bims-mitmed 2025-12-21 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–12–21
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Targeting PGC-1α axis Rescues Aberrant Development from Thyroid Hormone Defect in Brain Organoids.
Combined ketone body and glutamine supplementation restores aerobic energy production in AGC1-deficient neuronal progenitors.
Amino acid supplementation in mitochondrial aminoacyl-tRNA synthetase defects: two case reports of tyrosine supplementation in YARS2-associated disease and a review of the literature.
Partial restoration of mitochondrial dysfunction by AAV-Ant1 protects from dilated cardiomyopathy in Ant1-/- plus mtDNA mutant mice.
Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
Counseling and Prognostic Challenges in Survivorship and Mortality in Primary Mitochondrial Disease: Reshaping a Once Bleak Landscape.
Quantifying variability of mitochondrial markers in m3243A > G myopathy.
Obstetric history of women with m.3243A>G: an observational cohort study.
VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
Mitochondrial dysfunction in cellular senescence: a bridge to neurodegenerative disease.
Unequal mitochondrial segregation promotes asymmetric fates during neurogenesis.
TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
The cytochrome c oxidase subunit COX6B1 is required for redox-sensitive early assembly and late stabilization of complex IV.
Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.
Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.
The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.
A systematic bi-genomic split-GFP assay illuminates the mitochondrial matrix proteome and protein targeting routes.
Dysregulated hippocampal fatty acid metabolism following intermittent hypoxemia-induced neonatal brain injury is rescued by treatment with acetate.
Intravital observation of neuronal and immune cell dynamics in the developing mammalian brain.
MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
Mitochondria to the rescue: organelle trafficking in renal health and disease.
Neural stem cell quiescence is actively maintained by the epigenome.
Oxidative stress, mitochondrial dysfunction, and ferroptosis in the placenta of gestational diabetes mellitus.

Pharmacol Res. 2025 Dec 17. pii: S1043-6618(25)00496-7. [Epub ahead of print] 108071

Targeting PGC-1α axis Rescues Aberrant Development from Thyroid Hormone Defect in Brain Organoids.

Emanuela Bottani, Francesca Ciarpella, Benedetta Lucidi, Giulia Pedrotti, Chiara Santanatoglia, Eros Rossi, Enrica Cappellozza, Elisa De Tomi, Sissi Dolci, Giovanni Malerba, Giorgio Malpeli, Ilaria Decimo.

  Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas Ppargc1a gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment via activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.

Keywords:  brain organoids; fatty acid oxidation; mitochondria; neurodevelopment; thyroid hormone

DOI:  https://doi.org/10.1016/j.phrs.2025.108071
Cell Death Dis. 2025 Dec 15.

Combined ketone body and glutamine supplementation restores aerobic energy production in AGC1-deficient neuronal progenitors.

Simona Nicole Barile, Maria Chiara Magnifico, Eleonora Poeta, Felix Distelmaier, Luigi Viggiano, Nicola Balboni, Michele Protti, Sabrina Petralla, Antonella Pignataro, Giacomo Volpe, Monica De Luise, Massimo Bonora, Marica Antonicelli, Giorgia Babini, Francesca Massenzio, Vito Porcelli, Eleonora Lama, Roberto Arrigoni, Isabella Pisano, Veronica Addabbo, Anna Campana, Francesca Begnozzi, Stewart A Anderson, Giuseppe Fiermonte, Federico Manuel Giorgi, Paolo Pinton, Ferdinando Palmieri, Giuseppe Gasparre, Laura Mercolini, Luigi Palmieri, Douglas C Wallace, Julia Hentschel, Barbara Monti, Francesco Massimo Lasorsa.

AGC1 deficiency is a rare, early-onset encephalopathy caused by mutations in the SLC25A12 gene, encoding the mitochondrial aspartate/glutamate carrier isoform 1 (AGC1). Patients exhibit epileptic encephalopathy, cerebral hypomyelination, severe hypotonia, and global developmental delay. A hallmark biochemical feature of AGC1 deficiency is reduced brain N-acetylaspartate (NAA), a key metabolite involved in myelin lipid synthesis. However, the underlying mechanisms leading to the hypomyelinating phenotype remain unclear. In this study, we generated neuronal progenitors (NPs) derived from human-induced pluripotent stem cells (hiPSCs) of AGC1-deficient patients to investigate the metabolic and bioenergetic consequences of AGC1 loss. We demonstrated that AGC1-deficient NPs exhibit impaired proliferation, increased apoptosis, and a metabolic shift toward a hyperglycolytic phenotype due to defective mitochondrial pyruvate oxidation. RNA sequencing revealed downregulation of mitochondrial pyruvate carrier MPC1/2, limiting pyruvate-driven oxidative phosphorylation (OXPHOS) and reinforcing glycolysis as the primary energy source. Despite this metabolic shift, AGC1-deficient mitochondria retained the potential for OXPHOS when alternative anaplerotic substrates were provided. Notably, the administration of ketone bodies, in combination with glutamine, fully restored mitochondrial respiration, suggesting a mechanistic basis for the clinical improvements observed in AGC1-deficient patients undergoing ketogenic diet therapy. Our study highlights the importance of alternative metabolic pathways in maintaining neuronal energy homeostasis in AGC1 deficiency and offers insights into potential therapeutic strategies aimed at bypassing the mitochondrial pyruvate oxidation defect.

