bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–02–22
eighteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
  2. Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
  3. The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency.
  4. Cellular mechanisms of brain lipid metabolism in health and disease.
  5. Mitochondrial double-stranded RNA drives aging-associated cognitive decline.
  6. A switchable role of neuronal BNIP3L/NIX in mitochondrial fate: fission or finish.
  7. Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy.
  8. Loss of function variants in HPDL impair human cortical development via alterations of mitochondrial function.
  9. Mitophagy and Ubiquitination Coordinate Context-Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion.
  10. Epigenetic regulation of serine biosynthesis by PHF8 during neurogenesis.
  11. N-Acetylglucosamine Selectively Attenuates Neuroinflammation in a Mouse Model of Mitochondrial Dysfunction.
  12. From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease.
  13. Role of lipoylation in mitochondrial supercomplex formation during C2C12 cell differentiation.
  14. Targeting oxidative stress and mitochondrial dysfunction via URG7 overexpression in an in vitro Parkinson's disease neuronal model.
  15. BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
  16. Acetyl-CoA Homeostasis via Mitochondrial Pyruvate Oxidation Governs Survival, Transcriptional Fidelity and Neural Specification in Primed Human Embryonic Stem Cells.
  17. Dual function of mitochondrial complex III in Plasmodium falciparum.
  18. Loss of PINK1 impairs mitophagy and accelerates ovarian aging independent of Parkin.
  1. Cell Metab. 2026 Feb 17. pii: S1550-4131(26)00012-4. [Epub ahead of print]
    Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
    Iñigo Chivite, Erika Monelli, Margalida Munar-Gelabert, Alicia G Gómez-Valadés, Abdiel Alvarado-Diaz, Macarena Pozo, Luis Varela, Sara Ramírez, Roberta Haddad-Tóvolli, Miriam Toledo, Júlia Fos-Domènech, Francisco Díaz-Castro, Iasim Tahiri, Pau García-Ramón, Mariana Ferreira, Chloé van Gelder, Anne Abot, Óscar Osorio-Conles, José Antonio Valer, Arnaud Obri, Maria Milà-Guasch, Jorge Alvarez Luis, Pilar Villacampa, Elena Eyre, Jordi Altirriba, Sabrina Genßler, Markus Haake, Christine Schuberth-Wagner, Xavier Remesar, Antonio Zorzano, Pablo M Garcia-Rovés, Francesc Ventura, Josep Vidal, Claude Knauf, Rubén Nogueiras, Tamas L Horvath, Katrien De Bock, Mariona Graupera, Marc Claret.
      Endothelial cells (ECs) are key metabolic gatekeepers, yet their role in metabolic health remains unclear. Given their central involvement in energy metabolism, mitochondria are ideally positioned to enable ECs to adapt to ever-changing metabolic requirements. Here, we explore the hypothesis that mitochondrial dynamics proteins in ECs influence whole-body metabolic status. Genetic deficiency of Mfn2 in ECs (Mfn2iΔEC), but not of Mfn1iΔEC, induces a mitohormetic response in the adipose vasculature, enhancing antioxidant defenses, mitochondrial fitness, and lipid oxidation, ultimately improving metabolic outcomes. Cultured ECs secrete the mitokine growth differentiation factor 15 (GDF15) via a forkhead box O1 (FOXO1)-dependent axis, a response also observed under stress conditions in vivo. Notably, Mfn2iΔEC mice exhibited elevated endothelial and circulating GDF15 levels, and neutralization of GDF15 partly attenuated their metabolic benefits. Consistent with mitohormetic activation, Mfn2iΔEC mice showed protection against diet-induced obesity and delayed age-related decline. Hence, vascular mitohormetic adaptations emerge as a novel mechanism promoting systemic metabolic health.
    Keywords:  GDF15; aging; diabetes; endothelial cells; mitochondria; mitofusin; mitohormesis; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.012
  2. Nat Metab. 2026 Feb 17.
    Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
    Andrea Curtabbi, Sara Natalia Jaroszewicz, Rocío Sanz-Cortés, Rebeca Acín-Pérez, Dimitrios Prymidis, Maksym Cherevatenko, Raquel Martínez-de-Mena, María Jesús Esteban-Amo, Miguel A de la Fuente, Christian Frezza, José Antonio Enríquez.
