bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–11–08
fourteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Thymidine Kinase 2 Deficiency in the Era of Approved Therapy: From Diagnosis to Evidence Across the Disease Spectrum.
  2. Development of mitochondrial base editing technology and its application in animals.
  3. In vivo frataxin expression of a triplex purified minicircle.
  4. Multi-omics profiling uncovers diagnostic biomarker panel, progression-associated subtypes, and prognostic signature in pediatric mitochondrial disease.
  5. Early milestones and neurodevelopment in children with mitochondrial disease.
  6. Rhes as a Potential Modulator of PINK1/Parkin-Dependent Mitophagy in Huntington's Disease.
  7. Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging.
  8. A selectivity filter in Tim17 mediates intramitochondrial protein sorting.
  9. Bidirectional mitochondrial transfer in the osteoimmune microenvironment: mechanisms and therapeutic perspectives.
  10. Migraine in mitochondrial diseases and disorders: a bioenergetic perspective.
  11. USP2 is associated with mitochondrial respiratory activity and cell viability in endometrial stromal cells in endometriosis.
  12. Epiblast complementation enables generation of live offspring from pluripotent stem cells.
  13. Amyloid beta governs mitochondrial lipid metabolism defects and neurodegenerative lysosomal stress.
  14. Berberine improves mitochondrial dysfunction in cells with atrophic gastritis via AMPK/PINK1/PRKN-dependent mitophagy.
  1. J Inherit Metab Dis. 2026 Nov;pii: e70263. [Epub ahead of print]49(6):
    Thymidine Kinase 2 Deficiency in the Era of Approved Therapy: From Diagnosis to Evidence Across the Disease Spectrum.
    Paloma Martin-Jimenez, Cristina Domínguez-González.
      Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial DNA (mtDNA) maintenance disorder caused by pathogenic variants in the nuclear TK2 gene. Loss of TK2 activity disrupts intramitochondrial deoxynucleotide pools, impairing mtDNA replication and resulting in a spectrum of quantitative (mtDNA depletion) and qualitative (multiple deletions) alterations whose severity is a key determinant of prognosis. Clinically, TK2d presents as a continuous phenotypic spectrum, from rapidly progressive infantile disease to adult-onset forms, predominantly manifesting as progressive myopathy with early bulbar and respiratory involvement, the principal drivers of morbidity and mortality, with overall severity inversely correlated with age at onset. Central nervous system involvement may occur in severe early-onset cases, whilst extramuscular manifestations are otherwise limited, with sensorineural hearing loss and subclinical axonal sensory neuropathy described across the spectrum. Circulating biomarkers, particularly GDF-15, support diagnosis, correlate with disease severity and show dynamic changes with treatment; serum creatinine, muscle MRI fat fraction and forced vital capacity further contribute to prognostic stratification. Oral supplementation with doxecitine and doxribtimine, recently approved by the FDA (2025) and EMA (2026) for patients with symptom onset ≤ 12 years, represents the first disease-modifying therapy for TK2d, demonstrating marked survival benefit, stabilisation of disease progression and partial recovery of motor function. Evidence in adult patients remains limited and largely retrospective, underscoring the need for dedicated prospective studies with outcome measures sensitive to slowly progressive phenotypes.
    Keywords:  GDF‐15; doxecitine and doxribtimine; mitochondrial DNA depletion syndrome; mitochondrial myopathy; thymidine kinase 2 deficiency (TK2d)
    DOI:  https://doi.org/10.1002/jimd.70263
  2. Acta Biochim Biophys Sin (Shanghai). 2026 Nov 06.
    Development of mitochondrial base editing technology and its application in animals.
    Yuhang Fan, Xiaoyi Wu, Jia Chen.
