bims-mitdis 2026-01-18 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2026–01–18
forty-two papers selected by
Catalina Vasilescu, Helmholz Munich

Mitochondrial diseases.
Mitochondrial Disorder in a Child With Brainstem Lesions Mimicking Thiamine Deficiency.
Towards CRISPR-based editing of the mitochondrial genome in yeast.
A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.
Mrx6 binds the Lon protease Pim1 N-terminal domain to confer selective substrate specificity and regulate mtDNA copy number.
Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.
Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.
Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
Mitochondrial Disorders Should Be Considered as a Differential Diagnosis of Thiamine Deficiency.
Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
Potassium ion homeostasis modulates mitochondrial function.
Mitochondrial ligase MAPL drives pyroptotic cell death.
The need to understand the underlying mechanisms associated with mitochondrial therapies in assisted reproduction before further clinical trials are performed.
Mitochondrial fission during mitophagy requires both inner and outer mitofissins.
What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
Tmem110 regulates the conformation of TRPML1 to maintain endolysosomal homeostasis and prevent mitochondrial DNA leakage and pathological self-DNA processing.
Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
Evaluation of MASSARRAY technique in detecting mitochondrial disease mutations.
Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study.
FALCON-qPCR: a new method for the quantification of oxidative lesions in mitochondrial DNA.
On the Feasibility of Clinical Studies with Cross-Linking Mass Spectrometry.
UQCRC1 deficiency impairs mitophagy via PINK1-dependent mechanisms in Parkinson's disease.
Atypical tetracyclines promote longevity and ferroptotic neuroprotection via translation attenuation.
Robust mitochondria segmentation and morphological profiling using soft X-ray tomography.
Intercellular mitochondrial transfer rewires redox signaling and metabolic plasticity: mechanisms, disease relevance and therapeutic frontiers.
Research Progress on Idebenone in Neurodegenerative Diseases.
Unveiling the neuroprotective power of mitochondrial transfer in orofacial inflammatory pain through ER membrane remodeling.
Mitochondria-derived peptides in liver disease: Emerging regulators of hepatic metabolism and therapeutic targets.
Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex.
Suppressive Genetic Interactions Between Haploinsufficient Mitochondrial Genes Encoded in the 22q11.2 Microdeletion Locus Define Brain and Cardiac Phenotypes.
MitoCommun: a database for decoding mitochondrial communication networks.
Development of a split-toxin CRISPR screening platform to systematically identify regulators of human myoblast fusion.
The nuclear and mitochondrial genomes need to tango. How is their dance synchronized during development?
DNMT1 knockdown mitigates sepsis-induced myocardial dysfunction by preventing TFAM-mediated mitochondrial DNA cytosolic escape and subsequent cGAS-STING to regulate macrophage M2 polarization.
Assembling unregulated DNA segments bypasses synthesis screening: regulate fragments as select agents.
CHAMP1 is an essential regulator for human myoblast fusion and muscle development.
Juvenile-Onset Cerebrotendinous Xanthomatosis with Novel Compound Heterozygous CYP27A1 Mutations: Case Series and Literature Review.
Early multi-omic signatures and machine learning models predict cardiomyocyte differentiation efficiency and enable robust hPSC differentiation to cardiomyocytes.
Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.
Overcoming the widespread flaws in the annotation of vertebrate selenoprotein genes in public databases.
Cancer might evade immune defences by stealing mitochondria.
Bedaquiline inhibits the ATP synthase leak channel and prevents glutamate-induced neuronal death.

Nat Biotechnol. 2026 Jan;44(1): 38

Mitochondrial diseases.

DOI: https://doi.org/10.1038/s41587-025-02973-6
Cureus. 2025 Dec;17(12): e98909

Mitochondrial Disorder in a Child With Brainstem Lesions Mimicking Thiamine Deficiency.

Mohamad A Asfour, Jennifer Nedimyer Horner, Kanika Gupta, Gleidson Silva, Tushar Chandra, Gian Rossi.

  Mitochondrial diseases are among the most common genetic disorders. Known as the "powerhouse" of the cell, mitochondria generate energy via oxidative phosphorylation, a process that involves five enzyme complexes. The MT-ND5 gene, which encodes part of Complex I, is especially prone to mutations and is linked to various mitochondrial disorders. Since mitochondria are concentrated in metabolically active organs such as the brain, heart, liver, muscles, and kidneys, these systems are particularly vulnerable to dysfunction. In the brain, mitochondrial disease symptoms often arise in regions with high metabolic demand, such as the brainstem. Disruptions in oxidative phosphorylation due to nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase chain 5 (MT-ND5) mutations can prevent energy production from meeting cellular demands, leading to serious neurological consequences. This report describes the neuroimaging and clinical presentation of a child with an MT-ND5 pathogenic variant, highlighting characteristic MRI findings and the diagnostic challenges posed by overlapping features with other metabolic disorders, such as thiamine deficiency.