      Dihydroorotate dehydrogenase is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here we show that expression of the Saccharomyces cerevisiae URA1 gene (ScURA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. ScURA forms a homodimer in the cytosol that uses fumarate as an electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing ScURA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, ScURA enables growth of mitochondrial-DNA-lacking ρ0 cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.
    DOI:  https://doi.org/10.1038/s42255-026-01454-7
  3. iScience. 2026 Feb 20. 29(2): 114717
    The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency.
    Meagan J McManus, Yi Zhu, Cesar Alves, Neha Kohli, Patricia Prada-Dacasa, Laura Sanchez-Benito, Elisenda Sanz, Irene Yee, Lozen Robinson, Malkah Sheldon, Walter J McHugh, Abhay Ranganathan, Jennie Meng, Nina Duncan, Alvar Grönberg, Douglas C Wallace, Sarah Piel, Michael Karlsson, Steven J Moss, Lee Webster, Magnus J Hansson, Eskil Elmér, Johannes K Ehinger, Albert Quintana, Todd J Kilbaugh.
      Leigh syndrome is a fatal pediatric neurodegenerative disease caused by mitochondrial dysfunction, which can be modeled in the Ndufs4 KO mouse with mitochondrial respiratory chain complex I (CI) deficiency. This study explores NV354, a prodrug of succinate with enhanced oral bioavailability and brain uptake, as a potential therapy to counteract this devastating condition. NV354 modulated whole-body respiration and metabolic flexibility, prevented late-stage motor dysfunction, delayed clinical ataxia scores, and improved body weight development, but had otherwise minimal effect on neurobehavior and lifespan of the animals. The succinate prodrug prevented development of the brain stem lesions pathognomonic for Leigh syndrome, attenuated neuronal loss in the brainstem, diminished activation of astrocytes, blocked hypertrophic microglial accumulation, and reduced reactive oxygen species (ROS) levels in the brain. NV354 also partially alleviated motor symptoms and metabolic decompensation in a rat model of Parkinson disease induced by the CI inhibitor rotenone. In conclusion, the succinate prodrug NV354 shows promise as a potential treatment of mitochondrial CI-related neurodegeneration.
    Keywords:  biochemistry; biological sciences; natural sciences; neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.114717
  4. Nat Cell Biol. 2026 Feb 20.
    Cellular mechanisms of brain lipid metabolism in health and disease.
    Francesco Petrelli, Carlotta Gilardi, Carla Marie Igelbüscher, Diana Panfilova, Alicia Rey, Rosa Chiara Paolicelli, Marlen Knobloch.
      Lipid metabolism has recently regained considerable attention in neuroscience, as disturbances in lipid metabolic pathways have been linked to neurodevelopmental and neurodegenerative diseases. Here we examine brain lipid metabolism from a cellular perspective, focusing on lipid uptake, de novo synthesis, storage, breakdown and intercellular transfer. We cover the recent literature showing how these processes are important during brain development and how they occur in diverse brain cell types, including astrocytes, oligodendrocytes, neural stem and progenitor cells, microglia and neurons in the adult brain. We further discuss the consequences of disrupted lipid metabolism and highlight emerging insights into neuron-glia lipid exchange, as well as the importance of lipid droplets for brain health and disease.
    DOI:  https://doi.org/10.1038/s41556-026-01880-5
  5. Cell Res. 2026 Feb 16.
    Mitochondrial double-stranded RNA drives aging-associated cognitive decline.
    Lixiao Zhang, Xiang Li, Hongdi Luo, Yujia Huo, Guangkeng Zhou, Pengcheng Wang, Sipeng Wu, Xinyong Lin, Kai Dai, Jiahao Shi, Zebao Wang, Jiaxin Xu, Renjian Li, Siyi Chen, Zhe Sun, Chunlin Zhao, Zizhuo Zhou, Zhenhong Wang, Chensi Liang, Jun Zhu, Xingjun Chen, Jintao Luo, Yong Yu, Zhirong Zhang, Geng Wang.
      Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61A1 and its involvement in aging-associated cognitive decline. SEC61A1 regulates ER-mitochondria contact sites, affecting mitochondrial DNA and RNA synthesis and subsequently leading to changes in innate immune signaling mediated by mitochondrial double-stranded RNA (mt-dsRNA). This pathway is activated in aged wild-type mice, Alzheimer's disease patients, and 5×FAD mice. Tissue-specific overexpression of Sec61a1 in the mouse cortex (Sec61a1Tg) is sufficient to induce cognitive decline without affecting motor activity. Knockdown of Sec61a1 or Mavs ablates mt-dsRNA-mediated innate immune signaling and alleviates cognitive decline in naturally aging wild-type mice. These results reveal a molecular mechanism of aging- and disease-associated cognitive decline and provide a potential therapeutic tool for intervention.
    DOI:  https://doi.org/10.1038/s41422-026-01224-w
  6. Autophagy. 2026 Feb 19. 1-2
    A switchable role of neuronal BNIP3L/NIX in mitochondrial fate: fission or finish.
    Xinlei Mo, Xingxian Zhang, Xiangnan Zhang.
      BNIP3L/NIX is a mitophagy receptor highly expressed in the brain. Unlike most mitophagy receptors that are recruited to mitochondria only upon stress, BNIP3L constitutively localizes to the mitochondrial outer membrane, suggesting functions beyond stress-induced mitophagy. Here, we identify a non-mitophagic role of BNIP3L in neuronal physiology. Conditional deletion of Bnip3l in glutamatergic neurons of the basolateral amygdala selectively impairs contextual fear memory in mice, a phenotype rescued by both wild-type BNIP3L and a mitophagy-deficient BNIP3L mutant lacking the LC3-interacting region motif. Mechanistically, BNIP3L competitively binds AMP-activated protein kinase (AMPK), thereby relieving AMPK-dependent inhibitory phosphorylation of DNM1L/DRP1 (dynamin 1 like) at Ser637. This interaction promotes rapid mitochondrial fission, supporting synaptic energy availability during memory encoding. Together, these findings reveal a switchable function of BNIP3L in neurons, acting either to acutely regulate mitochondrial dynamics to meet energetic demand or to engage mitophagy when mitochondrial function becomes compromised.
    Keywords:  BNIP3L/NIX; Basolateral amygdala; fear memory; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2634183
  7. Sci Adv. 2026 Feb 20. 12(8): eadx7815
    Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy.
    Eugene Yu-Chuan Kang, Yun-Ju Tseng, Wei-Hao Peng, Hui-Chuan Hung, Pei-Hsuan Lin, Katrina P Montales, Emmet Sherman, John Peregrin, Ethan Hunghsi Wang, Chunya Kang, Yu-Chuan Teng, Chen-Yang Huang, Chia-Lung Tsai, Ian Yi-Feng Chang, Jiazhang Chen, Gülgün Tezel, Ye He, Tai-De Li, Linsey Stiles, Orian Shirihai, Stephen H Tsang, Chi-Chun Lai, Chi-Neu Tsai, Chyuan-Sheng Lin, Nan-Kai Wang.
      Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy caused by OPA1 variants, leading to retinal ganglion cell (RGC) degeneration and vision loss. The mechanisms behind RGC vulnerability to mitochondrial dysfunction remain unclear. We developed a patient-specific Opa1V291D/+ knock-in mouse model to investigate mitochondrial dysfunction and retinal metabolism in ADOA. We observed that Opa1V291D/+ mice exhibited anatomical and functional RGC abnormalities recapitulating the ADOA phenotypes. Reduced optic atrophy 1 (OPA1) protein levels were noted in Opa1V291D/+ mice, accompanied by decreased protein stability. Moreover, mitochondrial function was compromised, as indicated by reduced Complex I activity, increased oxidative stress, and diminished adenosine triphosphate production in the retinas of Opa1V291D/+ mice. Spatial metabolomics revealed energy deficits in the inner retina and heightened glycolysis in the outer retina. Immunostaining showed decreased expression of glycolytic proteins in the ganglion cell layer. Single-nucleus RNA sequencing disclosed significant down-regulation of energy-production genes in RGCs, while other retinal cell types remained unaffected. These findings emphasize the specific vulnerability of RGCs to bioenergetic crises, connecting disrupted energy homeostasis to their degeneration. By increasing the nicotinamide adenine dinucleotide (NAD+)/reduced form of NAD+ (NADH) redox ratio through the overexpression of mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) in RGCs, we demonstrated improved RGC function and survival through enhanced energy metabolism and reduced oxidative stress. These findings confirm that disrupted energy metabolism leads to RGC degeneration and emphasize the enhancement of the NAD+/NADH redox ratio as a promising treatment strategy to protect RGCs from degeneration in ADOA.