DOI: https://doi.org/10.1038/s41419-025-08314-4
Front Pediatr. 2025 ;13 1699348

Amino acid supplementation in mitochondrial aminoacyl-tRNA synthetase defects: two case reports of tyrosine supplementation in YARS2-associated disease and a review of the literature.

Giulia Ferrera, Giorgia Segre, Eleonora Lamantea, Daniele Ghezzi, Marta Rivelli, Anna Ardissone.

   Background: Mitochondrial diseases (MDs) caused by pathogenic variants in aminoacyl-tRNA synthetase (ARS) genes, either cytosolic (ARS1) or mitochondrial (ARS2), are rare and clinically diverse. YARS2 deficiency causes myopathy, lactic acidosis, and sideroblastic anemia (MLASA2). No treatments exist, although targeted amino acid (AA) supplementation could function as a possible therapy, as many ARS variants retain partial activity. While benefits have been reported in several ARS1 disorders, evidence in ARS2 diseases, including YARS2 deficiency, remains limited.
Methods: We report two siblings with genetically confirmed MLASA2 due to homozygous YARS2 variants who received oral tyrosine for 12 months. Clinical, biochemical, cardiac, and thyroid safety assessments were performed at baseline and follow-up. Standardized measures tracked motor function, symptoms, and quality of life. A systematic review of AA supplementation in ARS2 deficiencies was also conducted.
Results: Tyrosine was well tolerated. The more severely affected sibling showed improvements in motor function, endurance, and quality of life, with modest prolongation of transfusion intervals. The milder sibling reported increased energy and functional gains. Cardiac function remained stable. Literature review revealed only five prior ARS2 cases treated with AA supplementation, with variable outcomes.
Conclusion: YARS2-related MLASA2 is a severe disorder associated with high morbidity and premature mortality. No spontaneous recovery has been reported, supporting tyrosine as the likely driver of observed improvements. No cardiac or thyroid toxicities were detected during treatment. Prior reports, although limited, support the feasibility of this treatment. Our findings suggest tyrosine is a promising candidate therapy in YARS2 deficiency; larger multicenter studies are needed to validate our data.

Keywords:  ARS2; MLASA2; YARS2; amino acids; aminoacyl-tRNA synthetase defect; treatment; tyrosine

DOI:  https://doi.org/10.3389/fped.2025.1699348
Nat Commun. 2025 Dec 15.

Partial restoration of mitochondrial dysfunction by AAV-Ant1 protects from dilated cardiomyopathy in Ant1-/- plus mtDNA mutant mice.

Alessia Angelin, Kierstin Keller, Peiran Lu, Joseph W Guarnieri, Gabrielle A Widjaja, Rasheed Sule, Kevin Janssen, Arnold Olali, Zimu Cen, Valeria Carosi, Maina Beauplan, Deborah G Murdock, Prasanth Potluri, Liming Pei, Douglas C Wallace.

Primary mitochondrial disease (PMD) patients manifesting cardiomyopathy are twice as likely to die as other PMD patients. One PMD with cardiomyopathy is caused by null mutations in the heart-muscle isoform of the adenine nucleotide translocator (SLC25A4, ANT1) gene, with the severity of cardiomyopathy mediated by mitochondrial DNA. To optimize strategies for addressing mitochondrial cardiomyopathy, we generated an Ant1 null mouse and combined it with the ND6P25L mitochondrial DNA mutation to mimic the hypertrophic versus dilated cardiomyopathies observed in patients. Here, we transduce the neonatal Ant1-/- and Ant1-/-+ND6P25L mouse hearts with an AAV2/9-pDes-Gfp-mAnt1 cDNA vector. We show that restoration of just 10% of Ant1 gene expression was sufficient to ameliorate the cardiomyopathies in these mice. Proteomics and single-nucleus RNA sequencing reveal the reversal of dysregulated mitochondrial metabolic genes, including PGC1α, as well as cardiac contractile and extracellular matrix proteins. Hence, a modest increase in cardiac mitochondrial energetics can have profound benefits on cardiac function and is effective in treating mitochondrial cardiomyopathy.