Keywords:  brain; genetic diseases; magnetic resonance imaging; mitochondria; mitochondrial disease; mt-nd5; neuroradiology; oxidative phosphorylation; thiamine deficiency

DOI:  https://doi.org/10.7759/cureus.98909
Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2505894123

Towards CRISPR-based editing of the mitochondrial genome in yeast.

Sifei Yin, Daniel F Jarosz, Alice Y Ting.

  Mitochondria, which evolved from symbiotic bacteria, possess their own genomes (mtDNA) and support independent transcription and translation within the organelle. Given the essential role of mtDNA in energy production, metabolism, as well as cellular homeostasis, and the high density of confirmed pathogenic mutations that map to mtDNA, there is a pressing need for versatile methods to study and manipulate this genome. Although CRISPR technology has revolutionized the editing of nuclear genomes, it has not been successfully extended to mtDNA, primarily due to the challenge of delivering single guide RNAs (sgRNAs) across both outer and inner mitochondrial membranes. Here we develop a survival-based reporter in Saccharomyces cerevisiae to screen for potential RNA import motifs. We identify a 40-nucleotide aptamer (IM83) that facilitates sgRNA entry into the mitochondrial matrix, enabling CRISPR editing by a mitochondrially-localized adenine base editor. We show that mitochondrial import of IM83 is ATP-dependent and enhanced by the tRNA synthetase Msk1. Further investigations identify barriers to efficient CRISPR editing of mtDNA, including loss of membrane potential associated with mitochondrial targeting of the base editor. These insights lay the groundwork for future improvements in CRISPR-based editing of mtDNA in eukaryotes.

Keywords:  CRISPR editing; RNA technology; base editing; mitochondrial RNA import; mitochondrial gene editing

DOI:  https://doi.org/10.1073/pnas.2505894123
Cell Mol Life Sci. 2026 Jan 12.

A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.

Marlena Helms, Angelika B Harbauer.

  Neurons have adapted the transport and positioning of mitochondria to fit their extended shape and high energy needs. To sustain mitochondrial function, neurons developed systems that allow local biogenesis and adaption to locally regulate mitochondrial form and function. Likewise, fine-tuned degradative systems are required to protect the neurons from mitochondrial dysfunction. Throughout both domains of mitostasis, the local synthesis of the mitochondrial damage-induced kinase PINK1 emerges as a central player. Along with other nuclear encoded mitochondrial proteins, its mRNA associates with mitochondria to sustain mitochondrial function locally. It also regulates mitochondrial degradation, via regulation of proteases, the generation of mitochondria-derived vesicles and mitophagy. In this review, we provide a general overview of the mechanisms governing mitochondrial health in neurons, with a special focus on the role of PINK1 in this endeavor.

Keywords:  Local translation; Mitochondrial proteases; Mitophagy; mRNA transport

DOI:  https://doi.org/10.1007/s00018-025-06054-4
Nucleic Acids Res. 2026 Jan 14. pii: gkaf1390. [Epub ahead of print]54(2):

Mrx6 binds the Lon protease Pim1 N-terminal domain to confer selective substrate specificity and regulate mtDNA copy number.

Simon Schrott, Ilaria Marafelli, Charlotte Gerle, Sebastian Bibinger, Lea Bertgen, Giada Marino, Serena Schwenkert, Romina Rathberger, Johannes M Herrmann, Christof Osman.

Mitochondrial DNA (mtDNA) copy number regulation remains incompletely understood, despite its importance in cellular function. In Saccharomyces cerevisiae, Mrx6 belongs to the Pet20-domain-containing protein family, consisting of Mrx6, Pet20, and Sue1. Notably, absence of Mrx6 leads to increased mtDNA copy number. Here, we identify the C-terminus of Mrx6 as essential for its stability and interaction with the mitochondrial matrix protein Mam33. Deletion of Mam33 mimics the effect of Mrx6 loss, resulting in elevated mtDNA copy number. Bioinformatics, mutational analyses, and immunoprecipitation studies corroborate that a subcomplex of Mam33 and Mrx6 trimers interacts with the substrate recognition domain of the conserved mitochondrial Lon protease Pim1 through a bipartite domain in the Pet20 domain of Mrx6. Loss of Mrx6, its paralog Pet20, Mam33, or mutations disrupting the interaction between Mrx6 and Pim1 stabilize key proteins required for mtDNA maintenance, the RNA polymerase Rpo41 and the HMG-box-containing protein Cim1. We propose that Mrx6, alongside Pet20 and Mam33, regulates mtDNA copy number by modulating substrate degradation through Pim1. Additionally, Mrx6 loss alters Cim1's function, preventing the detrimental effect on mtDNA maintenance observed upon Cim1 overexpression. The presence of three Pet20-domain proteins in yeast implies broader roles of Lon protease substrate recognition beyond mtDNA regulation.

