking.
  19. Therapeutic Targeting of the Mitochondrial Dysfunction-PANoptosis Axis: Mechanistic Insights and Emerging Strategies.
  20. The NAD-brain pharmacokinetic study of NAD augmentation in blood and brain using oral precursor supplementation.
  21. Demonstration of beat-to-beat, on-demand ATP synthesis in ventricular myocytes reveals sex-specific mitochondrial and cytosolic dynamics.
  1. Cell. 2026 Mar 18. pii: S0092-8674(26)00230-8. [Epub ahead of print]
    Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson's disease models.
    Shiwei Du, Qi Long, Yanshuang Zhou, Jiangqin Fu, Hao Wu, Liang Yang, Yaohang Xie, Yingzhe Ding, Maolei Zhang, Jingyi Guo, Mengfei Wang, Jiajun Lin, Mingli Hu, Jian Zhang, Deyang Yao, Wei Li, Feixiang Bao, Ge Xiang, Yi Wu, Yile Huang, Haozhao Liang, Rui Wang, Heying Li, Baodan Chen, Chong Li, Junwei Wang, Jiwei Zhang, Dajiang Qin, Jianwei Sun, Yun Zhu, Fei Sun, Wuming Wang, Gang Lu, Wai-Yee Chan, Hui Zhao, Chenli Liu, Xingguo Liu.
      Mitochondrial transplantation holds significant potential for the treatment of mitochondrial diseases. However, how to efficiently deliver exogenous mitochondria to somatic cells or tissues remains unresolved. We present a mitochondrial transplantation approach to deliver mitochondria into the cells and tissues of mice and monkeys with high efficiency, based on encapsulating mitochondria with vesicles derived from the plasma membrane of erythrocytes. Treatment with encapsulated mitochondria complemented the loss, deletion, or mutation of mitochondrial DNA, thereby rescuing the associated bioenergetic and biochemical defects in patient-derived cells with mitochondrial disorders. Furthermore, mitochondrial capsules rescued the mitochondrial DNA depletion syndrome and Leigh syndrome in Dguok-/- and Ndufs4-/- mouse models, respectively. Moreover, in a mouse model of Parkinson's disease, mitochondrial capsules rescued neuron loss, improved motor skills, and restored mitochondrial function in the affected brain regions. Our study demonstrates the potential of this mitochondrial capsule as a treatment for mitochondrial disorders and proposes an "organelle therapy" strategy in regenerative medicine.
    Keywords:  Parkinson’s disease; degenerative disease; extracellular vesicle; mitochondria; mitochondrial diseases; mitochondrial transfer; mtDNA depletion syndrome; mtDNA mutation; organelle therapy
    DOI:  https://doi.org/10.1016/j.cell.2026.02.023
  2. Nat Commun. 2026 Mar 14.
    MFF budding from mitochondria regulates melanosome size and maturation.
    Ana Paula Magalhães Rebelo, Aurora Maracani, Samuele Greco, Federica Dal Bello, Lucia Santorelli, Marco Gerdol, Alberto Pallavicini, Tomas Knedlik, Sara Schiavon, Luca Scorrano, Philip S Goff, Christian Frezza, Elena V Sviderskaya, Paolo Grumati, Marta Giacomello.
      Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1 (DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-70572-3
  3. Nature. 2026 Mar 19.
    Masked mitochondria slip into cells to treat disease in mice.
    Edward Chen.
      
    Keywords:  Cell biology; Gene therapy; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-00869-2
  4. Nat Commun. 2026 03 16. pii: 2532. [Epub ahead of print]17(1):
    Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.
    Yu-Hsin Hsieh, Pauline Kautz, Lena Nitsch, Ambre M Giguelay, Janet Liebold, Veronika Dimitrova, Stephania Contreras Castillo, Freya Jungen, Gabor Zsurka, Genevieve Trombly, Markus Schuelke, Wolfram S Kunz, Caleb A Lareau, Leif S Ludwig.