      Mitochondrial DNA (mtDNA) mutations constitute major genetic determinants of mitochondrial disorders and contribute to the progressive dysfunction of energy-demanding tissues. However, precise manipulation of the mitochondrial genome remains a formidable challenge for decades due to the unique structural and biological features of mitochondria. Recent breakthroughs in mitochondrial base-editing technologies address longstanding barriers in mitochondrial genome engineering by enabling programmable nucleotide conversion without introducing DNA double-strand breaks. Mitochondrial base editing evolves rapidly from a proof-of-concept strategy in cultured cells into a versatile platform for generating animal models, dissecting mitochondrial gene function and exploring therapeutic interventions for mitochondrial diseases. Recent advances enable the creation of animals carrying defined pathogenic mtDNA variants and provide initial evidence supporting the feasibility of in vivo mitochondrial genome correction and disease amelioration. Here, we review the evolution of mitochondrial base-editing technologies and summarize the major editing platforms, with particular emphasis on recent advances in editor engineering, expansion of targeting capabilities, generation of animal disease models and emerging therapeutic applications. We further discuss the remaining challenges, including editing precision, target-site accessibility, delivery efficiency, and comprehensive safety evaluation. Finally, we highlight future opportunities for developing next-generation mitochondrial genome-editing systems and advancing their translation toward clinical applications.
    Keywords:  base editing; gene editing; mitochondrial disease
    DOI:  https://doi.org/10.3724/abbs.2026192
  3. Gene Ther. 2026 Oct 31.
    In vivo frataxin expression of a triplex purified minicircle.
    Negin Mozafari, Salomé Milagres, Raul Cuellar, Karin E Lundin, Maureen Fredriks, Tina-Thien Ho, M D Golam Azam, Jill S Napierala, Marek Napierala, Jesper Wengel, C I Edvard Smith, Pontus Blomberg, Rula Zain.
      Friedreich's ataxia (FRDA) is a progressive neurodegenerative disorder caused by (GAA•TTC)n repeat expansions in the Frataxin (FXN) gene, resulting in reduced expression of Frataxin, a mitochondrial protein essential for energy production and iron-sulfur cluster assembly. Minicircles (MCs) are non-viral DNA vectors offering improved safety and efficiency over conventional plasmids. We used a novel method to purify MCs using biotin-conjugated triplex-forming and strand-invading oligonucleotides (ONs). A 21 bp H-DNA-forming sequence was incorporated into the plasmids to enhance binding specificity of the ONs. The ON-plasmid complexes were removed using streptavidin magnetic beads. This approach yielded highly purified MCs. In FRDA patient-derived fibroblasts, the purified MCs expressed FXN mRNA and restored Frataxin protein levels to those observed in healthy cells, demonstrating the therapeutic potential of this approach. More interestingly, MC-FXN treatment of an FRDA mouse model using hydrodynamic tail vein injection resulted in an 18-fold and 3-fold increase of Frataxin in the mice livers and hearts, respectively, supporting the translational relevance of this modality.
    DOI:  https://doi.org/10.1038/s41434-026-00653-x
  4. Nat Commun. 2026 Oct 09. pii: 11476. [Epub ahead of print]17(1):
    Multi-omics profiling uncovers diagnostic biomarker panel, progression-associated subtypes, and prognostic signature in pediatric mitochondrial disease.
    Xiaoting Lou, Zhehui Chen, Yuwei Zhou, Keyi Li, Jieyu Feng, Ding Li, Ruowei Zhu, Peng Luo, Chunxia Zhang, Xiujuan Wei, Qiongya Zhao, Yanling Yang, Hezhi Fang, Jianxin Lyu.
      Pediatric mitochondrial disease (PMD) is challenging due to its genetic heterogeneity, diagnostic difficulty, and unpredictable trajectories. Current biomarkers lack sensitivity to diagnose PMD or predict its severe course. Here, we show a multi-omics framework with longitudinal monitoring to resolve these challenges. We identify metabolic and transcriptomic dysregulation in PMD, deriving a robust 7-feature multi-omics diagnostic panel (6 metabolites, 1 transcript). In an independent validation cohort, this panel achieved superior diagnostic accuracy (AUC = 0.96) compared to conventional biomarkers. Beyond diagnosis, we addressed the need for patient stratification. Unsupervised proteomic clustering revealed two subtypes (Cluster I and II) that diverged over time; Cluster II patients had downregulation of cytoskeletal and immune pathways and worse clinical outcomes at 12 months. We leveraged these insights to develop a 12-transcript prognostic signature that predicts clinical prognostication with high accuracy (AUC = 0.85). This study establishes a molecular framework for PMD, offering validated tools for precision diagnosis and prognostic stratification.