DOI: https://doi.org/10.1093/nar/gkaf1390
J Inherit Metab Dis. 2026 Jan;49(1): e70142

Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.

Karin Terburgh, Nastassja Sweeney, Roan Louw.

  The deficiency of mitochondrial complex I (CI), a key regulator of cellular energy homeostasis and metabolic flexibility, is a prevalent driver of cardiovascular pathology in mitochondrial disorders. The Ndufs4 knockout (KO) mouse model of Leigh syndrome (LS), which lacks a critical CI subunit, exhibits severe cardiac abnormalities secondary to encephalomyopathy. However, the metabolic basis of LS-associated cardiac dysfunction remains poorly understood. This study aims to evaluate how whole-body CI deficiency affects cardiac bioenergetics and metabolism in late-stage Ndufs4 KO mice. We assessed respiratory chain enzyme activities and oxygen consumption rates using kinetic spectrophotometric assays and high-resolution respirometry, respectively, in mitochondria isolated from Ndufs4 KO and wild-type mouse hearts. Cardiometabolic profiling was performed on a well-powered cohort, employing untargeted GC-TOFMS, 1H-NMR and semi-targeted LC-MS/MS. Ndufs4 KO hearts showed a 98.9% reduction in CI activity and a 63.9% decline in CI-driven respiration, halving CI's contribution to combined CI + II respiration and prompting a shift toward CII-driven respiration. Cardiometabolic profiles revealed significant reductions in energy-generating substrates, including long-chain fatty acids, glucose, lactic acid and 3-hydroxybutyric acid, along with lower levels of anaplerotic amino acids and TCA cycle intermediates, particularly succinic acid. Additionally, profound disruptions were observed in dimethylglycine, glutamic acid and lysine metabolism. We conclude that whole-body CI deficiency results in severe cardiac bioenergetic and metabolic dysregulation, characterised by reduced CI-dependent respiration and extensive substrate reduction across multiple metabolic pathways. These findings underscore the metabolic vulnerability of the CI-deficient heart and suggest potential therapeutic targets for managing cardiomyopathy in mitochondrial disease.

Keywords:  Leigh syndrome; Ndufs4 knockout mice; complex I deficiency; heart metabolism

DOI:  https://doi.org/10.1002/jimd.70142
Pharmacol Res. 2026 Jan 10. pii: S1043-6618(26)00011-3. [Epub ahead of print]224 108096

Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.

Andrea Mancini, Elisabetta Betterini, Matteo Bordi, Francesco Cecconi.

  Mitochondria are central hubs of cellular metabolism, integrating nutrient catabolism, ATP production, redox balance, and biosynthetic precursor supply. Recent work has revealed that their influence extends beyond canonical bioenergetics to include intimate connections with cytosolic multi-enzyme assemblies. Among these, the purinosome, the complex dedicated to de novo purine biosynthesis, has emerged as a paradigmatic example of how metabolic pathways achieve efficiency through spatial and functional coupling. This Review highlights the dynamic interplay between purinosomes and mitochondria. We describe how mitochondrial metabolism supplies key substrates, including aspartate, glycine, and formate, while oxidative phosphorylation provides the ATP required for nucleotide synthesis. We discuss how purinosomes assemble through liquid-liquid phase separation, position near mitochondria in response to energetic stress, and act as adaptive metabolic hubs that sense and integrate growth and nutrient signals. Finally, we examine how disruption of this mitochondrion-purinosome axis contributes to disease, from rare neurodevelopmental disorders to cancer and neurodegeneration.

Keywords:  Cancer biology; Metabolons; Mitochondria metabolism; Nucleotide metabolism; Organelle contact sites; Purine synthesis

DOI:  https://doi.org/10.1016/j.phrs.2026.108096
Nat Commun. 2026 Jan 10.

Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.

Minh Duc Nguyen, Ana Sierra-Magro, Vivek Singh, Anas Khawaja, Alba Timón-Gómez, Antoni Barrientos, Joanna Rorbach.

The mitochondrial respiratory chain comprises four multimeric complexes (CI-CIV) that drive oxidative phosphorylation by transferring electrons to oxygen and generating the proton gradient required for ATP synthesis. These complexes can associate into supercomplexes (SCs), such as the CI + CIII₂ + CIV respirasome, but how SCs form, by joining preassembled complexes or by engaging partially assembled intermediates, remains unresolved. Here, we use cryo-electron microscopy to determine high-resolution structures of native human CI + CIII₂ + CIV late-assembly intermediates. Together with biochemical analyses, these structures show that respirasome biogenesis concludes with the final maturation of CIV while it is associated with fully assembled CI and CIII₂. We identify HIGD2A as a placeholder factor within isolated and supercomplexed CIV that is replaced by subunit NDUFA4 during the last step of CIV and respirasome assembly. This mechanism suggests that placeholders such as HIGD2A act as molecular timers, preventing premature incorporation of NDUFA4 or its isoforms and ensuring the orderly progression of pre-SC particles into functional respirasomes. Since defects in CIV assembly, including NDUFA4 deficiencies, cause severe encephalomyopathies and neurodegenerative disorders, understanding the molecular architecture and assembly pathways of isolated and supercomplexed CIV offers insight into the pathogenic mechanisms underlying these conditions.