    DOI:  https://doi.org/10.1126/sciadv.adx7815
  8. Cell Death Dis. 2026 Feb 20.
    Loss of function variants in HPDL impair human cortical development via alterations of mitochondrial function.
    Matteo Baggiani, Maria Andrea Desbats, Valentina Naef, Michela Giacich, Daniele Galatolo, Serena Mero, Sara Zampieri, Valentina Cappello, Agata Valentino, Leonardo Salviati, Filippo Maria Santorelli, Devid Damiani.
      Human brain development is highly regulated by several spatiotemporal processes, which disruption can result in severe neurological disorders. Emerging evidence highlights the pivotal role of mitochondrial function as one of these fundamental pathways involved in neurodevelopment. Our study investigates the role of 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) protein in cortical neurogenesis and mitochondrial activity, since mutations in the HPDL gene are associated with a childhood-onset form of hereditary spastic paraplegia characterized by corticospinal tract degeneration and cortical abnormalities. Starting from mutant neuroblastoma cells, we demonstrated that HPDL is important to respiratory chain supercomplex assembly and cellular redox balance. Moreover, RNA-seq studies revealed dysregulated pathways related to brain development. Generation of cortical neurons and organoids from HPDL patient-derived induced pluripotent stem cells exhibited premature neurogenesis at early differentiation stages, likely leading to depletion of cortical progenitors, as evidenced by decreased proliferation, slight increase of apoptosis, and unbalanced cortical type composition at later stages. Cortical organoids showed failure to grow at a normal rate, a feature highly reminiscent of the "microcephaly" observed in severe HPDL children. Mitochondrial morpho-functional characterization in mutant neurons confirmed disruption of OxPhos chain functionality in neuroblastoma knock-out model cells and HPDL mutant cortical progenitors also displayed defects in respirasome assembly and increased ROS generation rate. Treatment of mutant cortical cells with antioxidants and CoQ10 intermediates partially rescued premature neurogenesis depending on the mutational context, suggesting potential future personalized therapeutic strategies. Our findings reveal a critical role for HPDL in coordinating cortical progenitor proliferation, neurogenesis, and mitochondrial function, shedding light on a better understanding of the related clinical presentations.
    DOI:  https://doi.org/10.1038/s41419-026-08476-9
  9. Adv Sci (Weinh). 2026 Feb 17. e19792
    Mitophagy and Ubiquitination Coordinate Context-Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion.
    Bin-Hsu Mao, Bo-Kai Su, Ying-Jan Wang, Ting-Yuan Tu.
      Metastatic invasiveness emerges from coordinated intrinsic programs and microenvironmental cues that converge on mitochondrial quality control (MQC). Here, we use "context" to denote stage- and site-aware constellations of tumor-intrinsic states (e.g., mtROS tone, mtDNA integrity, epigenetic wiring, cellular stiffness, oncogenic mutations) and extrinsic landscapes (oxygen-nutrient availability, ECM mechanics, stromal/inflammatory signals). These axes jointly shape mitochondrial adaptation by tuning bioenergetics, redox balance, metabolic plasticity, fission-fusion dynamics, mechanosensitive hubs, and Ca2 + homeostasis. As pressures intensify, mitochondrial vulnerabilities-such as mtDNA compromise and mtUPR activation-signal the engagement of mitophagy to preserve organelle fitness under stress. Through these coupled changes in mitochondrial performance and stress responses, context governs EMT/MET plasticity and transitions across migratory, invasive, and proliferative states. Mechanistically, ubiquitin conjugation, via E3 ligases and deubiquitinases, serves as an integrating conduit that links mitochondrial remodeling and mitophagy to cytoskeletal reprogramming and invasive behavior. This ubiquitin-mitochondria interface therefore represents a coherent therapeutic entry point; translational strategies including PROTAC-enabled targeting and selective E3/DUB or mitophagy-pathway modulators may rebalance pathological ubiquitin signaling, restore mitochondrial homeostasis, and constrain tumor dissemination.
    Keywords:  EMT–MET plasticity; extracellular matrix mechanics; hypoxia and nutrient deprivation; mitochondrial ROS; mitochondrial dynamics; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1002/advs.202519792
  10. EMBO Rep. 2026 Feb 19.
    Epigenetic regulation of serine biosynthesis by PHF8 during neurogenesis.
