bims-mitmed 2026-11-15 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–11–15
eighteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial base editing for disease modeling and therapeutic correction.
Blood-Based Lipid Peroxidation and Ferroptosis-Related Markers in Friedreich's Ataxia.
MitoTALENs reduce mutant mitochondrial DNA carryover following pronuclear transfer.
Mitochondrial translation deficiency limits the cardiac benefit of ketogenic diet in early-onset cardiomyopathy.
Impaired Mitochondrial Translation and Bioenergetic Dysfunction Associated with the MT-RNR1 m.1014A>G Variant.
Lipid mediated ER stress contributes to the pathogenesis of mitochondrial myopathies.
ER-mitochondria contacts orchestrate mitochondrial transport via C19orf12.
Restoring Bioenergetics in the Traumatized Eye: The Emergence of Mitochondrial Implantation as a Treatment for Acute Ocular Injury.
Mitochondrial translation and coordinated cytosolic translation in metabolic homeostasis and disease.
Mitochondria-localized circRNA BRAKE restrains adipogenesis under nutrient overload by disrupting ATP synthase assembly in mice.
Mitochondrial protein import defects enhance tumour immunogenicity.
Mitochondria-RNA Binding Protein Crosstalk in Neurodegeneration: Mechanisms Linking Mitochondrial Stress, RNA Dysregulation and Neuronal Vulnerability.
Placental programming of metabolic diseases: molecular pathways from maternal pregnancy complications to offspring metabolic risk.
Metformin promotes placental adaptation to hypoxic stress through mitochondrial and translational pathways.
Neuronal and mitochondrial phenotypes in iPSC-derived bipolar disorder models with and without a family history of mitochondrial disease.
Exercise-conditioned serum drives mitochondrial remodeling in neurons.
A p32 family RNA editing factor acts in mitochondrial ribosome biogenesis.
Cannabidiol abrogates the atypical enlargement of mitochondria in Tafazzin-deficient B-lymphoblastoid cells.

Genome Biol. 2026 Aug 13. pii: 351. [Epub ahead of print]27(1):

Mitochondrial base editing for disease modeling and therapeutic correction.

Seongho Hong, Sanghun Kim, Je Kyung Seong, Youngho Kim, Hyunji Lee.

Recent development of mitochondrial DNA (mtDNA) editors has made it possible to generate experimental models carrying patient-relevant mtDNA mutations, characterize disease-associated phenotypes in cells and animals, and directly correct pathogenic variants in vivo. Here, we summarize the current landscape of mtDNA base editors and discuss key considerations for their application to mitochondrial disease model generation, including target selection, cross-species conservation, editing window constraints, strand bias, sequence-context dependence, and the balance between editing efficiency and safety. We further review strategies for validating mtDNA-edited models at functional, molecular, and organismal levels, and highlight recent studies demonstrating therapeutic rescue in animal models.

DOI: https://doi.org/10.1186/s13059-026-04244-2
Mov Disord. 2026 Nov 09.

Blood-Based Lipid Peroxidation and Ferroptosis-Related Markers in Friedreich's Ataxia.

Lidia Sarro, Sara Petrillo, Alessia Mongelli, Riccardo Ronco, Anna Castaldo, Andrea Quatrana, Caterina Torda, Federica Loia, Roberta Telese, Enrico Bertini, Fiorella Piemonte, Caterina Mariotti.

   BACKGROUND: Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced levels the mitochondrial frataxin protein. Systemic oxidative stress and iron-dependent lipid peroxidation, commonly associated with ferroptosis, have a critical role in disease pathogenesis.
OBJECTIVES: We aimed to evaluate longitudinal changes of blood-based indexes of oxidative stress and ferroptosis-related molecules in adults and children with FRDA.
METHODS: We measured plasma levels of 4-hydroxyl-2-nonenals (4-HNE) and hydroxyeicosatetraenoic acid (15-HETE), and blood concentration of glutathione (GSH), glutathione disulfide (GSSG), in 62 FRDA patients (48 adults and 14 children) and 63 age matched healthy controls. mRNA levels of major genes targeting the nuclear factor erythroid 2-related factor 2 (NRF2) were also evaluated. Peripheral concentrations of lipid peroxidation markers and ferroptosis-related molecules were correlated with age, disease duration, and severity of ataxia signs. Clinical and biochemical evaluations were performed at baseline and at 1-year follow-up.
RESULTS: FRDA patients had significantly increased levels of 4-HNE and GSSG and decreased levels of GSH, compared to controls. Children with FRDA had lower levels of glutathione peroxidase 4 (GPX4) mRNA than adult patients. At 1-year follow up, plasma 4-HNE levels remained stable, and blood GPX4 mRNA increased only in adult patient cohort. GPX4 correlated with age, disease duration, and clinical scores.
CONCLUSIONS: We provide preliminary evidence of defective GPX4 expression in the early phase of the disease. Our data suggest that GPX4 may represent a biomarker for disease progression and a possible candidate target for therapeutic strategies. © 2026 International Parkinson and Movement Disorder Society.