DOI: https://doi.org/10.1038/s41467-025-67134-4
EMBO Mol Med. 2025 Dec 19.

Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.

Márcio Augusto Campos-Ribeiro, Erminia Donnarumma, Hendrik Nolte, Paul Cobine, Elodie Vimont, Dusanka Milenkovic, Juan Diego Hernandez-Camacho, Francina Langa-Vives, Etienne Kornobis, Esthel Pénard, Sonny Yde, Thomas Langer, Véronique Paquis-Flucklinger, Timothy Wai.

  Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10S59L variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.

Keywords:  CHCHD10; Cardiomyopathy; Cytochrome c; Mitochondrial Disease; OMA1

DOI:  https://doi.org/10.1038/s44321-025-00358-5
Pediatr Neurol. 2025 Nov 27. pii: S0887-8994(25)00370-4. [Epub ahead of print]175 223-228

Counseling and Prognostic Challenges in Survivorship and Mortality in Primary Mitochondrial Disease: Reshaping a Once Bleak Landscape.

Ibrahim Elsharkawi, Amy Goldstein, Rebecca D Ganetzky, Eva Morava.

  Primary mitochondrial diseases comprise a clinically, genetically, and biochemically heterogenous group of disorders associated with multisystemic involvement and significant morbidity and mortality of various etiologies. To date, no disease modifying therapies have been FDA approved, and treatment is largely symptomatic and supportive. Because of the rarity of mitochondrial specialists, most patients with mitochondrial diseases are cared for by clinicians without mitochondrial-specific expertise. Therefore, these clinicians by necessity rely on existing literature or older prognostic approaches which may be discordant with modern clinical practice and evolving therapeutic strategies and outcomes. Furthermore, existing literature may be skewed to the more severe end of the spectrum as publications may disproportionately focus on the most severe or unusual cases. Prognostic, therapeutic, and palliative discussions should ideally take place in a multidisciplinary setting where shared decision making can take place between the patient, family, and clinician team. Prognosis is increasingly shaped by the unprecedented development of various therapeutic modalities and personalized medicine. We aim to highlight the multipronged challenges and considerations faced in counseling patients and caregivers and draw from our own patient cohorts and observations in contemporary mitochondrial medicine to offer additional insights and future considerations for approaching patient counseling and prognostication.

Keywords:  Leigh syndrome; MELAS; Mitochondrial disease prognosis; Mitochondrial dysfunction; Primary mitochondrial disease; Survivorship

DOI:  https://doi.org/10.1016/j.pediatrneurol.2025.11.019
Sci Rep. 2025 Dec 19.

Quantifying variability of mitochondrial markers in m3243A > G myopathy.

Tiago M Bernardino Gomes, Jordan B Childs, Valeria Di Leo, Charlotte Warren, Gavin Hudson, Doug M Turnbull, Conor Lawless, Amy E Vincent.

  Myopathy is a prevalent and disabling feature of mitochondrial disease, in which skeletal muscle accumulates fibres with mitochondrial dysfunction in a variable mosaic pattern. This intra-individual spatial heterogeneity, a key consideration in longitudinal assessments, remains largely uncharacterised, hindering mechanistic studies and clinical trials by obscuring or confounding findings. We quantified this variability in m.3243 A > G-related myopathy, a leading cause of adult mitochondrial disease. Post-mortem biopsies from quadriceps femoris and tibialis anterior muscles of four patients were analysed for single-fibre deficiency in oxidative phosphorylation (OXPHOS) complex I and IV, while homogenate mitochondrial DNA (mtDNA) copy number and m.3243 A > G heteroplasmy were respectively determined by quantitative PCR and pyrosequencing. Bootstrapped combinatorial analyses established thresholds for minimum meaningful change above the 97.5th percentile, while accounting for anatomical biopsy distancing. Spatial variability in the proportion of OXPHOS-deficient fibres increased with distancing; within the same muscle, this threshold was 13.8% for NDUFB8 and 9.8% for MT-CO1. Variability in mtDNA copy number modestly increased with distance, while m.3243 A > G heteroplasmy remained largely stable, with within-muscle thresholds of 1,136 copies per nucleus and 8.2%, respectively. These findings provide assay-specific thresholds and offer mechanistic and translational insights for trial design, patient monitoring, and reliable detection of disease progression or therapeutic response.