    Marta H Artes, Simona Iacobucci, María J Barallobre, Paula Carballeira, Marta Garcia-Cajide, Alejandro Pérez-Venteo, Natalia Padilla, Bárbara S Viegas, Aitana Díaz-Vásquez, A Silvina Nacht, Guillermo P Vicent, Maria L Arbonés, Xavier de la Cruz, Marta Nieto, Neus Agell, Caroline Mauvezin, Marian A Martínez-Balbás.
      Progenitor proliferation during neurodevelopment requires tight coordination of epigenetic regulation and metabolism. However, the crosstalk between these processes remains poorly understood. To investigate this, we examine in neural stem cells the role of PHF8, a histone demethylase whose mutations are linked to Siderius-Hamel syndrome, a rare neurodevelopmental disorder. Through an integrated multi-omics approach - combining transcriptomics, epigenomics, and metabolomics - we identify PHF8 as a key driver of the serine biosynthesis pathway, safeguarding the intracellular serine pool essential for neural progenitor proliferation. PHF8 fine-tunes chromatin accessibility at promoters of metabolic genes, ensuring their activation during development. Loss of PHF8 disrupts amino acid metabolism, blocks autophagy, and hinders vesicle formation. Ultimately PHF8 depletion leads to replication defects, DNA damage, and proliferation arrest. In vivo, PHF8 deficiency in mouse embryos halts neurogenesis, progenitor expansion, and neuron generation in the developing brain. These findings identify PHF8 as a key molecular link between chromatin regulation, metabolic control, and neural development, offering new insights into the epigenetic basis of neurodevelopmental and metabolic disorders.
    Keywords:  Gene Transcription; Neural Stem Cells; Neurogenesis; PHF8; Serine Biosynthesis Histone Demethylation
    DOI:  https://doi.org/10.1038/s44319-026-00713-8
  11. Acta Physiol (Oxf). 2026 Mar;242(3): e70179
    N-Acetylglucosamine Selectively Attenuates Neuroinflammation in a Mouse Model of Mitochondrial Dysfunction.
    Laura Jiménez-Sánchez, Paula Ruiz-López, Pilar González-García, Janne Purhonen, Juan Manuel Martínez-Gálvez, Sergio López-Herrador, Julia Corral-Sarasa, María Elena Díaz-Casado, Carmen Venegas, Isaac Santos-Pérez, Enrica Olivieri, Adriana L Rojas, Luis Carlos López.
       AIM: Mitochondrial dysfunction plays a central role in multiple neurodegenerative diseases, yet the temporal sequence of cellular events underlying neurodegeneration remains poorly defined. This study aimed to characterize the progression of neurodegeneration in a mouse model of fatal mitochondrial encephalopathy and to evaluate the therapeutic potential of oral N-acetylglucosamine supplementation.
    METHODS: A mouse model of primary coenzyme Q deficiency was used to examine neurodegeneration at presymptomatic, symptomatic and terminal stages. Neuronal integrity, glial activation, myelination and inflammatory responses were assessed using histological, molecular and ultrastructural approaches, together with behavioral analysis of motor coordination. N acetylglucosamine was administered orally from 1 month of age, and its effects on neuroinflammation, myelin integrity and motor performance were evaluated.
    RESULTS: Astrocyte activation and neuronal loss were detected before the onset of clinical symptoms, whereas proinflammatory microglia appeared at later disease stages. Early myelin abnormalities were accompanied by an initial increase in oligodendrocyte precursor cells, suggesting a compensatory response to early myelin stress. Oral N-acetylglucosamine supplementation reduced glial activation and neuroinflammatory markers, likely through modulation of inflammatory signaling pathways. Although treatment did not fully reverse structural damage or restore myelin protein expression, it led to a significant improvement in motor coordination.
    CONCLUSION: These findings define a temporal sequence of early glial activation, neuronal loss, and myelin alterations in mitochondrial encephalopathy. Targeting glial responses and neuroinflammation at early disease stages may mitigate neurodegenerative progression and improve functional outcomes, highlighting a physiologically relevant therapeutic window for mitochondrial disorders.