    DOI:  https://doi.org/10.1038/s41467-026-78387-y
  5. Dev Med Child Neurol. 2026 Nov 02.
    Early milestones and neurodevelopment in children with mitochondrial disease.
    Eliza M Gordon-Lipkin, Maegan Wood, Madeleine Hesselgesser, Cristan Farmer, Lisa Joseph, Shannon Kruk, Peter J Mcguire, Audrey Thurm.
       AIM: To quantify neurodevelopmental functioning in children with primary mitochondrial disease (MtD), and to assess relationships with other clinical data.
    METHOD: This study was performed as a cross-sectional analysis of a longitudinal cohort. Inclusion criteria were age over 12 months, genetically confirmed MtD. Clinical data were obtained by caregiver interview and medical records abstraction. Measures included IQ, Vineland Adaptive Behavior Scales, Third Edition, the International Pediatric Mitochondrial Disease Scale (IPMDS), and Gross Motor Functional Classification System (GMFCS) level. An exploratory approach analyzed the relationship between clinical data and other measures, using Vineland Adaptive Behavior Scales, Third Edition as a dependent variable.
    RESULTS: The cohort included 32 children, mean age 7 years (SD = 3 years 6 months). The most common genotypes included MT-ATP6 (n = 6) and the mitochondrial aminoacyl tRNA synthetase family of genes. Regarding phenotype, 15 out of 32 (47%) met clinical criteria for Leigh syndrome. Clinical descriptors of disability included 18 out of 32 (56%) with intellectual disability/global developmental delay; 13 out of 32 (40%) were non-ambulatory and 6 out of 32 (19%) reported developmental regression, primarily in the motor domain. The mean Full Scale IQ was 54 (SD = 27) and adaptive behavior composite (ABC) standard score was 66 (SD = 20) with motor subscale lower than other domains. The ABC was negatively associated with IPMDS, GMFCS, and seizures. Of those who walked and talked by 24 months and had neuroimaging with zero or one brain region affected (n = 9), eight (89%) had adaptive function in the average range.
    INTERPRETATION: Children with MtD exhibit a wide range of neurodevelopmental function. Overall MtD adaptive function was low, with motor-predominant disability, and correlated negatively with other measures of severity. Episodic developmental regression occurred in a minority of this cohort but primarily affected motor skills.
    DOI:  https://doi.org/10.1111/dmcn.70598
  6. J Integr Neurosci. 2026 Oct 26. 25(10): 53852
    Rhes as a Potential Modulator of PINK1/Parkin-Dependent Mitophagy in Huntington's Disease.
    Muhammad Saim, Hayder Al-Kazzaz, Haris Ahmad.
      Huntington's disease (HD) is an inherited neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin (HTT) gene, resulting in progressive motor, cognitive, and psychiatric impairment. Despite the widespread expression of mutant huntingtin (mHTT), disease progression is characterized by the selective degeneration of striatal neurons. Mitochondrial dysfunction and impaired mitophagy have emerged as important contributors to HD pathogenesis; however, the mechanisms underlying defective mitochondrial quality control remain incompletely understood. Ras homolog enriched in the striatum (Rhes), a small striatal-enriched guanosine triphosphatase (GTPase), has been implicated in mitophagy-related signalling. In this study, we examined the potential relationship between Rhes and PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy in HD. We propose that Rhes contributes to selective striatal vulnerability by promoting mitochondrial depolarization through BCL2 interacting protein 3-like (NIX/BNIP3L), facilitating activation of the PINK1/Parkin mitophagy pathway, while enhancing autophagosome biogenesis through Beclin-1 signalling. If validated, our proposed pathway would open new avenues for therapeutic development in HD.