Keywords:  Friedreich ataxia; Glutathione; Glutathione peroxidase 4; Lipid peroxidation; Oxidative stress; Plasma biomarkers

DOI:  https://doi.org/10.1002/mds.70603
Cell Rep Methods. 2026 Nov 11. pii: S2667-2375(26)00367-X. [Epub ahead of print] 101666

MitoTALENs reduce mutant mitochondrial DNA carryover following pronuclear transfer.

Noemi Castelluccio, Andrei Rybouchkin, Sandra R Bacman, Gabriele Ferrari, Wim Trypsteen, Delphine De Sutter, Krishna C Pavani, Sofie Symoens, Sven Eyckerman, Carlos T Moraes, Ward De Spiegelaere, Dominic Stoop, Björn Heindryckx.

  Preventing transmission of maternally inherited mitochondrial diseases remains a major challenge in reproductive medicine. Nuclear transfer (NT) offers a promising strategy by replacing mutant mitochondrial DNA (mtDNA) while preserving the nuclear genome; nevertheless, residual mtDNA carryover can persist in reconstructed embryos and potentially expand, leading to disease recurrence. Using a heteroplasmic mouse model harboring the pathogenic m.5024C>T mutation, we evaluated two approaches to reduce mtDNA carryover following pronuclear transfer (PNT): mitochondrially targeted transcription activator-like effector nucleases (mitoTALENs) and induced mitophagy. PNT alone markedly lowered heteroplasmy, reducing mutant mtDNA from 68.5% to 2.4%, on average. Application of mitoTALENs post-PNT further reduced residual mutant mtDNA below 1%, with levels as low as 0.2%, without compromising embryonic development. In contrast, mitophagy induction via SQSTM1 overexpression failed to reduce heteroplasmy, consistent with inefficient lysosomal recruitment in embryos. Additionally, we validated digital PCR (dPCR) as a sensitive and robust method for quantifying mtDNA copy number and low-level heteroplasmy.

Keywords:  CP: biotechnology; CP: developmental biology; MitoTALENs; digital PCR; heteroplasmy; mitochondrial disease; mitophagy; pronuclear transfer

DOI:  https://doi.org/10.1016/j.crmeth.2026.101666
J Bioenerg Biomembr. 2026 Nov 07. pii: 62. [Epub ahead of print]58(1):

Mitochondrial translation deficiency limits the cardiac benefit of ketogenic diet in early-onset cardiomyopathy.

Ozlem Kartal, Sukru Anil Dogan.

  Mitochondrial cardiomyopathy is a devastating disorder with no effective treatment. Ketogenic diet (KD) has shown therapeutic benefit in some mitochondrial disease models but failed or caused harm in others, suggesting its efficacy depends on the underlying genetic defect. KD has ameliorated cardiomyopathy in models where the electron transport chain retains structural integrity, yet it has not been tested in a model with a primary defect in mitochondrial translation. We therefore examined KD in heart- and skeletal muscle-specific Dars2 knockout mice (hmKO), a model of fatal early-onset mitochondrial cardiomyopathy caused by loss of mitochondrial aspartyl-tRNA synthetase, which is essential for translation of all 13 mitochondrial DNA-encoded oxidative phosphorylation subunits. Male hmKO mice and wild type littermates received either a ketogenic or normal chow diet from weaning until the humane endpoint. KD induced a partial shift toward cardiac fatty acid metabolism and activated mitochondrial biogenesis signaling. However, these adaptations did not improve survival, cardiac hypertrophy, skeletal muscle atrophy, motor performance, respiratory chain complex abundance, enzyme activities, or cardiac ATP levels. KD reduced antioxidant gene expression, without increasing protein carbonylation, and amplified the mitokine response, with increased GDF15 and FGF21 in the heart and serum. These findings show that substrate availability alone cannot restore cardiac bioenergetics when mitochondrial translation capacity is severely impaired. Instead, mitochondrial translation machinery defines a critical boundary for metabolic interventions in mitochondrial cardiomyopathy. Our results argue that the therapeutic potential of KD in mitochondrial disease is mechanism-dependent and should not be generalized across genetically and bioenergetically distinct forms of mitochondrial cardiomyopathy.

Keywords:  Aminoacyl-tRNA synthetase; DARS2; Ketogenic diet; Mitochondrial cardiomyopathy; Mitochondrial translation; Stress responses

DOI:  https://doi.org/10.1007/s10863-026-10143-9
Int J Mol Sci. 2026 Oct 24. pii: 9513. [Epub ahead of print]27(21):

Impaired Mitochondrial Translation and Bioenergetic Dysfunction Associated with the MT-RNR1 m.1014A>G Variant.