    Keywords:  N‐acetylglucosamine; coenzyme Q; mitochondria; neuroinflammation
    DOI:  https://doi.org/10.1111/apha.70179
  12. Mol Genet Metab. 2026 Feb 12. pii: S1096-7192(26)00035-1. [Epub ahead of print]147(4): 109752
    From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease.
    Oliver Heath, Francisco Del Caño-Ochoa, Safa Baris, Rosalba Carrozzo, David Coman, Felix Distelmaier, Carolyn Ellaway, Rene G Feichtinger, Andrea Finocchi, Sergio Guerrero-Castillo, Rebecca Halligan, Iris Hannibal, Amy Kritzer, Uta Lichter-Konecki, Kajus Merkevicius, Bianca Panis, Robert D S Pitceathly, Chiara Pizzamiglio, Katarzyna Iwanicka-Pronicka, Shamima Rahman, Laurie Seltzer, Meinolf Siepermann, Galit Tal, Ron A Wevers, Szymon Ziętkiewicz, Santiago Ramón-Maiques, Johannes A Mayr, Saskia B Wortmann.
       BACKGROUND: CLPB-related mitochondrial disease causes congenital neutropenia, developmental delay/intellectual disability, progressive brain atrophy, movement disorders, cataracts, and 3-methylglutaconic aciduria. Both monoallelic and biallelic forms exist. This retrospective cohort study compared clinical outcomes and genotype-structure-phenotype correlations across zygosity groups.
    METHODS: Sixty-three individuals (41 biallelic, 22 monoallelic; 6 unpublished) with disease-causing CLPB variants were identified via literature review and a multicenter survey. In silico modeling assessed structural impact. A modified CLPB Disease Burden Index (DBI) quantified severity.
    RESULTS: Median age at last follow-up was 4.0 years (IQR: 0.25-12.6) in biallelic and 12.0 years (IQR: 5.3-21.0) in monoallelic cases. Death occurred in 66% of biallelic and 23% of monoallelic individuals, with earlier median age at death in biallelic cases (6 months vs 2.4 years). Biallelic cases had significantly higher DBI scores and poorer survival (4-year survival: 50% vs 82%). Stop/stop genotypes were associated with greater disease burden than missense combinations. Structural predictions-particularly variants causing nonsense-mediated decay or ankyrin domain disruption-were stronger survival predictors than zygosity or age of onset. Early-onset disease (<12 months) correlated with more severe progression. Later onset often resulted in milder phenotypes. Hematologic and neurologic features overlapped across zygosity; cataracts and dystonia were more common in biallelic cases. Milestone attainment was poor, with <50% walking or speaking, and only 10-20% doing so on time. Four monoallelic patients received hematopoietic stem cell transplants with mixed outcomes. Granulocyte colony-stimulating factor was associated with improved survival.
    CONCLUSIONS: This is the largest cohort study to date comparing biallelic and monoallelic CLPB deficiency. Structural variant impact-particularly ankyrin domain disruption-emerged as a key prognostic factor.
    Keywords:  3-methylglutaconic aciduria; Ankyrin repeat region; CLPB; Cataracts; Congenital neutropenia; Genotype-phenotype correlation; Mitochondrial chaperonopathy; Protein modeling; Zygosity
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109752
  13. J Biochem. 2026 Feb 20. pii: mvag014. [Epub ahead of print]
    Role of lipoylation in mitochondrial supercomplex formation during C2C12 cell differentiation.
    Hijiri Oshio, Isshin Shiiba, Anju Takeda, Souichirou Matsumoto, Yuto Ishikawa, Shun Nagashima, Ryoko Inatome, Shigeru Yanagi.
      In mitochondria, the pyruvate dehydrogenase complex (PDHC) serves as a key metabolic regulator by converting glycolysis-derived pyruvate into acetyl-CoA, thereby controlling carbon flux into the tricarboxylic acid (TCA) cycle. PDHC activity is tightly regulated by two post-translational modifications: phosphorylation of the E1 subunit and lipoylation of the E2 subunit. While phosphorylation of E1 reversibly suppresses pyruvate dehydrogenase (PDH) activity, lipoylation of E2 is essential for intracomplex electron transfer reactions, and together these modifications define PDHC enzymatic activity. Mitochondrial respiratory supercomplexes (SCs) play a critical role in efficient electron transfer during mitochondrial respiration, and PDH has been reported to regulate SC organization. However, it remains unclear whether this regulatory mechanism, including subunit phosphorylation, is linked to protein lipoylation. In this study, we examined the impact of protein lipoylation on the phosphorylation status of the PDHC E1 subunit and on mitochondrial respiratory supercomplex formation during C2C12 differentiation. To this end, suppression of lipoic acid synthase (LIAS), a key enzyme responsible for mitochondrial protein lipoylation, in C2C12 cells resulted in dephosphorylation of the PDHC E1 subunit and formation of specific mitochondrial respiratory supercomplexes. These findings suggest that PDHC E1 dephosphorylation and specific mitochondrial respiratory supercomplex assembly can occur under conditions of impaired E2 lipoylation.