      Mitochondrial DNA (mtDNA) mutations occur more frequently than nuclear mutations and are associated with various diseases. While single-cell sequencing enables mtDNA variant heteroplasmy analysis, a holistic view of mtDNA mutational landscapes in individual cells has remained limited. Here, we leverage mitochondrial single-cell ATAC-seq and mtDNA-hypermutated POLGD274A knock-in HEK293 cell lines to introduce two metrics-single-cell mtDNA mutations per million base pairs (scmtMPM) and heteroplasmy-weighted mitochondrial local constraint scores (scwMSS)-to capture cellular mutational loads and somatic mosaicism. We demonstrate that individual POLGD274A cells exhibit complex mutational landscapes, with pathogenic mutations and truncating variants only present at subthreshold levels, indicative of their negative selection. In human healthy donors and mitochondriopathy patients, we identify constrained mutations in complex I, highlighting previously unrecognized mtDNA mutational landscape heterogeneity present on the single-cell level. Overall, scmtMPM and scwMSS provide a framework to investigate fundamental properties of mitochondrial genetics, disease, and somatic mosaicism.
    DOI:  https://doi.org/10.1038/s41467-026-70399-y
  5. Nat Commun. 2026 Mar 17.
    Structures of respiratory supercomplexes and ATP synthase oligomers in mammalian mitochondrial inner membrane.
    Atsuki Nakano, Takahiro Masuya, Shinsuke Akisada, Moe Ishikawa-Fukuda, Kaoru Mitsuoka, Hideto Miyoshi, Masatoshi Murai, Ken Yokoyama.
      Understanding the functional mechanisms of membrane protein complexes requires structural analysis within their native membrane environment. Here, we applied cryo-electron microscopy to determine the structures of FoF1 ATP synthase and respiratory supercomplexes (SCs) on sub-mitochondrial particles (SMPs) isolated from bovine heart mitochondria. Most FoF1 complexes were observed as dimers stabilized by the regulatory factor IF₁, and a tetrameric assembly comprising two FoF1-IF₁ dimers arranged linearly was also identified. This finding indicates that the tetrameric units of FoF1 are present in the mitochondrial inner membrane and contribute to shaping cristae tips in mammalian mitochondria. Fo domain maps resolve the e-subunit- c₈-ring interface and show no discrete density for a tightly bound lipid within the c₈-ring. In addition to the previously reported SCs compositions CI₁CIII₂CIV₁ and CI₁CIII₂CIV₂, our analysis identified an additional assembly with the composition CI₁CIII₂CIV₃, as well as a CI₂CIII₂CIV₆ mega-complex. This approach enables rapid structural determination of FoF1 ATP synthase and SCs from minimal membrane fractions, providing a foundation for elucidating the molecular basis of metabolic disorders and mitochondrial diseases at the level of higher-order architecture.
    DOI:  https://doi.org/10.1038/s41467-026-70578-x
  6. iScience. 2026 Mar 20. 29(3): 115111
    Disturbed mitochondrial maturation in cardiolipin remodeling-deficient cardiomyocytes.
    Nanami Senoo, Macie S Sheridan, Yvonne Wohlfarter, Mackenzie T Primrose, Emmanouil Tampakakis, Markus A Keller, Steven M Claypool.
      Barth syndrome, a rare X-linked genetic disorder, features early-onset cardiomyopathy. The causal gene, TAFAZZIN, encodes a transacylase that mediates the acyl chain remodeling of cardiolipin, a critical phospholipid in the inner mitochondrial membrane. While Barth syndrome exhibits hallmark cardiolipin abnormalities, the precise mechanisms linking TAFAZZIN deficiency and disturbed cardiolipin metabolism to progressive cardiac dysfunction remain unclear. In this study, we modeled Barth syndrome cardiomyopathy in human induced pluripotent stem cell-derived cardiomyocytes with in vitro maturation treatments that simulate heart developmental stimuli. We found that cardiomyocyte maturation involves progressive cristae dynamics associated with protein and lipid alterations in the inner mitochondrial membrane. TAFAZZIN-deficient cardiomyocytes fail to adapt to the developmental stimuli, resulting in damaged cristae, compromised mitochondrial respiration, and cardiomyocyte dysfunction. These results demonstrate that TAFAZZIN deficiency perturbs functional and structural development of mitochondria, which may contribute to mitochondrial dysfunction and associated childhood progression to cardiomyopathy in Barth syndrome.
    Keywords:  Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115111
  7. Cell Rep Methods. 2026 Mar 13. pii: S2667-2375(26)00038-X. [Epub ahead of print] 101338
    MitoTracker transfers from astrocytes to neurons independently of mitochondria.