Irene Marrone, Blendi Ura, Fulvio Celsi, Luisa Zupin, Eduardo Maria Sommella, Valentina Golino, Paolo Peruzzo, Chiara Ciardi, Maria Teresa Bonati, Elena Genova, Massimo Zeviani, Alessandro Mauro Spinelli, Valeria Capaci.

  Pathogenic variants in MT-RNR1 are classically associated with aminoglycoside-induced sensorineural hearing loss through disruption of the mitochondrial 12S rRNA decoding center. Their contribution to pediatric neurological disease remains poorly defined. We identified a novel homoplasmic MT-RNR1 variant, m.1014A>G, in a patient with drug-resistant focal epilepsy beginning at 9 months of age who remained undiagnosed after trio whole-exome sequencing filtered using an extensive epilepsy gene panel. The variant was also detected in her mother. Structural modeling suggests that the variant, affecting a highly conserved region of the mitochondrial 12S rRNA, may alter the mitochondrial small ribosomal subunit assembly. To investigate its pathogenicity, we performed comprehensive functional studies in patient-derived fibroblasts. Unlike canonical MT-RNR1 variants, m.1014A>G did not confer aminoglycoside toxicity. Functional in vitro studies on patients' fibroblasts demonstrated increased 12S/16S rRNA ratios, reduced abundance of both mitoribosomal subunit proteins, decreased levels of mitochondrially encoded respiratory-chain subunits, and impaired oxidative phosphorylation. These abnormalities were accompanied by mitochondrial network fragmentation, increased mitochondria-lysosome colocalization suggestive of enhanced mitophagy and reduced mitochondrial DNA copy number. Altogether, the findings are consistent with defective mitoribosome assembly and altered mitochondrial translation, resulting in a bioenergetic defect. Our study points to a previously unrecognized candidate pathogenic mechanism associated with MT-RNR1 and may expand the phenotypic spectrum of MT-RNR1-related disorders to include maternally inherited infantile-onset epileptic encephalopathy. These findings highlight the importance of dedicated mitochondrial DNA analysis in children with unexplained early-onset epilepsy despite negative nuclear genomic testing.

Keywords:  MT-RNR1; bioenergetics; mitochondrial disease; mitoribosome; translation defect

DOI:  https://doi.org/10.3390/ijms27219513
Mol Metab. 2026 Nov 11. pii: S2212-8778(26)00156-0. [Epub ahead of print] 102472

Lipid mediated ER stress contributes to the pathogenesis of mitochondrial myopathies.

Inaya Laubach, Guido Primiano, Nneka Southwell, Nicola Rizzardi, Belem Yoval-Sánchez, Christian Bergamini, Serenella Servidei, Alexander Galkin, Giovanni Manfredi, Qiuying Chen, Marilena D'Aurelio.

  Mitochondrial diseases are a heterogeneous group of genetic disorders caused by impaired oxidative phosphorylation (OxPhos). When skeletal muscle is predominantly affected, they are defined as primary mitochondrial myopathies. Although the genetic causes of mitochondrial myopathies and the resulting bioenergetic impairments are well established, the metabolic drivers behind progressive muscle dysfunction remain poorly defined. This gap in knowledge may contribute to the lack of effective treatments for these disorders. OxPhos defective muscle initiates a metabolic response coordinated by systemic signals which results in muscle and adipose tissue wasting. Here, we show ectopic muscle lipid accumulation in a COX10 KO mouse model of mitochondrial myopathy due to inability to oxidize fatty acids in muscle. In both the mouse model and in mitochondrial patients, we find an increase in ceramides, which is mechanistically linked to chronic ER stress, phosphorylation of eIF2α, and activation of ATF4 signaling. We propose that Ph-eIF2α-mediated attenuation of global protein synthesis and ATF4-initiated atrophy pathways contribute to muscle wasting and weakness. Importantly, inhibition of de novo synthesis of ceramides with myriocin reduces ER stress and ATF4 signaling and improves muscle proteostasis, body weight, and motor functions in the COX10 KO mouse. Together, these findings highlight the role of lipid metabolism as a contributor to mitochondrial myopathy and identify lipid-mediated stress pathways that can be targeted therapeutically.

Keywords:  COX10; ER stress; ceramides; lipid metabolism; mitochondrial myopathy; muscle wasting

DOI:  https://doi.org/10.1016/j.molmet.2026.102472
Cell Discov. 2026 Nov 10. pii: 80. [Epub ahead of print]12(1):

ER-mitochondria contacts orchestrate mitochondrial transport via C19orf12.