Keywords:  Heteroplasmy; M.3243A > G; Mitochondria; Mitochondrial DNA copy number; Myopathy; Oxidative phosphorylation

DOI:  https://doi.org/10.1038/s41598-025-33106-3
J Med Genet. 2025 Dec 18. pii: jmg-2025-110875. [Epub ahead of print]

Obstetric history of women with m.3243A>G: an observational cohort study.

Petra Kuikka, Hilkka Nikkinen, Kari Majamaa, Mika Henrik Martikainen.

   BACKGROUND: Mitochondrial diseases are genetic disorders arising from pathogenic variants in nuclear or mitochondrial DNA (mtDNA) characterised by respiratory chain dysfunction. Clinical manifestations are diverse, and treatment is mostly symptomatic. Mitochondria are maternally inherited, but new reproductive technologies may prevent the transmission of pathogenic mtDNA. We decided to investigate the pregnancies of women with the m.3243A>G mtDNA variant.
METHODS: 16 women with m.3243A>G were included in this retrospective, observational cohort study. Medical records were screened for pregnancies managed at Oulu University Hospital (Oulu, Finland) during the years 1960-2020. Main outcomes were obstetric complications as well as maternal and neonatal morbidity. All eligible pregnancies (n=38) were reviewed for the course of pregnancy and delivery as well as maternal and neonatal health.
RESULTS: The median of maternal m.3243A>G load in muscle or buccal epithelium was 59% (range 30-76%). There were 30 deliveries and 31 born children. Among singleton pregnancies, gestational diabetes was present in seven (24%), gestational hypertension or pre-eclampsia in three (10%) and preterm delivery in two (7%). Mean birth weight was 3537 g (1020-5310 g), with a z-score of 0.80±1.37 for girls and 0.77±1.05 for boys. Seven newborns (12%) were treated in the neonatal intensive care unit.
CONCLUSION: Women harbouring m.3243A>G may have an elevated risk for obstetric complications, such as gestational diabetes and gestational hypertension. Their babies may have an elevated risk of preterm birth and need for intensive care. Pregnancies of women with m.3243A>G should be followed carefully.

Keywords:  Genetic Diseases, Inborn; Neurology; Neuromuscular Diseases; Reproductive Health; Reproductive medicine

DOI:  https://doi.org/10.1136/jmg-2025-110875
Nat Commun. 2025 Dec 16.

VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.

Soo-Kyeong Lee, Hyun-Ji Ham, Semin Park, Hye Eun Lee, Ji Young Mun, Deok-Jin Jang, Jin-A Lee.

Mutations in the gene VPS13B, which encodes a Golgi-associated protein, cause the neurodevelopmental disorder Cohen syndrome, but the protein's function is unclear. Here we show that this protein is essential for mitochondrial morphology and quality control. Cells lacking VPS13B, including neurons derived from Cohen syndrome patients, exhibit abnormally elongated and fused mitochondria with reduced membrane potential and impaired mitophagy. Mechanistically, the protein localizes to Mitofusin 2-positive mitochondria via its C-terminal region and recruits phosphatidylinositol-4-phosphate-rich Golgi vesicles to mitochondrial fission sites. Loss of VPS13B or depletion of phosphatidylinositol-4-phosphate results in incomplete mitochondrial fission despite normal recruitment of Dynamin-related protein 1, indicating that lipid transfer by VPS13B is required for membrane fission. VPS13B links Golgi-derived lipid vesicles to the mitochondrial fission machinery, ensuring proper mitochondrial fission and quality control and potentially explaining the mitochondrial defects in Cohen syndrome.

DOI: https://doi.org/10.1038/s41467-025-67445-6
NPJ Aging. 2025 Dec 16. 11(1): 99

Mitochondrial dysfunction in cellular senescence: a bridge to neurodegenerative disease.

Adam J Hruby, Ryo Higuchi-Sanabria.

Senescent cells, characterized by a state of irreversible proliferative arrest and inflammatory profile, have emerged as drivers of age-related decline. Growing evidence suggests that alterations in mitochondrial function and morphology play a key role in the induction and maintenance of senescence, as well as in promotion of the proinflammatory senescence-associated secretory phenotype (SASP). In this review, we seek to survey the relationship between mitochondrial dysfunction and senescence, focusing on the consequences of changes in oxidative phosphorylation efficiency, calcium handling, mitochondrial metabolites, mitochondrial dynamics and quality control, and release of damage-associated molecular patterns. We first describe these changes before illustrating the pathways and mechanisms through which mitochondrial dysfunction results in cell cycle arrest and the SASP. Lastly, we showcase evidence relating cellular senescence to neurodegenerative disease and propose that mitochondrial dysfunction may act as a bridge between the two.