    Katriona L Hole, Rosalind Norkett, Emma Russell, Patrick Cottilli, Molly Strom, Jack H Howden, Nicola J Corbett, Janet Brownlees, Michael J Devine.
      The neuroprotective transfer of mitochondria from astrocytes to neurons has been primarily investigated by labeling astrocytic mitochondria with the dye MitoTracker. Here, we labeled astrocytic mitochondria with both a genetically encoded fluorophore (GFP) and MitoTracker dye and then imaged neurons immediately after co-culture with astrocytes or astrocyte-conditioned media (ACM). We report that MitoTracker transfers to neurons from both astrocytes and ACM, independently of mitochondrial transfer. Our observations provide an essential caveat to the use of this reagent and suggest that the investigation of astrocyte-neuron mitochondrial transfer, and other systems in which contact-independent transfer has been reported, requires the use of alternative labeling techniques.
    Keywords:  CP: cell biology; CP: neuroscience; MitoTracker; astrocyte; intercellular mitochondrial transfer; mitochondria; neuron
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101338
  8. Eur J Neurosci. 2026 Mar;63(6): e70463
    Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.
    Anna Henrich, Hannah Scheiblich.
      Mitochondria are central regulators of cellular metabolism, calcium homeostasis and survival. Owing to the brain's exceptional energy demand, mitochondrial dysfunction is tightly linked to neurodegenerative and neuroinflammatory disorders. Recent evidence challenges the traditional view of mitochondria as strictly cell-autonomous organelles, revealing that they can be exchanged between cells via intercellular transfer by extracellular vesicles, gap junctions or tunnelling nanotubes (TNTs) as part of an adaptive mechanism of metabolic support and signalling. Among the pathways mediating this intercellular exchange, TNTs-thin, actin-rich cytoplasmic bridges-have emerged as key conduits for mitochondrial transfer in the nervous system. TNTs enable bidirectional exchange of mitochondria between neurons, glia and vascular cells, thereby promoting bioenergetic recovery after injury and modulating immune and inflammatory responses. This review summarizes current evidence for TNT-mediated mitochondrial transfer in the brain and highlights the underlying molecular mechanisms that coordinate mitochondrial movement, including cytoskeletal dynamics, mitochondrial trafficking machinery and stress-induced signalling cascades. While mitochondrial donation can restore metabolic balance and promote neuroprotection, it may also facilitate the spread of pathological proteins, contributing to disease progression. Understanding the underlying molecular mechanism of TNT-mediated mitochondrial transfer provides a new framework for exploring metabolic communication and cellular resilience in the brain. By emphasizing emerging conceptual and mechanistic insights, we outline how advancing this field could pave the way for the development of innovative therapeutic strategies for neurodegenerative and neuroinflammatory disorders.
    Keywords:  Miro1/2; actin dynamics; cell–cell connectivity; cytoskeletal remodelling; intercellular communication
    DOI:  https://doi.org/10.1111/ejn.70463
  9. Cell. 2026 Mar 17. pii: S0092-8674(26)00224-2. [Epub ahead of print]
    Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
    Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.
      Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and type 2 diabetes.
    Keywords:  bioenergetics; diabetes; glyceroneogenesis; hepatic steatosis; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.cell.2026.02.017
  10. Sci Rep. 2026 Mar 20.
    Progressive cognitive impairment and ventricular tachycardia in a boy with biallelic POLG variants and a de novo RYR2 variation.
    Valentina Fumini, Alexandru Ionut Gilea, Elena Tacchetto, Leonardo Salviati, Enrico Baruffini, Mara Doimo.
      Routine use of next-generation sequencing has shown that most common phenotypes are genetically heterogeneous and that in many cases, mutations in the same gene may cause markedly different phenotypes. Furthermore, complex clinical presentations are often due to multiple coexisting genetic defects. Here, we describe a patient with a complex clinical phenotype: a childhood-onset neurodevelopmental disorder with progressive intellectual disability, and supraventricular tachyarrhythmias that led to cardiac arrest in early teens. The complex phenotype is paralleled by a complex genotype. The neurological manifestations were likely due to biallelic POLG variants. POLG encodes the catalytic subunit of mitochondrial polymerase gamma. Pathogenic POLG variants cause both autosomal and recessive diseases, with a wide variety of clinical presentations. This heterogeneity makes validating novel substitutions challenging. One of the patient's variants, p.(W113R), was novel, and to assess its pathogenicity, we employed a functional yeast-based assay. The cardiac phenotype was likely due to a de novo pathogenic variant in the RYR2 gene, which encodes a calcium release channel that plays an essential role in heart excitation-contraction coupling. The yeast assay was essential to establish the pathogenicity of the novel POLG variant and to correctly characterize this complex genotype.