Xiayuhe Pei, Shuqian Zhang, Peiyang Li, Yutong Wu, Yiru Cheng, Xia Feng, Yiqian Wu, Xiaoshuai Huang, Ning Huang, Bei Liu, Junlin Teng, Jianguo Chen, Craig Blackstone, Pengli Zheng.

Endoplasmic reticulum (ER)-mitochondria contact sites facilitate lipid transfer, calcium signaling, and mitochondrial division; however, their role in mitochondrial transport remains unclear. Here, we identify hereditary spastic paraplegia (HSP)-associated protein C19orf12 as an ER-anchored regulator of mitochondrial trafficking. The loss of C19orf12 leads to perinuclear mitochondrial clustering in cells, impaired anterograde transport in neurons, and progressive locomotor dysfunction in mice that recapitulates key features of HSP in humans. Mechanistically, C19orf12 forms a discrete complex with the mitochondrial Rho GTPase Miro1 and the Kinesin-1 motor Kif5b, thereby providing a molecular link between ER-mitochondria contacts and microtubule-based anterograde transport. Ca2+ also modulated C19orf12-Miro1 behavior in vitro and showed a biphasic association with mitochondrial motility in live cells. Therefore, our findings establish ER‒mitochondria contact sites as logistical hubs for Kinesin-1 motor loading and highlight the importance of the Ca2+-tunable C19orf12 scaffold in sustaining directional mitochondrial transport, providing a mechanistic framework for how C19orf12 loss may contribute to neurodegeneration.

DOI: https://doi.org/10.1038/s41421-026-00934-0
Int J Mol Sci. 2026 Nov 03. pii: 9837. [Epub ahead of print]27(21):

Restoring Bioenergetics in the Traumatized Eye: The Emergence of Mitochondrial Implantation as a Treatment for Acute Ocular Injury.

Emma Peveri, Daniella Beiner, Andrew J W Huang, Jian-Xing Ma, Amish Asthana, Anthony Atala, Giuseppe Orlando, Yuanyuan Zhang.

  Acute ocular injuries-such as chemical burns, ischemic insults, and mechanical trauma-frequently lead to irreversible vision loss by triggering rapid intracellular adenosine triphosphate (ATP) depletion, mitochondrial calcium overload, severe oxidative stress, and profound mitochondrial dysfunction. Current clinical management primarily focuses on suppressing inflammation and preventing secondary infection, but it fails to address the underlying bioenergetic collapse that drives cellular degeneration. While stem cell and extracellular vesicle therapies have been widely investigated, direct mitochondrial transplantation has recently emerged as a novel strategy for metabolic rescue. This review evaluates the therapeutic potential of exogenously administered mitochondria to mitigate mitochondrial dysfunction and acute trauma in the eye. Emerging preclinical studies demonstrate that transplanted mitochondria can be internalized by selected ocular cell types, conferring short-term cytoprotection, preserving retinal ganglion cell viability, and accelerating corneal epithelial repair. However, robust evidence regarding long-term mitochondrial integration, functional fusion, durable metabolic rescue, and clinical efficacy remains limited. Despite critical challenges in delivery, stability, and dosing, mitochondrial transplantation represents a promising frontier in regenerative ophthalmology that directly targets bioenergetic failure to preserve vision.

Keywords:  acute ocular injury; bioenergetic failure; metabolic rescue; mitochondrial transplantation; ocular trauma

DOI:  https://doi.org/10.3390/ijms27219837
FEBS Lett. 2026 Nov 09.

Mitochondrial translation and coordinated cytosolic translation in metabolic homeostasis and disease.

Boseon Kim, Thi Thanh Mai Tran, Nakyung Kang, Min-Woo Lee, Mihye Lee.

  Mitochondria are essential organelles that regulate cellular metabolism, signaling, and stress responses. Their function depends on coordinated protein synthesis from the mitochondrial and nuclear genomes, together with mechanisms that preserve mitochondrial proteostasis. Translation of both nuclear- and mitochondrial-encoded transcripts is dynamically regulated in response to developmental, metabolic, and environmental cues, allowing mitochondria to remodel their proteome and adapt to changing physiological demands. Disruption of these processes impairs respiratory complex assembly, mitochondrial function, and protein homeostasis, contributing to a wide range of metabolic, cardiovascular, muscular, neurodegenerative, and immune disorders. In this review, we summarize the evolutionary specialization of the mitochondrial translational machinery and the molecular mechanisms that regulate mitochondrial protein synthesis. We discuss recent advances in cytosolic translational control of nuclear-encoded mitochondrial proteins, mito-nuclear coordination, tissue-specific regulation of mitochondrial proteostasis, and their implications for human disease. Finally, we highlight emerging challenges and future directions in the translational regulation of mitochondrial protein synthesis and its relevance to mitochondrial biology and disease.