    Keywords:  Huntington disease; autophagy; huntingtin protein; mitochondria; mitochondrial diseases; mitophagy; neurodegenerative diseases; neurons; proteins; ubiquitination
    DOI:  https://doi.org/10.31083/JIN53852
  7. Front Aging Neurosci. 2026 ;18 1903701
    Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging.
    Emilie M Legault, Juan-Pablo Izabal Gamez, Janelle Drouin-Ouellet.
       Introduction: In humans, aging is associated with an increased risk of developing neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). In neurons, the effect of aging on intrinsic molecular processes, and how they tie to age-related neurodegeneration remains unclear. Animal studies have shown that mitochondrial function decline, autophagy impairment and defective elimination of damaged mitochondria by mitophagy are all central features of neuronal aging. However, very few studies have investigated such events in human neurons, due to a lack of models showing aging features. Therefore, there is a crucial need for a better understanding of the effect of aging on neuronal health.
    Methods: Here, we use direct neuronal reprogramming, which maintains signatures of cellular aging, to study the effect of aging on mitochondrial health and mitophagy in human neurons derived from healthy donors ranging from 11 to 91 years old. We use confocal imaging to assess colocalization of mitochondria with autophagic structures following mitophagy induction.
    Results: We show age-related mitochondrial impairment in neurites of induced neurons (iNs) derived from older donors. Additionally, in these neurites, we show an accumulation of mitochondria targeted for degradation in autophagosomes and LAMP1-positive lysosomal vesicles following mitophagy induction. These impairments culminate into incomplete elimination of damaged mitochondria, despite preserved activity of the lysosomal enzymes assessed.
    Conclusion: This study shows for the first time age-related mitophagy impairment in human neurons, and confirms findings of age-related mitochondrial impairments in human neurons. By doing so, this study paves the way for more in-depth mechanistic studies that would allow for the identification of therapeutic targets for anti-aging treatment and in the context of age-associated neurodegenerative diseases.
    Keywords:  aging; direct neuronal reprogramming; human neurons; induced neurons; lysosomal function; mitochondria; mitochondrial health; mitophagy
    DOI:  https://doi.org/10.3389/fnagi.2026.1903701
  8. Nat Commun. 2026 Oct 07. pii: 11424. [Epub ahead of print]17(1):
    A selectivity filter in Tim17 mediates intramitochondrial protein sorting.
    Annika Egeler, Sanjoy Paul, Rosario Valenti, Annika Nutz, Tamara Flohr, Erik Marcel Heller, Markus Räschle, Maya Schuldiner, Gerhard Hummer, Johannes M Herrmann.
      Mitochondria import hundreds of proteins into the matrix and the inner membrane (IM). The translocase of the IM of mitochondria (TIM23 complex) sorts these proteins using topogenic signals in their structure and directs them into the matrix or inserts them into the IM. How these signals are deciphered is unknown. Here we show that Tim17, the protein-conducting subunit of the TIM23 complex, contains a highly conserved selectivity filter for incoming proteins. Using a fluorescence-based sorting reporter, we identified the mitochondrial oxidoreductase Dmo2 (akin to DMAC1 in humans) as factor for intramitochondrial protein sorting. Molecular dynamics simulations show that a Dmo2-dependent disulfide bond into Tim17 constitutes a negatively charged selectivity filter at the vestibule of the TIM23 complex that arrests membrane proteins and facilitates the lateral insertion. Our work provides a molecular rationale as to how the TIM23 translocase differentiates between soluble and membrane proteins.
    DOI:  https://doi.org/10.1038/s41467-026-77990-3
  9. Front Endocrinol (Lausanne). 2026 ;17 1978936
    Bidirectional mitochondrial transfer in the osteoimmune microenvironment: mechanisms and therapeutic perspectives.
    Lei Huang, Xin Chen, Yuqin Guo, Fang Guo, Yanfan Zhang, Xuanyi Li, Zhili Dong, Xiaoxing Kou.