    Keywords:  C2C12 differentiation; LIAS; Mitochondria; PDHC; Respiratory supercomplexes
    DOI:  https://doi.org/10.1093/jb/mvag014
  14. Sci Rep. 2026 Feb 19.
    Targeting oxidative stress and mitochondrial dysfunction via URG7 overexpression in an in vitro Parkinson's disease neuronal model.
    Ilaria Nigro, Rocchina Miglionico, Ludovica Lela, Luigi Milella, Faustino Bisaccia, Maria Francesca Armentano.
      
    Keywords:  6-Hydroxydopamine (6-OHDA); Mitochondrial dysfunction; Neurodegenerative diseases; Neuroprotection; Oxidative stress; URG7 protein
    DOI:  https://doi.org/10.1038/s41598-026-38925-6
  15. Mol Cell. 2026 Feb 13. pii: S1097-2765(26)00032-8. [Epub ahead of print]
    BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
    Brandon Chen, Drew C Stark, Pankaj V Jadhav, Theophilus M Lynn-Nguyen, Benjamin S Halligan, Nicholas J Rossiter, Nicole Sindoni, Myungsun Shin, Joao A Paulo, Matthew Chang, Imhoi Koo, Sergei Koshkin, Sanjana Eyunni, Paolo Ronchi, Michelle T Paulsen, Harrison S Greenbaum, Mariana T Ruckert, Pietro Morlacchi, David A Hanna, Jason Lin, Rachel M Guerra, Tao Liu, David J Pagliarini, Ruma Banerjee, Abhijit Parolia, Mats E Ljungman, Andrew D Patterson, Joseph D Mancias, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.
      Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCSs revealed common mechanisms of induction and function, providing clarity to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCSs and cellular metabolism.
    Keywords:  bromodomain protein; endoplasmic reticulum-mitochondria contact sites; high-throughput screening; mitochondrial electron transport chain
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.012
  16. J Cell Physiol. 2026 Feb;241(2): e70153
    Acetyl-CoA Homeostasis via Mitochondrial Pyruvate Oxidation Governs Survival, Transcriptional Fidelity and Neural Specification in Primed Human Embryonic Stem Cells.
    Ning Zhong, Yujie Liu, Min Shao, Hanzhi Zhao, Yongqiang Wang, Junjie Gu, Qinwen Chen, Huiyong Yin, Ying Jin, Bing Liao.
      Human embryonic stem cells (hESCs) hold immense promises for regenerative medicine and exhibit two distinct pluripotency states: primed and naïve. However, metabolic regulation underlying these states remains incompletely understood. In particular, mitochondrial pyruvate oxidation in pluripotency regulation has not been documented. Here, we combined an inducible dihydrolipoamide S-acetyltransferase (DLAT) knockout model and pharmacological inhibition of mitochondrial pyruvate uptake (via the mitochondrial pyruvate carrier inhibitor UK5099) to dissect the state-specific effects of mitochondrial pyruvate oxidation in isogenic naïve and primed hESCs. Primed hESCs lacking DLAT or treated with UK5099 displayed pronounced cell death, reduced global protein acetylation levels, and transcriptional dysregulation. These defects were partially rescued by sodium acetate supplementation, implicating a reduction in acetyl-CoA abundance as a key mechanism. Notably, a set of neural lineage genes was specifically downregulated by disrupted mitochondrial pyruvate oxidation in primed hESCs, revealing the importance of mitochondrial pyruvate oxidation-mediated acetyl-CoA production in priming neural differentiation. In line with this, disruption of mitochondrial pyruvate oxidation impaired the differentiation process of primed hESCs towards neuroectoderm. In contrast, DLAT depletion in naïve hESCs did not affect cell growth and the naïve pluripotency state, highlighting the pluripotency state-dependent function of mitochondrial pyruvate oxidation. Our study uncovers the pivotal roles of mitochondrial pyruvate oxidation-mediated acetyl-CoA production for sustaining survival and transcriptional fidelity as well as facilitating neural differentiation in primed hESCs. Moreover, we emphasize that the function of mitochondrial pyruvate oxidation in hESCs is pluripotency state-dependent. These findings provide new cues for optimizing hESC maintenance and differentiation through targeted metabolic manipulation.