Keywords:  RNA localization; metabolism; mitochondrial dysfunction; mitochondrial protein; mito‐nuclear coordination; translational control

DOI:  https://doi.org/10.1002/1873-3468.70502
Nat Commun. 2026 10 13. pii: 11577. [Epub ahead of print]17(1):

Mitochondria-localized circRNA BRAKE restrains adipogenesis under nutrient overload by disrupting ATP synthase assembly in mice.

Yanrui Huang, Tianxin Zhu, Xiaosi Hong, Yulin Yang, Jianyou Liao, Jiayu Liu, Chunni Li, Wei Wang, Sifan Chen, Phei Er Saw, Yanbing Li, Haipeng Xiao, Meng Ren, Shicheng Su, Yanrui Huang.

Impaired adipogenesis contributes to obesity-associated metabolic disorders, in which mitochondrial dysfunction plays an important role. Emerging evidence suggests that mitochondria-localized circular RNAs (circRNAs) influence mitochondrial function; however, whether they regulate adipogenesis and systemic metabolism is unclear. By profiling circRNAs in mitochondria isolated from the white adipose tissue (WAT) of obese male mice, we observe an upregulation of Birc6-circRNA Repressing Adipogenesis and Krebs-cycle Energy (BRAKE) in mitochondria. In vivo, adipocyte-specific circRNA BRAKE knockdown in male mice reduces body weight, restricts fat expansion, and improves insulin sensitivity. In vitro studies show that circRNA BRAKE inhibits adipogenesis. Mechanistically, circRNA BRAKE binds ATP5A and disrupts ATP synthase assembly, thereby reducing ATP production and mTORC1 signaling and suppressing adipogenesis. In omental WAT (oWAT) of patients with obesity, mitochondrial circRNA BRAKE levels are elevated and inversely correlated with mitochondrial bioenergetic function. Collectively, our data identify a mitochondria-localized circRNA that regulates energy metabolism and adipogenesis, suggesting that circRNA BRAKE may represent a potential therapeutic target for obesity-related metabolic diseases.

DOI: https://doi.org/10.1038/s41467-026-78378-z
Nature. 2026 Nov 11.

Mitochondrial protein import defects enhance tumour immunogenicity.

Thomas D Jackson, Jonathan M Palozzi, Christopher D McGann, Tevis Vitale, Ruth Choa, Hieu H M Nguyen, Joao A Paulo, Pedro Latorre-Muro, Jonathan G Van Vranken, Matthew Ravichandran, Bingsen Zhang, Manisha Yadav, Steven P Gygi, Pere Puigserver.

Tumour cells evade detection and elimination by the immune system through a suite of adaptations1, including the repression of antigen presentation, which is required for the recognition of tumour cells by CD8+ T cells. Mitochondria have emerged as targets for enhancing antitumour immunity; however, the extensive mitochondrial proteome has remained largely unstudied for its ability to modulate immune responses. Here we show that defects in the mitochondrial protein import machinery promote tumour immunogenicity and synergize with immune checkpoint blockade treatment in melanoma models. Mitochondrial protein import perturbation, specifically through depletion of the TIM23 import complex subunit TIMM50, enhances tumour immunogenicity through a pathway involving mitochondrial DNA escape, cGAS-STING pathway activation and interferon-β (IFNβ) secretion. Secreted IFNβ signals through the type I IFN receptor to activate the JAK-STAT pathway, resulting in increased antigen presentation on MHC class I complexes. Mitochondrial DNA escape in Timm50-depleted cells is linked to the formation of mitochondrial-derived vesicles. Depletion of SNX9 and RAB9, involved in mitochondrial-derived vesicle formation2, suppresses mitochondrial DNA-dependent type I IFN production and signalling. By disrupting mitochondrial proteostasis and membrane architecture, defective protein import in Timm50-depleted cells drives the immune phenotype. This study shows that mitochondrial protein import inhibition causes tumour immunogenicity, including sensitization to immune checkpoint blockade, by promoting mitochondrial DNA escape and IFNβ-driven MHC class I antigen presentation.

DOI: https://doi.org/10.1038/s41586-026-11249-1
Cell Mol Neurobiol. 2026 Aug 13. pii: 164. [Epub ahead of print]46(1):

Mitochondria-RNA Binding Protein Crosstalk in Neurodegeneration: Mechanisms Linking Mitochondrial Stress, RNA Dysregulation and Neuronal Vulnerability.

Aditya Goswami, Leia Lauer, Sofie Robinson, Reet Goyal, Kristian Herman, Ramkumar Mathur.