      The maintenance of bone homeostasis relies on a dynamic interplay between skeletal and immune cells. Traditional paracrine and receptor-based models cannot fully explain the reciprocal communication that underpins bone remodeling. Intercellular mitochondrial transfer refers to the movement of one or more mitochondria from a donor cell to a recipient cell. In this review, this term is distinguished from the intercellular transfer of mitochondrial components, which is described separately according to the nature of the transferred material. Mitochondrial transfer occurs via three primary pathways: direct contact, extracellular vesicles (EVs), and free mitochondrial release. Emerging evidence positions intercellular mitochondrial transfer as a novel form of organelle-level communication in the regulation of bone homeostasis. Although mitochondrial transfer has been documented extensively in bone-related pathologies, its context-dependent, bidirectional regulatory roles within the osteoimmune microenvironment have yet to be systematically elucidated. To address this gap, we systematically summarize the molecular mechanisms governing mitochondrial transfer within the osteoimmune microenvironment, with a particular emphasis on the bidirectional communication network between skeletal cells and immune cells. We further discuss its dual pathophysiological roles in bone-related disorders and highlight emerging therapeutic strategies based on mitochondrial transfer. We also propose a novel framework for bone remodeling interventions that centers on precise control of both transfer directionality and mitochondrial quality. This conceptual integration provides a theoretical foundation and translational guidance for precision regenerative medicine and immunometabolic therapies in bone-related diseases.
    Keywords:  bone metabolism; immunometabolism; mitochondrial quality control; mitochondrial transfer; osteoimmunology
    DOI:  https://doi.org/10.3389/fendo.2026.1978936
  10. Biochem Pharmacol. 2026 Nov 04. pii: S0006-2952(26)00937-8. [Epub ahead of print] 118594
    Migraine in mitochondrial diseases and disorders: a bioenergetic perspective.
    Walter H Moos, Douglas V Faller, Ioannis P Glavas, Iphigenia Kanara, Krishna Kodukula, Efstathios Papavassiliou, Julie Pernokas, Mark Pernokas, Carl A Pinkert, Whitney R Powers, Konstantina Sampani, Kosta Steliou, Robert J Zamboni, Demetrios G Vavvas.
      Migraine is a neurological disorder increasingly recognized as involving systemic and neuronal bioenergetic vulnerability - a state marked by cellular energy disruption, impaired mitochondrial function, and reduced ATP-generating capacity. Accumulating evidence implicates mitochondrial dysfunction and impaired oxidative phosphorylation as contributors to migraine pathophysiology, linking cellular energy deficits to cortical spreading depression, trigeminovascular activation, and oxidative stress. These pathophysiological mechanisms and related channelopathies shape the cellular energetic landscape. Under these conditions, metabolic disturbances influence symptom variability and phenotype heterogeneity, although the directionality of these relationships reflects a dynamic, bidirectional feedback loop between bioenergetic stress and migraine pathobiology. Here, we describe mechanisms by which limited energetic reserve modulates migraine onset, symptom evolution, and recovery. We review phase-specific bioenergetic shifts across the migraine cycle and highlight how these core cellular processes modulate network excitability. In parallel, we summarize key biomarkers, including calcitonin gene-related peptide and growth differentiation factor 15, together with related salivary or oral-fluid assays, which assist in multi-compartment biological profiling. This pathobiological axis interfaces with localized molecular signaling cascades, including pituitary adenylate cyclase-activating polypeptide signaling, sirtuin biology, microRNA-based and epigenetic regulation, and gene-informed mechanisms. This progression underscores a growing interest in molecular pathways governing neuronal energy balance and in exploratory metabolic and mitochondrial-supportive compounds. Together, these observations offer a mechanistic overview of migraine as a disorder where metabolic homeostasis affects expression, severity, and recovery - a framework that may inform future biomarker research and mechanistically targeted interventions, particularly in individuals with primary mitochondrial disease.