    Keywords:   POLG ; POLG-related disorder; RYR2 ; Neurodevelopmental disorder; supraventricular tachyarrhythmias; yeast model
    DOI:  https://doi.org/10.1038/s41598-026-44913-7
  11. iScience. 2026 Mar 20. 29(3): 115024
    Skeletal muscle metabolism in health and disease: Mechanisms, interventions, and clinical perspectives.
    Donghai Lin, Linglin Zhang, Caihua Huang, Wei Shao.
      Skeletal muscle is a vital metabolic organ that regulates systemic energy homeostasis by coordinating glucose uptake, fatty acid oxidation, and amino acid metabolism. Its remarkable capacity for dynamic adaptation, termed metabolic flexibility, underpins physical performance and protects against metabolic diseases such as obesity, type 2 diabetes, and sarcopenia. This review provides an integrative synthesis of the molecular and signaling networks that orchestrate skeletal muscle metabolism, focusing on key regulators including insulin, AMPK, mTOR, and PGC-1α. We also examine how disruptions in these pathways lead to mitochondrial dysfunction, lipid dysregulation, and muscle wasting. We explore the therapeutic landscape across pharmacological, exercise-based, and nutritional interventions, emphasizing mitochondrial-targeted strategies and myokine-mediated communication as emerging modalities for restoring metabolic resilience. Additionally, we emphasize the growing importance of multi-omics technologies and inter-tissue communication in improving mechanistic understanding and advancing precision medicine. This review integrates mechanistic, translational, and clinical perspectives to underscore the importance of a systems-level approach to skeletal muscle metabolism. This approach is essential for developing targeted, multidimensional therapies aimed at enhancing metabolic health and extending healthspan.
    Keywords:  endocrinology; health sciences; medical specialty; medicine
    DOI:  https://doi.org/10.1016/j.isci.2026.115024
  12. Nat Biotechnol. 2026 Mar;44(3): 369
    In vivo base editing reverses a neurodevelopmental disorder.
    Iris Marchal.
      
    DOI:  https://doi.org/10.1038/s41587-026-03070-y
  13. FEBS J. 2026 Mar 19.
    Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
    Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.
      The stress-inducible protein Sestrin2 (SESN2) has recently emerged as an orchestrator of mitochondrial signaling. The regulation of mitochondria-related pathways, such as aerobic respiration, is thought to be mediated by SESN2, but the underlying mechanisms are not fully understood. Here, we characterized mitochondria in Sesn2-knockdown myoblasts under physiological conditions using oxygen consumption rate measurements, fluorescence microscopy, and protein content analysis. We discovered that SESN2 is essential for sustaining oxidative phosphorylation and maintaining the mitochondrial network organization. SESN2 loss diminished ATP production, decreased the levels of nuclear- and mitochondrial-encoded complex IV subunits, and increased superoxide generation. Moreover, the assessment of mitochondrial distribution in Sesn2-knockdown cells revealed a more fragmented network. This was associated with an increased ratio of short to long optic atrophy 1 (OPA1) forms. Remarkably, disruption of mitochondrial signaling suppressed cellular proliferation and altered both cell and nuclear morphology. In summary, our findings suggest that SESN2 plays an important role in maintaining cellular homeostasis, partly through its impact on mitochondrial function.
    Keywords:  SESN2; mitochondria; mitochondrial dynamics; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/febs.70497
  14. Mitochondrion. 2026 Mar 13. pii: S1567-7249(26)00037-1. [Epub ahead of print]89 102147
    Quantitative imaging of mitochondrial redox conditions at the single-organelle level.
    Steffen Pöschel, Michael Müller.