Mitochondria have long been organelles, recognized as bioenergetic organelles. Additionally, mitochondria have recently emerged as central hubs of RNA regulatory networks. A growing body of evidence demonstrates that mitochondria and RNA-binding proteins (RBPs) engage in a two-way dialogue to integrate stress responses, proteostasis, and adaptive cellular programs. Several RBPs linked to neurodegenerative diseases, such as TDP-43, FUS, TIA-1, TIAR, and Pumilio family proteins, directly impact mitochondrial biogenesis, fusion-fission dynamics, and mitophagy. In turn, mitochondrial signaling can reprogram RBP behavior via post-translational modification, recruitment to mitochondrial membranes, and stress-induced translocation to cytoplasmic ribonucleoprotein granules. Interference with this regulatory axis significantly impacts on neuronal homeostasis. Mislocalization of RBPs is often linked to mitochondrial fragmentation, compromised oxidative phosphorylation, decreased ATP production, and increased reactive oxygen species (ROS) production. Notably, mitochondrial dysfunction is a common early event, even before apparent neuron loss, in several neurodegenerative diseases. Emerging data also points to a role for the mitochondria RBP interface in selective neuronal vulnerability, particularly in motor neurons that rely heavily on both mitochondrial bioenergetics and highly regulated RNA metabolism. Here, we review recent work that has helped define the molecular underpinnings of mitochondrial RBP crosstalk, discussing emerging tools that have facilitated these findings (including super-resolution microscopy, RNA interactome mapping, and mitochondrial proteomics), while highlighting therapeutic approaches that seek to restore mitochondrial and RNA homeostasis. Understanding the interface between mitochondria and RBPs provides a novel paradigm for neurodegeneration and may open new therapeutic opportunities.

DOI: https://doi.org/10.1007/s10571-026-01788-6
Front Endocrinol (Lausanne). 2026 ;17 1860825

Placental programming of metabolic diseases: molecular pathways from maternal pregnancy complications to offspring metabolic risk.

Duo Zhou.

   Introduction: The placenta is increasingly recognized as a dynamic regulatory organ that translates both maternal and paternal physiological and pathological states into developmental signals into developmental signals shaping offspring health across the lifespan. In the context of maternal metabolic and obstetric complications, placental function extends far beyond the regulation of fetal growth, influencing key aspects of development including endocrine set points, nutrient allocation, inflammatory responses, vascular adaptation, and molecular programming across fetal organs.
Results: This review examines how maternal conditions -such as obesity, gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy, undernutrition, micronutrient imbalance, and maternal inflammatory stress -induce structural, endocrine, vascular, metabolic, and epigenetic alterations in the placenta. We further explore how these changes disrupt critical molecular pathways, including nutrient sensing and transport, oxidative stress responses, mitochondrial function, angiogenesis and glucocorticoid signaling, immune regulation, and gene expression. A central focus is the convergence of placental mechanisms across diverse maternal disorders, leading to shared offspring phenotypes such as insulin resistance, increased adiposity, dyslipidemia, impaired glucose regulation, altered appetite control, and elevated risk of cardiometabolic disease later in life.
Conclusion: Additionally, we address sex-specific placental adaptations, fetal tissue vulnerability, and the translational potential of placental biomarkers and omics-based approaches supported by mechanistic experimental models. By positioning the placenta as the primary biological interface linking maternal complications to offspring susceptibility to endocrine and complex metabolic diseases, this review provides an integrated framework for understanding developmental programming in metabolic health.

Keywords:  fetal programming; gestational diabetes mellitus; hypertensive disorders of pregnancy; intergenerational impact; metabolic risk; placenta; placental dysfunction; placental programming

DOI:  https://doi.org/10.3389/fendo.2026.1860825
J Transl Med. 2026 Aug 17. pii: 1419. [Epub ahead of print]24(1):

Metformin promotes placental adaptation to hypoxic stress through mitochondrial and translational pathways.

Elif Kadife, Alesia Harper, Ishara Atukorala, Sarah Ellis, Fiona C Brownfoot.