    Keywords:  DLAT; acetyl‐CoA; histone acetylation; human embryonic stem cells; human naïve pluripotency; human primed pluripotency; mitochondrial pyruvate oxidation
    DOI:  https://doi.org/10.1002/jcp.70153
  17. PLoS One. 2026 ;21(2): e0334727
    Dual function of mitochondrial complex III in Plasmodium falciparum.
    River S Rell, Anurag Shukla, Joanne M Morrisey, Ijeoma C Okoye, Michael W Mather, Akhil B Vaidya.
      Complex III of the malaria parasite mitochondrial electron transport chain (mtETC) has been validated as an attractive target for currently used antimalarials. We previously showed that the main function of mtETC in blood stage Plasmodium falciparum is to regenerate ubiquinone, which serves as an obligatory co-substrate of dihydroorotate dehydrogenase (DHOD), an essential mitochondrial enzyme for pyrimidine biosynthesis. P. falciparum can be rendered resistant to all mtETC inhibitors by provision of a bypass mediated by cytosolic yeast DHOD, a fumarate-reducing enzyme. Malaria parasite mitochondrial DNA (mtDNA) encodes only 3 proteins, each a component of mtETC. However, attempts to eliminate mtDNA in transgenic parasites expressing yDHOD have been unsuccessful, suggesting the possibility that essential function(s) other than the canonical redox reactions of the mtETC also require mtDNA maintenance. Here we have tested the hypothesis that Complex III serves the dual functions of processing imported mitochondrial proteins, as well as ubiquinone regeneration. We have generated transgenic lines that conditionally express mitochondrial processing peptidase a (MPPα), which is also a component of Complex III. Using these parasites, we have determined that MPPα is essential even when the need for mitochondrial electron transport is bypassed. MPPα knockdown also resulted in hypersensitivity of the parasites to proguanil, a drug that synergizes with mtETC inhibitors such as atovaquone. Pulldown with MPPα followed by proteomics revealed the association of multiple mitochondrially targeted proteins, in addition to all components of Complex III. These results are consistent with the suggestion that Complex III in P. falciparum serves both mtETC and protein processing functions in mitochondrial physiology.
    DOI:  https://doi.org/10.1371/journal.pone.0334727
  18. Free Radic Biol Med. 2026 Feb 16. pii: S0891-5849(26)00121-8. [Epub ahead of print]248 29-42
    Loss of PINK1 impairs mitophagy and accelerates ovarian aging independent of Parkin.
    Xinxin Zeng, Huihui Xie, Wandi Zhang, Yongxing Yu, Mengchen Wang, Yuqing Jiang, Ruizhi Guo, Yingpu Sun, Qingling Yang.
      PINK1 and Parkin are central regulators of mitophagy, a quality-control process essential for mitochondrial homeostasis and implicated in aging. However, their specific roles in ovarian physiology remain unclear. Here, we show that Pink1 deletion in mice leads to decreased ovarian weight, diminished ovarian reserve, and reduced oocyte quality, accompanied by increased granulosa cell apoptosis, accelerated ovarian ageing, and impaired fertility. Pink1 deficiency also compromises ovulation efficiency, increases oocyte cytoplasmic fragmentation, and disrupts meiotic spindle assembly, resulting in markedly reduced developmental competence of early embryos. Mechanistically, bulk and single-cell RNA sequencing reveal that loss of PINK1 impairs mitophagy and promotes transcriptional signatures of ovarian aging. In contrast, Parkin deletion exerts minimal effects on mitophagy, mitochondrial function, or ovarian physiology. Together, these findings identify PINK1, but not Parkin, as a critical regulator of ovarian aging through modulation of mitophagy.
    Keywords:  Mitophagy; Oocytes; Ovarian aging; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.024
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