      Mitochondria are morphologically and functionally heterogeneous and dynamically adapt to the current metabolic status of their hosting cell. Moreover, they are prominent sources but also sensitive targets of redox modulation and oxidative stress. Such subcellular ROS/redox signals are considered pivotal aspects in health and disease. Yet, their deciphering requires advanced optical tools. Here we took advantage of transgenic redox-indicator mice expressing a mitochondria-targeted reduction/oxidation-sensitive green fluorescent protein (roGFPm) in excitatory projection neurons. By excitation-ratiometric two-photon microscopy we quantified in acute brain slices the redox conditions of individual mitochondria. After developing adequate redox sensor calibrations and solving laser-mediated bleaching issues, we finally chose caudoputamen, which showed the most promising mitochondrial arrangement for our imaging approach. Confirming the reliability of single-mitochondria redox imaging, we characterized the interplay of redox state and mitochondrial morphology. In general, roGFPm was more oxidized in spherical than in filamentous mitochondria. Acute hypoxia reverted mitochondria to a more roundish shape and evoked a reducing shift. Furthermore, the fraction of spherical mitochondria increased with aging. Around postnatal day (pd)350, a significantly higher fraction of roundish mitochondria was present in females than in males. In addition, from pd150 on, female mice showed lower degrees of roGFPm oxidation than males. Both findings might be linked to estrogen levels, which decrease in female mice with reproductive senescence around pd350. In view of the pivotal role of mitochondria for cellular wellbeing and their involvement in various neuropathologies, the established single-organelle redox-imaging approach will foster further detailed studies.
    Keywords:  2-photon microscopy; Aging; Hypoxia; Mitochondria; Reactive oxygen species; Redox imaging; roGFP
    DOI:  https://doi.org/10.1016/j.mito.2026.102147
  15. iScience. 2026 Mar 20. 29(3): 115171
    Extracellular matrix signals promote actin-dependent mitochondrial elongation and activity.
    Priya Gatti, Pritha Mukherjee, Priyanka Dey Talukdar, Wesley Freppel, Anahita Kasmaie, Joseph Kanou, Laurent Chatel-Chaix, Urmi Chatterji, Marc Germain.
      Mitochondria are crucial metabolic organelles regulated by both intracellular and extracellular cues. The extracellular matrix (ECM) is a key component of the cellular environment that controls cellular behavior and metabolic activity. Here, we determined how ECM signaling regulates mitochondrial structure and activity. To distinguish mitochondrial regulation from general ECM-regulated survival cues, we used mammospheres derived from breast cancer cells because of their ability to grow in suspension culture in the absence of ECM. Using this system, we demonstrate that the association of mammospheres with the ECM results in dramatic mitochondrial elongation, along with enhanced mitochondrial respiration and ATP production. This remodeling occurs independently of DRP1 activity but relies on integrin signaling and actin polymerization. Therefore, our findings demonstrate that ECM-driven actin polymerization plays a crucial role in remodeling mitochondrial networks to promote OXPHOS, which represents a vital step for migrating cells to enhance cellular adhesion and facilitate cell growth.
    Keywords:  Biological sciences; Cell biology; Integrative aspects of cell biology; Organizational aspects of cell biology; Specialized functions of cells
    DOI:  https://doi.org/10.1016/j.isci.2026.115171
  16. Life Sci. 2026 Mar 19. pii: S0024-3205(26)00147-5. [Epub ahead of print]393 124338
    Placental dysregulation of mitochondrial morphology and dynamics as a hallmark of maternal age-related adaptation.
    Juan M Toledano, Maria Puche-Juarez, María Paz Carrillo, Javier Diaz-Castro, Javier Sanchez-Romero, Francisco Manuel Ocaña-Peinado, Catalina de Paco Matallana, Estefania Martín-Alavarez, Jorge Moreno-Fernandez, Julio J Ochoa.
       AIMS: Advanced maternal age (AMA), increasingly prevalent worldwide, is linked to obstetric risk even in clinically uncomplicated pregnancies. Mitochondria are essential for trophoblast metabolism and stress adaptation, and their alteration is associated with gestational pathologies. However, it remains unclear whether maternal age alone alters placental mitochondrial homeostasis.
    MATERIALS AND METHODS: Human placentas from AMA and control pregnancies were analysed by transmission electron microscopy (TEM) to assess mitochondrial ultrastructure and mitochondria-endoplasmic reticulum contacts (MERCs). Western blotting was used to evaluate regulators of mitochondrial fusion, fission, and mitophagy.