DOI: https://doi.org/10.1038/s41467-025-68274-3
HCA Healthc J Med. 2025 ;6(6): 499-500

Mitochondrial Disorders Should Be Considered as a Differential Diagnosis of Thiamine Deficiency.

Josef Finsterer.

  Description This letter to the editor addresses limitations to diagnosing thiamine deficiency for multisystem disorders and discusses the potential differential diagnoses that must be considered.

Keywords:  SARS-CoV-2; beriberi; differential diagnosis; mitochondrial diseases; thiamine deficiency

DOI:  https://doi.org/10.36518/2689-0216.2014
Nat Metab. 2026 Jan 16.

Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.

Kimberly S Huggler, Kyle M Flickinger, Matthew H Forsberg, Carlos A Mellado Fritz, Gavin R Chang, Meghan F McGuire, Christian M Capitini, Jason R Cantor.

Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis.

DOI: https://doi.org/10.1038/s42255-025-01428-1
J Cell Biol. 2026 Apr 06. pii: e202505110. [Epub ahead of print]225(4):

Potassium ion homeostasis modulates mitochondrial function.

Adam James Waite, Beiduo Rao, Elizabeth Schinski, Nathaniel H Thayer, Manuel Hotz, Austin E Y T Lefebvre, Celeste Sandoval, Daniel E Gottschling.

Age-associated decline in mitochondrial membrane potential (MMP) is a ubiquitous aspect of eukaryotic organisms and is associated with many aging-related diseases. However, it is not clear whether this decline is a cause or consequence of aging, and therefore whether interventions to reduce MMP decline are a viable strategy to promote healthier aging and longer lifespans. We developed a screening platform in Saccharomyces cerevisiae to identify mutations that slowed or abrogated the age-associated decline in MMP. Characterization of the longest-lived mutant revealed that reduced internal potassium increased MMP and extended lifespan. Distinct interventions improved cellular MMP and lifespan: deleting a potassium transporter; altering the balance between kinases and phosphatases that control potassium transporter activity; and reducing available potassium in the environment. Similarly, in isolated mitochondria, reducing the concentration of potassium was sufficient to increase MMP. These data indicate that the most abundant monovalent cation in eukaryotic cells plays a critical role in tuning mitochondrial function, consequently impacting lifespan.

DOI: https://doi.org/10.1083/jcb.202505110
Nat Struct Mol Biol. 2026 Jan 15.

Mitochondrial ligase MAPL drives pyroptotic cell death.

Yue Feng.

DOI: https://doi.org/10.1038/s41594-025-01735-x
Hum Reprod. 2026 Jan 13. pii: deaf247. [Epub ahead of print]

The need to understand the underlying mechanisms associated with mitochondrial therapies in assisted reproduction before further clinical trials are performed.

Justin C St John, Raymond J Rodgers.

  Over a number of years, there has been growing interest in the introduction of more invasive ARTs, such as nuclear transfer, otherwise referred to as mitochondrial donation, and mitochondrial supplementation/transfer into clinical medicine. They have been proposed to overcome repeated failed fertilization or developmental arrest or to prevent carriers of mitochondrial DNA disease from having affected children. These technologies require considerable manipulation of the oocyte, which can affect its epigenetic programming that was established as it grew and developed into a fertilizable oocyte. Consequently, when a nucleus is transferred into an enucleated oocyte or pronuclei are transferred into an enucleated zygote, the nucleus must adapt to its new cytoplasmic environment in readiness for the waves of DNA demethylation and methylation that take place during preimplantation development. As a result, some key developmental gene networks are affected. Additionally, these approaches also affect patterns of mitochondrial DNA inheritance, with some embryos and offspring possessing mitochondrial DNA carried over into the oocyte with the nucleus, as well as the mitochondrial DNA from the donor oocyte. Similar outcomes result from the addition of extra mitochondrial DNA into oocytes through mitochondrial supplementation. We provide a background as to how these technologies evolved and discuss recent outcomes associated with clinical work so far undertaken within these approaches and their consequences for the offspring. We conclude that these technologies are not simply replacing or replenishing defective ooplasms with new or extra mitochondria but rather induce a series of genomic and epigenomic events that we do not yet fully understand. To our minds, these issues should be first addressed before clinical trials are continued.