DOI: https://doi.org/10.1038/s41514-025-00291-4
Nat Commun. 2025 Dec 15. 16(1): 11049

Unequal mitochondrial segregation promotes asymmetric fates during neurogenesis.

Benjamin Bunel, Rémi Leclercq, Rosette Goïame, Arnaud Gautier, Xavier Morin, Evelyne Fischer.

Asymmetric cell division plays a critical role during vertebrate neurogenesis by generating neuronal cells while maintaining a pool of progenitors. It relies on unequal distribution of cell fate determinants during progenitor division. Here, we use live imaging in the chick embryonic neuroepithelium to demonstrate that mitochondria behave as asymmetric fate determinants during mitosis. We show that the frequency of unequal distribution of mitochondria increases in parallel with the rate of asymmetric divisions during development. Furthermore, fate tracking experiments reveals that following progenitor division, a cell inheriting fewer mitochondria than its sister consistently differentiates into a neuron. We set up a chemogenetic approach to experimentally displace mitochondria specifically during mitosis to force their unequal inheritance and find that this drives premature neuronal differentiation. In this work, we establish a direct causal relationship between unequal mitochondrial inheritance and the asymmetric fate of sister cells in vivo, revealing a pivotal mechanism for neurogenesis.

DOI: https://doi.org/10.1038/s41467-025-66932-0
Nat Commun. 2025 Dec 17.

TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.

Massimo Vetralla, Lena Wischhof, Asrat Kahsay, Vanessa Cadenelli, Enzo Scifo, Beijia Xie, Miriana Sbrissa, Maëlle Sandhira Habert, Dan Ehninger, Rosario Rizzuto, Daniele Bano, Diego De Stefani.

The bidirectional transport of Ca2+ into and out of mitochondria regulates metabolism, signaling, and cell fate. While influx is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, efflux mechanisms are more diversified, involving Na⁺ or H⁺ exchange pathways. We here demonstrate that TMEM65 is a fundamental component of the Ca2+ efflux machinery of mitochondria. Its overexpression specifically enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion. This effect is inhibited by CGP-37157 and does not depends on NCLX, currently considered the bona fide mitochondrial Na+/Ca2+ exchanger. Its downregulation chronically elevates basal [Ca²⁺]mt and impairs efflux upon stimulation. In Caenorhabditis elegans, deletion of TMEM65 homologs compromises embryonic development under mild thermal stress, causing necrotic lesions that are suppressed by genetic inhibition of MCU-1. These findings highlight a molecular component that may be relevant in pathological settings in which excessive mitochondrial Ca2+ accumulation critically contribute to degenerative pathways.

DOI: https://doi.org/10.1038/s41467-025-67647-y
J Biol Chem. 2025 Dec 17. pii: S0021-9258(25)02922-9. [Epub ahead of print] 111070

The cytochrome c oxidase subunit COX6B1 is required for redox-sensitive early assembly and late stabilization of complex IV.

Kristýna Čunátová, Marek Vrbacký, Michal Knězů, Alena Pecinová, Lukáš Alán, Josef Houštěk, Erika Fernández-Vizarra, Tomáš Mráček, Petr Pecina.

  COX6B1 is a nuclear-encoded subunit of the human mitochondrial cytochrome c oxidase (cIV) located in its intermembrane space-facing region. The relevance of COX6B1 in mitochondrial physiopathology was highlighted by the missense pathogenic variants associated with cIV deficiency. Despite the assigned COX6B1 role as a late incorporation subunit, the COX6B1 human cell line knock-out (KO) exhibited a total loss of cIV. To get a deeper insight into the mechanisms driving the lack of cIV assembly or destabilization in the absence of COX6B1, we used the COX6B1 KO cell background to express alternative oxidase and COX6B1 pathogenic variants. These analyses uncovered that the COX6B1 subunit is indispensable for redox-sensitive early cIV assembly steps, besides its contribution to the stabilization of cIV in the late assembly stages. In addition, we have evidenced the incorporation of partially assembled cIV modules directly into supercomplex structures, supporting the 'cooperative assembly' model for respiratory chain biogenesis.

Keywords:  COX; COX6B1; COX6B2; OXPHOS assembly; alternative oxidase; cIV; complex IV; cytochrome c oxidase; mitochondrial deficiency; respiratory chain supercomplexes

DOI:  https://doi.org/10.1016/j.jbc.2025.111070
Nat Cell Biol. 2025 Dec 19.

Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.

Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B Compeer, Felix C Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L Dustin, Linda V Sinclair, Pekka Katajisto, Anna Katharina Simon.

T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.

DOI: https://doi.org/10.1038/s41556-025-01835-2
Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00939-6. [Epub ahead of print]85(24): 4587-4601.e7

The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.

Shuai Liu, Qingyu Li, Mengye Cao, Zefang Bimo Zhao, Cong Liu, Zhuoran Zhen, Jiankun Ren, Chengyang Liu, Danyang Ruan, Luna Zhang, Wenjuan Zhang, Hao Gong, Xiaolong Liu, Xuejie Zhang, Deng Pan, Weijun Pan, Jiajun Zhu.

  Mitochondria host a number of reductive biosynthetic pathways and rely on extensive metabolite exchanges with the cytosol to support cellular anabolic metabolism. Mitochondrial iron-sulfur cluster (Fe-S) biogenesis is essential for multiple cellular functions, and its disruption causes various inborn genetic diseases. How mammalian cells regulate Fe-S biogenesis remains incompletely understood. Here, mitochondria-focused CRISPR screening and DepMap-based gene co-essentiality analysis consistently reveal that components of the carrier translocase of the inner mitochondrial membrane (TIM22) complex, including TIMM29, are selectively required for Fe-S biogenesis. Mechanistically, loss of TIM22 complex function reduced iron transporter presence on mitochondria, thereby impairing iron uptake from the cytosol. Reconstituting mitochondrial iron level was sufficient to restore Fe-S biogenesis and proliferation of TIMM29-deficient cells or rescue the embryonic development of timm29-deficient zebrafish. Thus, a primary function of the TIM22 carrier translocase is to facilitate transporter-mediated iron uptake required for Fe-S biogenesis, underscoring a biosynthetic role of mitochondria in cellular anabolism.

Keywords:  TIM22 carrier translocase; cellular metabolism; iron-sulfur cluster; mitochondria

DOI:  https://doi.org/10.1016/j.molcel.2025.11.022
Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00943-8. [Epub ahead of print]85(24): 4483-4484

Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.

Erdem M Terzi, Richard Possemato.

Iron is a critical nutrient, especially to power mitochondrial iron-sulfur cofactor synthesis. In this issue of Molecular Cell, Liu et al.1 engineer a fluorescent iron sensor, enabling them to define a critical function of the mitochondrial translocase, TIM22, in powering mitochondrial iron use by proper targeting of the mitochondrial iron importers, the mitoferrins.

DOI: https://doi.org/10.1016/j.molcel.2025.11.026
Nat Commun. 2025 Dec 14.

The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.

Ina Kirmes, Grace Ching Ching Hung, Anne Hahn, Chuan-Yang Dai, Daniel Campbell, Arnaud Ahier, Rachel Shin Yie Lee, Alexander Palmer, Steven Zuryn.

Mitochondria play a central role in metabolism and biosynthesis, but function also as platforms that perceive and communicate environmental and physiological stressors to the nucleus and distal tissues. Systemic mitochondrial signaling is thought to synchronize and amplify stress responses throughout the whole body, but during severe or chronic damage, overactivation of mitochondrial stress pathways may be maladaptive and exacerbate aging and metabolic disorders. Here we uncover a protective micro(mi)RNA response to mtDNA damage in Caenorhabditis elegans that prolongs tissue health and function by interfering with mitochondrial stress signaling. Acting within muscle cells, we show that the miRNA miR-71 is induced during severe mitochondrial damage by the combined activities of DAF-16, HIF-1, and ATFS-1, where it restores sarcomere structure and animal locomotion by directly suppressing the inordinate activation of DVE-1, a key regulator of the mitochondrial unfolded protein response (UPRmt). Indirectly, miR-71 also reduces the levels of multiple neuro- and insulin-like peptides and their secretion machinery, resulting in decreased cell-non-autonomous signaling of mitochondrial stress from muscle to glia cells. miR-71 therefore beneficially coordinates the suppression of both local and systemic mitochondrial stress pathways during severe organelle dysfunction. These findings open the possibility that metabolic disorders could be ameliorated by limiting the overactivation of mitochondrial stress responses through targeted small RNAs.

DOI: https://doi.org/10.1038/s41467-025-67198-2
Elife. 2025 Dec 16. pii: RP98889. [Epub ahead of print]13

A systematic bi-genomic split-GFP assay illuminates the mitochondrial matrix proteome and protein targeting routes.