    Keywords:  Bioenergetics; Calcitonin gene-related peptide (CGRP); Cortical spreading depression (CSD); Growth differentiation factor 15 (GDF15); Migraine aura; Mitochondrial dysfunction; Mitochondrial syndromes (MELAS, MERRF, LHON, KSS); Molecular signaling pathways; Oxidative phosphorylation (OXPHOS); Oxidative stress; Salivary biomarkers; Trigeminovascular system
    DOI:  https://doi.org/10.1016/j.bcp.2026.118594
  11. BMC Womens Health. 2026 08 07. pii: 581. [Epub ahead of print]26(1):
    USP2 is associated with mitochondrial respiratory activity and cell viability in endometrial stromal cells in endometriosis.
    Qingqing Sun, Yijuan Cao, Juan Gu, Yaru Yang.
       BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of endometriosis, but the role of ubiquitin-specific protease 2 (USP2) remains unclear. This study aimed to determine whether USP2 modulates mitochondrial respiratory activity and proliferation in ectopic endometrial stromal cells (ESCs).
    METHODS: Twenty women with ovarian endometriosis who underwent laparoscopic surgery at the Department of Obstetrics and Gynecology, Xuzhou Central Hospital, between April 2024 and April 2025 were enrolled. Paired eutopic endometrial and ectopic endometriotic tissues were collected from each participant. Primary ESCs were isolated and cultured, and USP2 expression was downregulated or upregulated by lentiviral transduction. USP2 mRNA levels were quantified by reverse-transcription quantitative polymerase chain reaction, whereas the protein levels of USP2 and the mitochondrial complex IV subunits COX5B and COX6C were assessed by western blotting. Cell viability and proliferative activity were evaluated using the Cell Counting Kit-8 assay. Intracellular reactive oxygen species (ROS) levels were measured by flow cytometry, and the oxygen consumption rate (OCR) was determined using a Seahorse extracellular flux analyzer. Intracellular ATP content and mitochondrial complex IV enzymatic activity were measured using commercial assay kits.
    RESULTS: Compared with paired eutopic ESCs, ectopic ESCs exhibited greater proliferative activity, lower intracellular ROS levels, a higher OCR, increased intracellular ATP content, and elevated mitochondrial complex IV activity (all P < 0.01). In ectopic ESCs, USP2 knockdown reduced proliferative activity (P < 0.001), increased intracellular ROS levels (P < 0.01), and decreased OCR, intracellular ATP content, mitochondrial complex IV activity, and the protein levels of the complex IV subunits COX5B and COX6C (all P < 0.01). Conversely, USP2 overexpression in eutopic ESCs produced reciprocal changes, including increased proliferative activity, reduced intracellular ROS levels, and higher OCR, ATP content, complex IV activity, and COX5B and COX6C protein levels (all P < 0.01). Treatment with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), a mitochondrial uncoupler, attenuated the cellular and mitochondrial changes associated with USP2 overexpression.
    CONCLUSIONS: USP2 was more highly expressed in ectopic than in paired eutopic endometrial tissues. Its manipulation altered ectopic ESC proliferation and mitochondrial respiratory parameters, suggesting a potential role for USP2 in the proliferative and mitochondrial phenotype of ectopic ESCs.
    Keywords:  Cell proliferation; Ectopic endometrial stromal cells; Endometriosis; Mitochondrial respiration; Ubiquitin-specific protease 2
    DOI:  https://doi.org/10.1186/s12905-026-04781-9
  12. Cell Stem Cell. 2026 Nov 03. pii: S1934-5909(26)00391-7. [Epub ahead of print]
    Epiblast complementation enables generation of live offspring from pluripotent stem cells.
    Yi Ding, Seiya Oura, Daiji Okamura, Jun Wu.
      Blastocyst complementation enables the generation of donor pluripotent stem cell (PSC)-derived tissues in vivo, but its application has largely been limited to individual organs. Here, we establish epiblast complementation, a robust strategy for generating mice from donor PSCs. By creating an empty developmental niche in the host epiblast, we show that both wild-type and genetically modified naive PSCs can fully replace the host epiblast, contribute to all epiblast-derived tissues, and generate live offspring. Formative PSCs can also fully reconstitute the epiblast and support development to term, demonstrating developmental potential comparable to that of naive PSCs. Notably, a single naive PSC is sufficient to reconstitute the epiblast and give rise to live offspring. Together, these findings establish epiblast complementation as a functional assay for assessing PSC developmental potential and provide a strategy for generating genetically defined animals directly from cultured PSCs.