   BACKGROUND: Preeclampsia is a leading cause of maternal and perinatal morbidity worldwide, with no approved disease-modifying medical therapy. The disorder originates from placental insufficiency characterised by chronic hypoxia, oxidative stress, inflammation, and mitochondrial dysfunction within placental trophoblasts. Although metformin is widely used in pregnancy and has shown benefit in preeclampsia clinical trials, its mechanism of action including direct effects on placental protein synthesis and mitochondrial adaptation under hypoxic conditions remain poorly defined. Our aim was to determine how metformin modulates placental protein synthesis and mitochondrial function under physiological and hypoxic conditions relevant to placental dysfunction.
METHODS: Primary human placental trophoblasts were cultured under normoxic (8% O₂) or hypoxic (1% O₂) conditions and treated with metformin. Label-free quantitative proteomics was used to identify altered molecular pathways. Mitochondrial adaptation was assessed by analysis of mitochondrial dynamics markers, electron transport chain (ETC) complex expression, and reactive oxygen species (ROS) production.
RESULTS: Metformin upregulated proteins involved in RNA processing, protein synthesis, and metabolism, while downregulating proteins associated with extracellular matrix organization and apoptosis. Under hypoxic conditions, metformin increased markers of mitochondrial fission and significantly upregulated ETC complexes I, II, and IV. These changes were associated with reduced cellular ROS levels. Importantly, enhanced protein synthesis occurred without activation of unfolded protein response pathways, indicating preservation of cellular homeostasis.
CONCLUSION: Metformin enhances placental adaptation to hypoxic stress by coordinating protein synthesis and mitochondrial respiratory function while reducing oxidative stress. These mechanistic findings provide translational insight into how metformin may improve placental resilience and support its further evaluation as a therapeutic strategy for preeclampsia and other pregnancy complications driven by placental dysfunction.
TRIAL REGISTRATION: Not applicable. This study does not meet the NHMRC definition of a clinical trial.

Keywords:  Metformin; Mitochondria; Placenta; Preeclampsia; Trophoblasts

DOI:  https://doi.org/10.1186/s12967-026-08798-4
Neurobiol Dis. 2026 Nov 10. pii: S0969-9961(26)00419-5. [Epub ahead of print] 107673

Neuronal and mitochondrial phenotypes in iPSC-derived bipolar disorder models with and without a family history of mitochondrial disease.

Dana El Soufi El Sabbagh, Jaehyoung Choi, Lakshmini Balachandar, Eileen Haydarian, Jude Demyati, Zaara Mazhar, Angela Duong, Chiara Cristina Bortolasci, Courtney Irwin, Karun K Singh, Michael Berk, Ken Walder, L Trevor Young, Peter L Carlen, Ana Cristina Andreazza.

  Psychiatric disorders frequently accompany primary mitochondrial diseases (PMDs), suggesting shared biological pathways between mitochondrial function and psychiatric vulnerability. In this exploratory study, we investigated whether bipolar disorder (BD) occurring in the context of a family history of primary mitochondrial disease is associated with differences in neuronal and mitochondrial phenotypes. We generated induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and cortical neurons (CNs) from three non-psychiatric controls, three individuals with BD without a family history of mitochondrial disease, and three individuals with BD who did not themselves have mitochondrial disease but had relatives with clinically diagnosed mitochondrial (BD-FHMD). Our primary endpoints were distinguished network activity and cytosolic and mitochondrial Ca2+ dynamics, complemented by measurements of mitochondrial and cellular function and metabolomic profiles across differentiation. Across neurodifferentiation, we assessed neuronal network activity, calcium dynamics, mitochondrial and cellular health, and metabolomic signatures. BD neurons exhibited sustained hyperexcitability with increased firing and burst activity. In contrast, BD-FHMD neurons showed lower network activity with enhanced cytosolic calcium responses and prolonged mitochondrial calcium transients. BD-FHMD also exhibited stage-dependent mitochondrial alterations, while BD and BD-FHMD showed distinct developmental metabolic signatures. Together, these findings identify two distinct mitochondrial-associated phenotypes within BD. BD is characterized by a hyperexcitable neuronal phenotype associated with altered developmental metabolic programming, whereas BD-FHMD exhibits calcium dysregulation and altered mitochondrial developmental trajectories consistent with increased bioenergetic vulnerability. These findings suggest that BD occurring in the context of a family history of primary mitochondrial disease may be characterized by a distinct pattern of neuronal and mitochondrial dysfunction. Replication in larger, independently characterized cohorts will be important to determine whether this family-history-defined phenotype can contribute to biologically informed subtyping and therapeutic approaches in BD.

Keywords:  Bipolar disorder; Cortical neurons; Electrophysiology; Hyperexcitability; Mitochondrial dysfunction; iPSC

DOI:  https://doi.org/10.1016/j.nbd.2026.107673
iScience. 2026 Nov 20. 29(11): 118118

Exercise-conditioned serum drives mitochondrial remodeling in neurons.

Vivien Csikos, Colton R Lysaker, Brittany M Hauger, Taylor A Strope, Carlo Barnaba, Keith P Smith, Julie Allen, Patrycja Puchalska, John P Thyfault, Heather M Wilkins.