Keywords:  embryo; metaphase II spindle transfer; mitochondrial DNA; mitochondrial donation; mitochondrial supplementation; mtDNA; nuclear transfer; oocyte; pronuclear transfer

DOI:  https://doi.org/10.1093/humrep/deaf247
EMBO Rep. 2026 Jan 13.

Mitochondrial fission during mitophagy requires both inner and outer mitofissins.

Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Shun-Ichi Yamashita, Keiichi Inoue, Tomoyuki Fukuda, Nobuo N Noda, Tomotake Kanki.

  Mitophagy maintains mitochondrial homeostasis through the selective degradation of damaged or excess mitochondria. Recently, we identified mitofissin/Atg44, a mitochondrial intermembrane space-resident fission factor, which directly acts on lipid membranes and drives mitochondrial fission required for mitophagy in yeast. However, it remains unclear whether mitofissin is sufficient for mitophagy-associated mitochondrial fission and whether other factors act from outside mitochondria. Here, we identify a mitochondrial outer membrane-resident mitofissin-like microprotein required for mitophagy, and we name it mitofissin 2/Mfi2 based on the following results. Overexpression of an N-terminal Atg44-like region of Mfi2 induces mitochondrial fragmentation and partially restores mitophagy in atg44Δ cells. Mfi2 binds to lipid membranes and mediates membrane fission in a cardiolipin-dependent manner in vitro, demonstrating its intrinsic mitofissin activity. Coarse-grained molecular dynamics simulations further support the stable interaction of Mfi2 with cardiolipin-containing bilayers. Genetic analyses reveal that Mfi2 and the dynamin-related protein Dnm1 independently facilitate mitochondrial fission during mitophagy. Thus, Atg44 and Mfi2, two mitofissins with distinct localizations, are required for mitophagy-associated mitochondrial fission.

Keywords:  Atg44; Mfi2; Mitochondrial Fission; Mitofissin; Mitophagy

DOI:  https://doi.org/10.1038/s44319-025-00689-x
Neurology. 2026 Feb 10. 106(3): e214618

What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?

Eduardo Benarroch.

Mitochondrial dysfunction is a key pathogenic component of neurodegenerative disorders. Mitochondrial stress, created by accumulation of misfolded proteins, reactive oxygen species, and other mechanisms, triggers signals that promote changes in protein translation and gene transcription aimed at protecting and restoring mitochondrial function and maintaining cellular homeostasis. These quality control responses are the integrated stress response and the mitochondrial unfolded protein response. When triggered by mild mitochondrial stress, these adaptive responses promote mitohormesis, which enhances cell survival and lifespan. The exchange of information between mitochondria allows mitochondrial stress in specific tissues to initiate beneficial adaptations affecting mitochondrial populations in remote tissues and organs. Experimental and human observational studies indicate that approaches to trigger mitohormesis, such as physical exercise, have beneficial effects in neurodegenerative disorders.

DOI: https://doi.org/10.1212/WNL.0000000000214618
Nat Commun. 2026 Jan 15.

Tmem110 regulates the conformation of TRPML1 to maintain endolysosomal homeostasis and prevent mitochondrial DNA leakage and pathological self-DNA processing.

Zunyong Feng, Yuanbo Pan, Jing Zhou, Liuxi Chu, Qiang Li, Xuanbo Zhang, Ping Wu, Zhiliang Xu, Yanjiao Huang, Jianhua Zou, Xiaokun Li, Xiaoyuan Chen, Zhouguang Wang.

The mechanisms by which phagocytes handle large quantities of internalized organelles, such as mitochondria released during tissue injury, remain unclear. Here we show that the endoplasmic reticulum transmembrane regulator TMEM110 is a key determinant of disease severity in traumatic brain injury-associated multiple organ dysfunction. Loss of TMEM110 impairs the clearance of mitochondria aberrantly released into the circulation, leading to heightened autoimmune-mediated tissue injury and mortality. TMEM110 maintains lysosomal function by controlling the conformational transition of the lysosomal ion channel TRPML1 and generating localized calcium efflux sites, thereby preventing calcium overload, membrane disruption, and leakage of mitochondrial DNA into the cytosol. We further find that TMEM110 expression is restrained by the nucleic acid sensor STING under basal conditions, and that a naturally occurring interface mutation between TMEM110 and STING causes defective lysosomal DNA disposal and aberrant type I interferon activity. These findings identify a feedback pathway linking cytosolic DNA sensing to organelle homeostasis.

DOI: https://doi.org/10.1038/s41467-026-68382-8
Nat Cell Biol. 2026 Jan 12.

Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.

Siddharthan B Thendral, Sasha Bacot, Ian T Ryde, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.

The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity.

DOI: https://doi.org/10.1038/s41556-025-01854-z
Clin Chim Acta. 2026 Jan 10. pii: S0009-8981(26)00002-1. [Epub ahead of print]583 120820

Evaluation of MASSARRAY technique in detecting mitochondrial disease mutations.