    Keywords:  blastocyst complementation; chimera; epiblast; epiblast complementation; formative pluripotent stem cells; naive pluripotent stem cells; pluripotent stem cells; tetraploid complementation; transgenic animal
    DOI:  https://doi.org/10.1016/j.stem.2026.10.010
  13. EMBO Rep. 2026 Nov 02.
    Amyloid beta governs mitochondrial lipid metabolism defects and neurodegenerative lysosomal stress.
    Chase Walton, Natalia Oleinik, Mohamed Faisal Kassir, Han Gyul Lee, Narayan R Bhat, Kumar Sambamurti, Onder Albayram, Peggi Angel, Gavin Y Wang, Rajendran J C Bose, Khanh Ha, Jason R McCarthy, Besim Ogretmen.
      Mechanisms linking amyloid peptides to mitochondrial dysfunction and impaired mitophagy in Alzheimer's disease (AD) remain poorly defined. Here, we report that, in healthy aging neurons, mitochondrial ceramide synthase 1 (CerS1) localization accompanies increased mitochondrial C18-ceramide and mitophagy in damaged mitochondria. In neuronal, mouse, and human AD tissues, amyloid precursor protein (APP) or Aβ40, but not Aβ42, shows increased proximity or co-association with TOM20/TOM40 alongside reduced mitochondrial CerS1/C18-ceramide accumulation and mitophagy. Mitochondria-excluded mutant APP does not reproduce these responses in neuronal cells. WT-APP expression is associated with reduced p17/PERMIT-ICT1 proximity, which does not establish direct APP-ICT1 binding or disruption of complex formation. Reduced mitophagy also accompanies lysosomal Aβ42 accumulation and secretion from neurons. Aged CerS1top/top mice, expressing catalytically inactive CerS1, exhibit mitochondrial dysfunction, behavioral deficits, and amyloid-positive plaque accumulation. Treatment with the peptide-targeted nanoparticle Pen-Cera-LCL768, which accumulates in the brain after intranasal administration, increases mitophagy-related readouts, reduces plaque burden, and improves behavioral performance in aged 3xTg and CerS1top/top mice. Mdivi-1 attenuates treatment effects in 3xTg mice, but its lack of specificity limits conclusions about mitophagy dependence.
    DOI:  https://doi.org/10.1038/s44319-026-00984-1
  14. Arch Biochem Biophys. 2026 Nov 03. pii: S0003-9861(26)00320-6. [Epub ahead of print] 111047
    Berberine improves mitochondrial dysfunction in cells with atrophic gastritis via AMPK/PINK1/PRKN-dependent mitophagy.
    Yanan Wang, Yan Song, Cheng Guo, Yan Zhang, Feng Li, Xiaolei Yuan, Zhigang Lv, Baoxian Qi, Fei Liu.
      This study investigated the mechanisms of berberine (BBR) in chronic atrophic gastritis (CAG). In MNNG-treated GES-1 cells, BBR ameliorated mitochondrial dysfunction, enhanced cell viability and ATP production, restored mitochondrial membrane potential, and reduced mtROS levels. BBR activated PINK1/Parkin-mediated mitophagy and the AMPK/PGC-1α signaling pathway, effects that were reversed by the AMPK inhibitor Compound C. In a CAG mouse model, BBR improved gastric secretory function, alleviated histopathological damage, reduced inflammatory cytokine levels, and restored PINK1 and Parkin expression in gastric mucosa. BBR also restored AMPK phosphorylation and downstream PGC-1α expression, thereby enhancing mitophagy. Collectively, these findings demonstrate that BBR enhances PINK1/Parkin-mediated mitophagy and PGC-1α-mediated mitochondrial biogenesis by activating AMPK, ultimately restoring mitochondrial function in CAG.
    Keywords:  AMPK; Berberine; Chronic atrophic gastritis; Mitophagy; PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.abb.2026.111047
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