  Regular exercise and fasting are can improve brain health. How these interventions affect mitochondrial quality control processes in neurons is unknown. We hypothesized that circulating factors induced by acute exercise could stimulate neuronal mitophagy and mitochondrial remodeling.We treated primary cortical mouse neurons with serum collected from mice following a single bout of exhaustive treadmill running or sedentary controls. To determine if one bout of exercise activates brain mitophagy in vivo, we mice underwent an acute fasting and treadmill paradigm followed by electron microscopy of the frontal cortex. Proteomics analysis revealed widespread changes in mitochondrial and autophagy-related proteins and upregulation of mitochondrial biogenesis, protein quality control, and redox signaling. Acute exercise in a fasted state increased mitophagy. These results demonstrate that circulating acute exercise factors promote mitophagy and mitochondrial turnover in neurons. This supports the broader concept that exercise could enhance brain mitochondrial function.

Keywords:  exercise; mitochondria; mitophagy; neuron

DOI:  https://doi.org/10.1016/j.isci.2026.118118
Nucleic Acids Res. 2026 Nov 10. pii: gkag1169. [Epub ahead of print]54(21):

A p32 family RNA editing factor acts in mitochondrial ribosome biogenesis.

Prashant Chauhan, Ingrid Sveráková-Škodová, Jonathan E Wong, Jan Říha, Julie Dedková, Anna Huber, Lukas Müller, Evgeny S Gerasimov, Alena Zíková, Vyacheslav Yurchenko, Ondřej Gahura.

Biogenesis of mitochondrial ribosomes (mitoribosomes) in the unicellular parasite Trypanosoma brucei requires an exceptionally large toolkit of assembly factors, identified in stable precursors of large and small mitoribosomal subunits (mtLSU and mtSSU) by cryoEM. Here, using genetic modifications and proteomic characterization of the immunoprecipitated assemblosome, the earliest characterized mtSSU precursor, we determined that a cap of its distinctive protrusion of hitherto unknown composition consists of a p22 homotrimer. This protein was previously implicated in the uridine-insertion editing of the cytochrome c oxidase subunit II transcript. Our functional analysis confirmed this role but revealed that its ablation also causes a loss of mtSSU and a systemic reduction in mitochondrial translation, phenocopying the depletion of established mitoribosomal assembly factors. Consequently, the oxidative phosphorylation system and mitochondrial function are compromised. The p22 protein belongs to the p32 family. We showed that five of its six trypanosomal members are involved in mtSSU biogenesis. Notably, p32 proteins are associated with mitoribosomes in two other distant eukaryotic lineages. A eukaryote-wide mapping of p32 proteins documented that their presence correlates with the retention of mitochondrial genomes. Together, our findings redefine trypanosomal p22 as a dual-function coordinator of mitochondrial gene expression and reveal that the ancestral role of the p32 family is associated with mitochondrial translation.

DOI: https://doi.org/10.1093/nar/gkag1169
Biochem Biophys Res Commun. 2026 Nov 05. pii: S0006-291X(26)01615-3. [Epub ahead of print]843 154849

Cannabidiol abrogates the atypical enlargement of mitochondria in Tafazzin-deficient B-lymphoblastoid cells.

John Z Chan, Mishi Groh, Musa Musa, German Sciaini, Robin E Duncan.

  Barth Syndrome (BTHS) is a rare, X-linked disorder caused by the loss of function of Tafazzin, an enzyme responsible for the remodelling of cardiolipin. Although neutropenia is the best-characterized immunological deficit in BTHS, recent studies have also demonstrated deficiencies in B-cell and T-cell populations. BTHS patient-derived B-lymphoblastoid cells have been widely used to investigate the mitochondrial abnormalities associated with the disease. Our group, and others, have previously reported alterations in mitochondrial cristae architecture and the presence of abnormally enlarged mitochondria in these cells. Recently, we demonstrated that treatment of BTHS B-lymphoblastoids with the phytocannabinoid cannabidiol (CBD) restores maximal respiratory capacity, total cardiolipin content, the ratio of monolysocardiolipin to cardiolipin, and cell growth. However, the effects of CBD in restoring other mitochondrial parameters, including the relative abundance of various electron transport chain (ETC) proteins, and the profile of cardiolipin fatty acyl species, were ineffective or incomplete. Building on these findings, the present study aimed to examine whether CBD altered mitochondrial morphology and dynamics in Tafazzin-deficient B-lymphoblastoid cells. Using transmission electron microscopy, we found that CBD reversed the mitochondrial enlargement in BTHS B-lymphoblastoid cells but had no significant effect on cristae architecture. CBD fully reversed the elevated phosphorylation of Drp1 at the fission-inhibitory Ser637 site, strongly suggesting that the reduction in mitochondrial enlargement following CBD treatment involves the modulation of mitochondrial fission. Our results support the notion that cardiolipin composition, not just content, is important for mitochondrial ultrastructure in mammalian cells, and also supports a role for CBD in regulating mitochondrial dynamics.

Keywords:  Barth syndrome; Fission; Fusion; Mitochondria; Tafazzin; Transmission electron microscopy

DOI:  https://doi.org/10.1016/j.bbrc.2026.154849