Yury S Bykov, Solene Zuttion, Dunya Edilbi, Marina Polozova, Johanna Arnold, Sergey Malitsky, Maxim Itkin, Bruno Senger, Ofir Klein, Yeynit Asraf, Hadar Meyer, Hubert D Becker, Roza Kucharczyk, Maya Schuldiner.

  The majority of mitochondrial proteins are encoded in the nuclear genome. Many of them lack clear targeting signals. Therefore, what constitutes the entire mitochondrial proteome is still unclear. We here build on our previously developed bi-genomic (BiG) split-GFP assay (Bader et al., 2020) to solidify the list of matrix and inner membrane mitochondrial proteins. The assay relies on one fragment (GFP1-10) encoded in the mitochondrial DNA enabling specific visualization of only the proteins tagged with a smaller fragment, GFP11, and localized to the mitochondrial matrix or the inner membrane. We used the SWAp-Tag (SWAT) strategy to tag every protein with GFP11 and mated them with the BiG GFP strain. Imaging the collection in six different conditions allowed us to visualize almost 400 mitochondrial proteins, 50 of which were never visualized in mitochondria before, and many are poorly studied dually localized proteins. We use structure-function analysis to characterize the dually localized protein Gpp1, revealing an upstream start codon that generates a mitochondrial targeting signal and explore its unique function. We also show how this data can be applied to study mitochondrial inner membrane protein topology and sorting. This work brings us closer to finalizing the mitochondrial proteome and the freely distributed library of GFP11-tagged strains will be a useful resource to study protein localization, biogenesis, and interactions.

Keywords:  S. cerevisiae; automated microscopy; biochemistry; cell biology; chemical biology; dual localization; mitochondria; mitochondrial proteome; protein targeting; yeast genetics

DOI:  https://doi.org/10.7554/eLife.98889
Nat Commun. 2025 Dec 14.

Dysregulated hippocampal fatty acid metabolism following intermittent hypoxemia-induced neonatal brain injury is rescued by treatment with acetate.

Regina F Fernandez, Wedad Fallatah, Yuanyuan Ji, Jace W Jones, Cole C Johnson, Caitlin M Tressler, Kristine Glunde, Rida Ali, Ann B Moser, Michael J Wolfgang, Susanna Scafidi, Joseph Scafidi.

The brain is a lipid-rich organ that experiences rapid growth and development after birth in a period hallmarked by extensive lipid synthesis. We still lack a fundamental understanding of lipid metabolism during this critical time of brain development and how these dynamics occur in infants born extremely preterm (<28 weeks of gestation) suffering from brain injuries. Using an established model of neonatal brain injury due to intermittent hypoxemia, we recapitulate hippocampal-dependent cognitive impairments and examine the extent of changes in the brain's lipid profile. Our results show changes in hippocampal lipid composition and abnormal fatty acid profile. Furthermore, we provide evidence of an increase in mitochondrial fatty acid β-oxidation, a process that is not classically thought of occurring in the developing brain. We find that a specific alternative fuel, acetate, spares fatty acids from mitochondrial β-oxidation. Here, we show that treatment with acetate in vivo in the form of glycerol-triacetate promotes functional recovery and restores hippocampal fatty acid profile after neonatal brain injury.

DOI: https://doi.org/10.1038/s41467-025-67542-6
Cell. 2025 Dec 16. pii: S0092-8674(25)01313-3. [Epub ahead of print]

Intravital observation of neuronal and immune cell dynamics in the developing mammalian brain.

Zhen Long, Yongzhen Yu, Chenyi He, Linhe Xu, Yiming Yan, Zhuoru Li, Zengcai V Guo, Da Mi.

  The mammalian brain contains diverse neuronal and immune cell types that exhibit dynamic motions in response to distinct extracellular environments. However, technical limitations make it difficult to investigate complex cellular motions in the developing brain in vivo. Here, we establish the intravital imaging of externally immobilized embryos (IMEE) method for long-term, large-field, and deep-depth imaging of mouse embryos, excelling in viewing angle flexibility, procedural simplicity, and functional applicability. Through combining IMEE with in utero retro-orbital injection and topological analysis of vector fields, we characterize distinct neuronal migration patterns and illustrate interactions among neurons, immune cells, and vasculature under physiological conditions and environmental stress during brain development. Our results suggest that neuronal migration guidance and immune surveillance depend on cellular adaptation to the local environment through distinct motion patterns of somata or processes. Our findings provide critical insight into the environmentally adaptive nature of neural cells in the developmental landscape.