    KEY FINDINGS: placentas from AMA pregnancies showed a significant increase in mitochondrial number in both syncytiotrophoblast and cytotrophoblast cells, with regional variation between maternal and foetal sides. Despite increased abundance, mitochondria were smaller (reduced area and perimeter), indicating a fragmented phenotype, while circularity was unchanged. MERCs exhibited decreased distance and increased ER coverage, suggesting enhanced stress signaling and fission. Western blotting revealed decreased MFN1 with increased OPA1 and DRP1 expression, whereas MFN2, FIS1, and DNM2 remained unchanged. Mitophagy markers were dysregulated, with reduced OPTN and BNIP3 but elevated FUNDC1.
    SIGNIFICANCE: AMA is associated with fragmented and stress-adapted placental mitochondria, showing structural imbalance in dynamics and altered quality control even in the absence of clinical pathology. These features may reflect reduced placental capacity to buffer metabolic and stress challenges and contribute to increased vulnerability in pregnancies of older mothers, positioning mitochondria as a potential target for monitoring and improving outcomes in this population.
    Keywords:  Advanced maternal age; Mitochondria; Mitochondrial dynamics; Placenta; Pregnancy; Transmission electron microscopy
    DOI:  https://doi.org/10.1016/j.lfs.2026.124338
  17. Mol Metab. 2026 Mar 16. pii: S2212-8778(26)00036-0. [Epub ahead of print] 102352
    Pregnancy precipitates metabolic imbalance and accelerates death in an animal model of mitochondrial cardiomyopathy.
    Nicole M Sayles, Gabriella Casalena, Dazhi Zhao, Ryan W Dellinger, Holly E Holmes, Onorina Manzo, Alexander Galkin, Annarita Di Lorenzo, Giovanni Manfredi.
      During pregnancy, the heart undergoes major physiological and metabolic changes to increase cardiac workload and the demand for energy production is especially elevated during the trial of labor. Normally, cardiac structure and metabolism revert to the pre-pregnancy state shortly after delivery. However, in some cases peripartum/postpartum cardiomyopathy (PPCM) occurs, which increases a person's risk of major cardiac events following pregnancy. The molecular mechanisms underlying PPCM remain poorly understood. In this study, we investigate the transcriptional, metabolic, and bioenergetic profiles of postpartum (PP) hearts in a mouse model of cardiomyopathy caused by the pathogenic p.S55L mutation in the mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10). Heterozygote p.S55L mutant CHCHD10 mice develop acute heart failure during the immediate PP period. We observe cardiac remodeling, mitochondrial stress, and profound metabolic rewiring in PP mutant CHCHD10 hearts. Metabolic rewiring results decreased levels of heme and the depletion of key cofactors of energy metabolism, including NAD(H) and ADP. These findings suggest that mutant CHCHD10 hearts fail to meet the increased energy demands associated with the trial of labor due to the insufficient turnover rate of NAD+/NADH and ADP/ATP. We propose that this metabolic insufficiency drives PP mortality in mutant CHCHD10 mice. In support of this hypothesis, dietary supplementation with nicotinamide riboside and pterostilbene, a naturally derived polyphenol, increased PP survival and cardiac energy metabolites in mutant CHCHD10 mice. Our work provides novel insights into the molecular mechanisms of PP cardiomyopathy associated with mitochondrial stress and suggests potential beneficiary effects of dietary NAD(H) supplementation.
    Keywords:  CHCHD10; NAD(H); cardiomyopathy; metabolism; mitochondria; postpartum
    DOI:  https://doi.org/10.1016/j.molmet.2026.102352
  18. J Biol Chem. 2026 Mar 14. pii: S0021-9258(26)00245-0. [Epub ahead of print] 111375
    Bisphenol-A impairs hippocampal neurogenesis by disrupting Kinesin-1-dependent mitochondrial trafficking.
    Phoolmala, Saurabh Tiwari, Ranjeet Kumar Yadav, Shweta Singh Chauhan, Rajnish Kumar Chaturvedi.