Nahuda Chetu, Preyaporn Onsod, Budsaba Rerkamnuaychoke, Teerapong Siriboonpiputtana, Takol Chareonsirisuthigul.

  Mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA), leading to impaired energy production, cellular dysfunction, and tissue damage. Accurate and efficient detection of mitochondrial DNA (mtDNA) mutations is crucial for diagnosis and patient management. This study aimed to evaluate the performance of MassARRAY in detecting mtDNA mutations compared to the routinely used MLPA technique. 34 EDTA blood samples from patients with suspected mitochondrial disorders were analyzed using MassARRAY and MLPA methods. MassARRAY was customized to detect 14 mtDNA loci, while MLPA targeted six fixed genetic loci. Both techniques detected five positive cases: three with the m.11778G > A mutation (8.82%) and two with the m.14484 T > C mutation (5.88%). Additionally, MassARRAY uniquely identified the m.12026 A > G mutation and a heteroplasmic m.12258C > A variant (2.94%). MassARRAY also demonstrated advantages in terms of rapid turnaround time (approximately 8 h) and assay flexibility. In conclusion, MassARRAY offers a highly accurate and efficient alternative for detecting mtDNA mutations, with the added benefit of customizable probes. However, sequencing confirmation is recommended for broader mutation coverage.

Keywords:  Mitochondrial diseases; Multiplex MALDI-TOF mass spectrometry; Multiplex ligation-dependent probe amplification; mtDNA

DOI:  https://doi.org/10.1016/j.cca.2026.120820
Neurology. 2026 Feb 10. 106(3): e214401

Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study.

Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC)

BACKGROUND AND OBJECTIVES: Twinkle, encoded by the TWNK gene, is a mitochondrial DNA helicase that unwinds the double helix of DNA during replication, playing a pivotal role in mitochondrial function. Twinkle-related disorders encompass a variety of genetic disorders characterized by mitochondrial dysfunction. Although several phenotypes have been described, the full clinical and molecular spectrum remains poorly defined. The aim of this study was to characterize the phenotypic and genotypic variability among multinational patients diagnosed with Twinkle-related disorders.
METHODS: A retrospective cohort study was conducted in patients with Twinkle-related disorders at several specialized centers in Italy, France, Germany, Spain, Denmark, Hungary, and the United States, establishing the Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC). Data were collected from medical records, including clinical features, age at onset, disease progression, and results from genetic testing. Phenotypic categories included infantile-onset cerebellar ataxia, parkinsonism, primary mitochondrial myopathy (PMM), multisystem involvement, asymptomatic carriers, undetermined phenotypes, and other phenotypes. All patients' diagnoses were confirmed by genetic analysis, and their genetic variants were noted. Outcomes included prevalence of phenotypes, symptom chronology, and mutational patterns.
RESULTS: The study included a total of 189 patients (116 female), with a mean age at symptom onset of 40.3 years. At the time of analysis, 70.4% were alive. PMM was the predominant syndrome (85.2%), and most common features were progressive external ophthalmoplegia (84.7%) and skeletal myopathy (55.6%), followed by hearing loss (17.5%) and psychiatric symptoms (15.3%). Most patients (76.8%) presented with neuromuscular symptoms, with fewer showing CNS (19.6%) or multiorgan (3.6%) features at onset; by more than 8 years from onset, these proportions shifted to 54.4%, 23.3%, and 23.3%, respectively. A total of 73 TWNK variants (16 novel) were found, mostly missense, clustered in functionally critical regions.
DISCUSSION: This large multinational cohort analysis advances our understanding of Twinkle-related disorders by identifying mutational hotspots with clinical relevance and illustrating the broad phenotypic spectrum and progression patterns. In the context of such rare diseases, the formation of international collaborations, such as TReDIC, can enhance our understanding and support the design of upcoming clinical trials.

DOI: https://doi.org/10.1212/WNL.0000000000214401
Bioanalysis. 2026 Jan 12. 1-13

FALCON-qPCR: a new method for the quantification of oxidative lesions in mitochondrial DNA.

Veronica Bazzani, Eve Harding, Szymon Balinski, Mara Equisoain Redin, Dario Alessi, Pierfrancesco Del Mestre, Walter Baratta, Daniela Cesselli, Antonio Paolo Beltrami, Michał Turek, Umberto Baccarani, Carlo Vascotto.