Keywords:  brain development; intravital imaging; microglial surveillance; neuro-immune interactions; neuro-vascular interactions; neuronal migration

DOI:  https://doi.org/10.1016/j.cell.2025.11.017
Nat Cell Biol. 2025 Dec 15.

MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.

Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He.

Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1-DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization.

DOI: https://doi.org/10.1038/s41556-025-01829-0
Nephron. 2025 Dec 19. 1-18

Mitochondria to the rescue: organelle trafficking in renal health and disease.

Luca Perico, Giuseppe Remuzzi, Ariela Benigni.

BACKGROUND: Mitochondria are central regulators of cellular metabolism, redox signaling, and apoptosis. Their dysfunction plays a pivotal role in the pathogenesis of kidney diseases, including acute kidney injury and diabetic nephropathy.
SUMMARY: Recent advances have unveiled horizontal mitochondrial transfer as a novel intercellular communication by which renal cells exchange mitochondria to promote tissue repair through the modulation of metabolic processes, oxidative stress, apoptosis, and fibrosis.
KEY FINDINGS: Horizontal mitochondrial transfer, mediated by tunneling nanotubes and extracellular vesicles, has emerged as a potential homotypic rescue mechanism between injured tubular and glomerular cells. In addition, heterotypic mitochondrial transfer from mesenchymal stromal cells to renal cells has been described. These findings open new perspectives for exploring therapeutic mitochondrial transplantation in both acute and chronic kidney diseases. Nonetheless, significant challenges remain, including elucidating the poorly characterized biological mechanisms underlying mitochondrial transfer, optimizing delivery strategies, and defining the long-term safety and efficacy of mitochondrial-based therapies.

DOI: https://doi.org/10.1159/000550092
Cell Rep. 2025 Dec 18. pii: S2211-1247(25)01504-9. [Epub ahead of print]45(1): 116732

Neural stem cell quiescence is actively maintained by the epigenome.

Anna Malkowska, Jan Ander, Andrea H Brand.

  Homeostasis of the nervous system is maintained by a population of resident neural stem cells (NSCs) retained in a state of reversible cell-cycle arrest called quiescence. Quiescent NSCs can resume proliferation in response to different physiological stimuli. Reactivation requires changes in gene expression, much of which is regulated at the epigenomic level. We mapped epigenomic changes in NSC chromatin during stem cell quiescence and reactivation in Drosophila in vivo. Contrary to expectations, chromatin accessibility is increased in quiescent NSCs. Surprisingly, genes crucial for cell-cycle progression are repressed while remaining within permissive H3K36me3-bound euchromatin. At the same time, genes necessary for cell-cell communication are derepressed by eviction of histone H1 and transition to an SWI/SNF-enriched active state. Our results reveal global expansion of accessible chromatin in quiescent NSCs without concomitant transcriptional activation. Strikingly, this process reverses upon reactivation, indicating that opening of chromatin is a quiescence-specific event.

Keywords:  CP: molecular biology; CP: stem cell research; Targeted DamID; chromatin; histone modification; quiescence; stem cell

DOI:  https://doi.org/10.1016/j.celrep.2025.116732
J Mol Med (Berl). 2025 Dec 18. 104(1): 8

Oxidative stress, mitochondrial dysfunction, and ferroptosis in the placenta of gestational diabetes mellitus.

Xuan Zhou, Huiting Zhang, Lijie Wei, Zizhuo Wang, Shenglan Zhu, Jun Yu, Shaoshuai Wang, Wencheng Ding, Ling Feng, Jianli Wu.

  Gestational diabetes mellitus (GDM) has become a significant concern in the domain of women's health. The pathophysiology of GDM is complicated and not entirely understood. As a functional interface of the maternal and fetal metabolisms, it is evident that the placenta exerts an effect on the development of GDM. The placenta not only involves itself in insulin resistance via the production of hormones, but also serves as an organ abundant in mitochondria and exhibits intense metabolic activities, rendering it particularly vulnerable to the adverse effects of oxidative stress. In the high-glucose environment, excessive oxidative damage leads to mitochondrial dysfunction and further induces ferroptosis by facilitating lipid peroxidation. The objective of this review is to predominantly assess recent research, published within the last five years, that investigates the roles of placental oxidative stress, mitochondrial dysfunction, and ferroptosis as pathological mechanisms influencing the development of GDM. Understanding these pathological changes may help to better explore novel therapeutic strategies for GDM.

Keywords:  Ferroptosis; Gestational diabetes mellitus; Mitochondrial dysfunction; Oxidative stress; Placenta

DOI:  https://doi.org/10.1007/s00109-025-02629-7