      Mitochondrial trafficking ensures proper distribution of mitochondria in energy-demanding neural stem cells (NSCs) and neurons, by supplying ATP for neuronal function and survival. We studied the effects of xenoestrogen bisphenol-A (BPA), found in consumable plastic products, on axonal bi-directional mitochondrial trafficking/movement in neurons. Time-lapse live-cell imaging revealed that BPA exposure impaired anterograde and retrograde axonal mitochondrial trafficking, resulting in altered mitochondrial distribution and density in hippocampal NSCs-derived neurons. In silico docking studies identified plausible binding of BPA with Kinesin-1, Dynein, and Syntaphilin (SNPH). BPA postnatal exposure reduced mRNA expression and protein levels of mitochondrial trafficking motor proteins Kinesin-1(KIF5A) and Dynein, and increased mitochondrial static anchor protein SNPH in the rat hippocampus. BPA significantly reduced co-localization of KIF5A and Dynein with TOMM20, Nestin & β-III tubulin in vitro and Sox-2 & NeuN in vivo, and increased SNPH co-localization with TOMM20, Nestin & Sox-2, indicating impaired mitochondrial trafficking during NSCs proliferation and differentiation. Transmission Electron Microscopy revealed reduced axonal mitochondrial density, synaptic density, increased damaged mitochondria, and synaptic loss following BPA exposure. Pharmacological inhibition (Monastrol) and activation (Kinesore) of KIF5A mediated mitochondrial transport caused aggravated and mitigated BPA-mediated impairments in NSCs proliferation and neuronal differentiation. BPA-mediated inhibition of mitochondrial distribution, bioenergetics, and synaptic function was reversed by Kinesore, by increasing mitochondrial & synaptic density, mitochondrial movement, and reducing damaged synapses & mitochondria, leading to cognitive improvements. These findings implicate the role of Kinesin-1(KIF5A) in reversing BPA-mediated impaired mitochondrial transport, reduced hippocampal neurogenesis, and cognitive deficits in rats.
    Keywords:  Bisphenol-A (BPA); Dynein; Hippocampus; Kinesin-1(KIF5A); Mitochondrial trafficking; Neurogenesis; Neurotoxicity; SNPH; Xenoestrogen
    DOI:  https://doi.org/10.1016/j.jbc.2026.111375
  19. Transl Res. 2026 Mar 14. pii: S1931-5244(26)00062-9. [Epub ahead of print]
    Therapeutic Targeting of the Mitochondrial Dysfunction-PANoptosis Axis: Mechanistic Insights and Emerging Strategies.
    Arpit Sharma, Shruti S Raut, Alok Shukla, Amit Singh, Abha Mishra.
      Mitochondria are fundamental organelles that regulate cellular homeostasis through energy production, metabolic integration, and signaling cascades. Beyond their bioenergetic role, mitochondrial dysfunction is increasingly recognized as a pivotal instigator of PANoptosis, a novel, coordinated inflammatory cell death pathway that amalgamates key features of pyroptosis, apoptosis, and necroptosis. This integrated cell death is executed by multiprotein complexes termed PANoptosomes, which are nucleated by specific sensors like ZBP1, AIM2, and NLRC5. Central to this process is the release of mitochondrial danger signals, including reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), which act as potent upstream triggers. For instance, ROS can directly oxidize and activate necroptotic mediators like RIPK1, while cytosolic mtDNA engages innate immune sensors such as cGAS-STING and inflammasomes, thereby initiating PANoptosome assembly. Concurrently, defects in core mitochondrial processes including impaired oxidative phosphorylation, disrupted dynamics (fission/fusion), and faulty mitophagy exacerbate these inflammatory signals, creating a permissive environment for PANoptosis. This mitochondrial-PANoptosis axis is implicated in the pathogenesis of a broad spectrum of diseases. Consequently, therapeutic strategies targeting mitochondrial integrity or specific PANoptotic components hold significant promise for mitigating pathological inflammation and cell loss. This review focuses on the molecular mechanisms linking mitochondrial dysfunction to PANoptosis and explores the translational potential of this interplay to reshape therapeutic approaches in diseases.
    Keywords:  & Mitochondrial dysfunction; Cell death; Immune; PANoptosis; Therapeutics
    DOI:  https://doi.org/10.1016/j.trsl.2026.03.004
  20. iScience. 2026 Mar 20. 29(3): 114764
    The NAD-brain pharmacokinetic study of NAD augmentation in blood and brain using oral precursor supplementation.
    Haakon Berven, Magnus Svensen, Heidi Eikeland, Nora Tvedten, Erika V Sheard, Solveig Amdahl Af Geijerstam, Mona Søgnen, Adrian McCann, Lena Arnsten, Ove Årseth, Vivian Skjeie, Arve Hjellbrekke, Geir-Olve Skeie, Yamila N Torres Cleuren, Gonzalo S Nido, Kristoffer Haugarvoll, Frank Riemer, Charalampos Tzoulis, Christian Dölle.