  Accurate quantification of oxidative mitochondrial DNA (mtDNA) lesions remains technically challenging due to the limitations of existing assays, which often require large sample inputs, multi-day workflows, and offer limited sensitivity. Here we introduce FALCON-qPCR (Fpg-assisted Long-PCR), a streamlined, high-sensitivity method for quantifying oxidative damage in mtDNA. FALCON-qPCR couples digestion with formamidopyrimidine [fapy]-DNA glycosylase (Fpg) to long-range PCR and qPCR-based normalization, enabling precise lesion quantification from as few as 10,000 cells (~300 ng total DNA) within a single day. The assay provides a robust dynamic range and reproducibility across diverse biological systems, including human cell lines, hepatocellular carcinoma biopsies, and Caenorhabditis elegans. Compared with established methods, FALCON-qPCR exhibits markedly higher sensitivity in detecting mtDNA damage induced by hydrogen peroxide, antimycin A, and rotenone. Its performance was further demonstrated in assessing mitochondrial toxicity of ruthenium-based compounds, highlighting its potential for pharmacological screening. By integrating enzymatic lesion recognition with quantitative amplification in a unified workflow, FALCON-qPCR eliminates the need for mitochondrial isolation. This methodological advance provides a rapid, accurate, and scalable platform for studying oxidative DNA damage, with broad applicability in mitochondrial research and translational toxicology.

Keywords:  LongRange-PCR; Mitochondria; mitochondrial DNA damage; oxidative stress

DOI:  https://doi.org/10.1080/17576180.2025.2608757
J Proteome Res. 2026 Jan 13.

On the Feasibility of Clinical Studies with Cross-Linking Mass Spectrometry.

Sung-Gun Park, Ethan L Ostrom, Sophia Liu, David J Marcinek, James E Bruce.

  In living systems, protein function relies on many intra- and intermolecular interactions within a network called the interactome. The majority of available interactome data has been acquired with isolated proteins and complexes, but visualization of interactome changes in living systems is crucial to advance understanding of functional changes with diseases and for the development of improved therapies. With model animal systems, quantitative cross-linking mass spectrometry has been successfully applied to uniquely reveal interactome changes with mitochondrial dysfunction both in heart failure and with age-related muscle function decline. In this study, we investigated the feasibility of qualitative cross-linking mass spectrometry for mitochondrial interactome studies with clinically relevant human muscle biopsy samples and amounts. Analysis of biopsy samples from two volunteers resulted in the identification of 1350 nonredundant peptides from 177 mitochondrial proteins from all mitochondrial subcompartments. Many of the identified human biopsy cross-linked peptides were derived from protein complex and supercomplex assemblies that exhibited altered levels in model systems of heart failure and aging. The findings demonstrate the initial feasibility that these and other cross-linked species can be detected in human muscle biopsy samples to enable future studies of age- and disease-related changes in mitochondrial structure-function relationships.

Keywords:  OXPHOS complexes; XL-MS; cross-linking; dead-end peptides; human muscle biopsy; interactome; intra/inter cross-linked peptides; mitochondria; supercomplex

DOI:  https://doi.org/10.1021/acs.jproteome.5c00803
NPJ Parkinsons Dis. 2026 Jan 15.

UQCRC1 deficiency impairs mitophagy via PINK1-dependent mechanisms in Parkinson's disease.

Jeng-Lin Li, Shu-Yi Huang, Po-Yu Huang, Ssu-Ju Fu, Yu-Jung Tsao, Wenying Chang, Cheng-Li Hong, Yu-Chien Hung, Pei-Han Liu, Liang-Chuan Lai, Chin-Hsien Lin, Wei-Chung Chiang, Chih-Chiang Chan.

Oxidative phosphorylation (OXPHOS) and mitophagy are functionally interconnected cellular processes, the defects of which are considered key driving forces behind the pathogenesis of Parkinson's disease (PD). UQCRC1, a core subunit of the mitochondrial respiratory chain complex III, is a recently identified familial PD gene whose pathogenic mutations result in OXPHOS stress. Given its importance, however, the role of UQCRC1 in idiopathic PD as well as mitophagy has not been investigated. In this study, we collected 19 datasets comprising postmortem substantia nigra from 150 cases of non-disease controls and 185 cases of PD or incidental Lewy body disease (iLBD), and the meta-analysis of the UQCRC1 mRNA level showed reduced expression in idiopathic PD, suggesting the potential of UQCRC1 as a biomarker. Leveraging the SH-SY5Y cells and fly models, we showed that mitophagy was impaired upon UQCRC1 mutation or depletion. Notably, insufficiency of PINK1 mRNA was associated with UQCRC1 deficiency, and overexpression of Pink1 rescued the locomotion and mitophagy defects in the fly models with neuronal loss of uqcrc1. Treatment with two PINK1 activators, kinetin and MTK458, resulted in similar protective effects in the fly and cell models. Overall, we identified OXPHOS stress led by deficiency of UQCRC1 as an etiology of mitophagy defects in PD and PINK1 as a therapeutic target for UQCRC1-associated PD.

DOI: https://doi.org/10.1038/s41531-026-01262-6
bioRxiv. 2026 Jan 11. pii: 2026.01.09.698733. [Epub ahead of print]

Atypical tetracyclines promote longevity and ferroptotic neuroprotection via translation attenuation.