      Nicotinamide adenine dinucleotide (NAD) augmentation therapy (NAD-AT) is increasingly explored in clinical trials across multiple indications, especially neurological diseases, yet its human pharmacokinetic profile remains incompletely defined. We report findings from a phase I pharmacokinetic trial assessing systemic and cerebral responses to oral NAD precursors in healthy individuals (n = 6) and persons with Parkinson's disease (n = 6) receiving 1,200 mg/day nicotinamide riboside or nicotinamide mononucleotide. Blood NAD increased slowly, plateauing after approximately two weeks of treatment, and declined with similarly slow kinetics following treatment discontinuation. Cerebral NAD levels increased measurably after four weeks of treatment. NAD-related metabolites showed faster increase and washout dynamics compared to NAD itself. Collectively, these data suggest that effective NAD-AT requires sustained oral administration over at least 2-4 weeks and that once-daily dosing is sufficient to maintain stable NAD levels. NAD responses exhibited considerable interindividual variability, but were not influenced by disease status or sex, indicating broad applicability.
    Keywords:  Biopharmaceuticals; Health sciences; Pharmaceutical compounds formulation; Pharmaceutical preparation; Pharmaceutical science
    DOI:  https://doi.org/10.1016/j.isci.2026.114764
  21. J Physiol. 2026 Mar 14.
    Demonstration of beat-to-beat, on-demand ATP synthesis in ventricular myocytes reveals sex-specific mitochondrial and cytosolic dynamics.
    Paula Rhana, Collin Matsumoto, L Fernando Santana.
      The energetic demands on ventricular myocytes imposed by the transport of ions and cross-bridge cycling are well known, yet the spatiotemporal dynamics of ATP supply and demand remain poorly understood. Here, using confocal microscopy and genetically encoded fluorescent sensors targeted to mitochondria and cytosol, we visualized beat-to-beat ATP dynamics in ventricular myocytes from male and female mice. These probes showed fluctuations in mitochondrial ATP levels with each contraction, revealing two distinct, spatially localized waveforms - ATP 'gain' and ATP 'dip' - representing transient increases or decreases in matrix ATP levels, respectively. These waveforms were tightly phase-locked to intracellular Ca2+ transients and organized into energetic microdomains. Inhibition of the mitochondrial Ca2+ uniporter or the adenine nucleotide translocase attenuated these ATP transients. Although female myocytes exhibited larger mitochondrial ATP transients than their male counterparts, their mitochondrial volume was lower. Female myocytes also exhibited tighter coupling between the sarcoplasmic reticulum and mitochondria and showed a higher density of mitofusin 2 and ATP synthase catalytic α-subunit per unit volume, suggesting more efficient ATP production. Cytosolic ATP transients mirrored mitochondrial waveforms and domain structure in both male and female myocytes. During faster pacing, diastolic cytosolic ATP rose more rapidly in female myocytes, whereas beat-locked ATP transients increased in both sexes but proportionally more in males than in females. These findings demonstrate that ATP is synthesized on a beat-to-beat basis in a modular, microdomain-specific manner. We propose that male myocytes rely on greater mitochondrial mass for energetic scaling, whereas female cells employ architectural precision to optimize ATP delivery. KEY POINTS: It is known that each heartbeat requires precise ATP delivery to fuel ion transport and cross-bridge cycling, but the timing and spatial organization of ATP production in heart cells has been unclear. Using advanced imaging and genetically encoded sensors, we visualized beat-to-beat ATP fluctuations in the mitochondria and cytosol of individual male and female mouse ventricular myocytes. Mitochondrial ATP levels rose or fell with each beat in spatially confined regions, forming ATP 'gain' or 'dip' microdomains that were synchronized with Ca2+ transients. At higher firing rates, beat-locked, diastolic ATP transients rose more quickly in female myocytes, but were larger in male myocytes, highlighting distinct sex-specific strategies for matching energy supply to contractile demand. Ventricular myocytes 'live paycheck-to-paycheck', producing just enough ATP on demand to fuel each beat. Male and female myocytes adopt distinct strategies to meet this demand: male myocytes scale output through greater mitochondrial mass, while female myocytes achieve energetic precision via enhanced sarcoplasmic reticulum-mitochondrial coupling.
    Keywords:  excitation–contraction coupling; excitation–metabolic coupling; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1113/JP289683
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