Khalyd J Clay, Manuel Sanchez-Alavez, Ian Newman, Na Na, Ana P Verduzco Espinoza, Alan To, Shannon Saad, Hollis T Cline, Michael Petrascheck.

Preclinical and clinical studies have reported neuroprotective and geroprotective effects of tetracyclines that are independent of their antibiotic activity, but the underlying mechanisms remain unclear. Here, we systematically profile widely used tetracyclines, including impurities and degradation products, and identify translation attenuation as the shared driver of their neuroprotective and longevity-promoting effects, independent of classical tetracycline mechanisms. Instead, we uncover two mechanistically distinct classes of tetracyclines. Mitochondrial-targeting tetracyclines (MitoTets), exemplified by doxycycline, inhibit the mitochondrial ribosome and attenuate cytosolic translation through activation of the Integrated Stress Response (ISR). In contrast, atypical tetracyclines such as 4-epiminocycline and 12-aminominocycline act as cytosolic-targeting tetracyclines (CytoTets), directly inhibiting the cytosolic ribosome, bypassing the ISR, and protecting neurons from ferroptotic cell death. CytoTets are non-antibiotic, brain-penetrant, and neuroprotective in mouse and human neurons, establishing the tetracyclines as a tunable chemical scaffold for selectively targeting translation in aging and neurodegeneration.
Highlights: The tetracyclines broadly attenuate translation in multiple eukaryotic modelsTranslation attenuation results from both ISR-dependent and ISR-independent mechanismsDiscovery of atypical, cytosolic targeting tetracyclines (CytoTETs) that protect from ferroptosis ISR-independentlyCytoTETs inhibit translation and are neuroprotective in human-derived neurons and mouse hippocampus.

DOI: https://doi.org/10.64898/2026.01.09.698733
J Struct Biol. 2026 Jan 08. pii: S1047-8477(26)00007-9. [Epub ahead of print]218(1): 108291

Robust mitochondria segmentation and morphological profiling using soft X-ray tomography.

Arun Yadav, Anshu Singh, Aneesh Deshmukh, Pushkar Bharadwaj, Anuj Baliyan, Kate White, Jitin Singla.

  Mitochondrial morphology is central to cellular function, yet large-scale quantification is limited by the lack of high-resolution whole-cell imaging and efficient segmentation tools. Soft X-ray tomography (SXT) provides native-state 3D whole-cells images, but organelle segmentation remains a bottleneck. We present MitoXRNet, a data- and parameter-efficient 3D deep learning model for mitochondria and nucleus segmentation in SXT tomograms. Using multi-axis 3D slicing, Sobel filter-based boundary enhancement, and a combined Binary-Cross-Entropy and Robust-Dice loss, MitoXRNet achieves a 73.8% Dice score on INS-1E cells with only 1.4 M parameters, outperforming existing methods. A larger 22.6 M variant generalized well to unseen data. Automated segmentation enabled quantitative analysis of mitochondrial remodeling under metabolic stimuli: glucose increased mitochondrial volume and matrix density, while GIP and GKA increased mitochondria number, reduced volume, and elevated density, indicating smaller, denser, more dynamic populations. MitoXRNet provides a scalable framework for high-throughput morphological and biophysical profiling of organelles in native-state SXT data.

Keywords:  Deep Learning; Gastric Inhibitory Polypeptide (GIP); Glucokinase Activator (GKA); Mitochondria Remodeling; Mitochondria Segmentation; Soft X-Ray Tomography

DOI:  https://doi.org/10.1016/j.jsb.2026.108291
Redox Biol. 2026 Jan 09. pii: S2213-2317(26)00017-0. [Epub ahead of print]90 104019

Intercellular mitochondrial transfer rewires redox signaling and metabolic plasticity: mechanisms, disease relevance and therapeutic frontiers.

Jiahui Wang, Rongqing Li, Li Qian.

  Intercellular mitochondrial transfer is recognized as a central mechanism that shapes redox homeostasis, metabolic plasticity, and cellular resilience across multiple tissues. Through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junction channels (GJCs), and cell fusion, mitochondria move between donor and recipient cells to restore bioenergetic capacity, buffer oxidative stress, and tune redox-sensitive signaling networks. Recent work has begun to clarify the regulatory framework governing donor-recipient specificity, cargo selection, and the stress-activated cues that trigger organelle exchange. Mitochondrial transfer also exerts distinct, context-dependent influences on disease trajectories. It mitigates injury in neurological damage, ischemia-reperfusion conditions, immune dysfunction, aging, and inflammatory pain, largely by reprogramming mitochondrial function and reactive oxygen species (ROS) dynamics. Conversely, in cancer, mitochondrial acquisition enhances metabolic flexibility, invasiveness, and resistance to therapy. Current therapeutic approaches, including mitochondrial transplantation, EV-based delivery systems, and mitochondria-enhanced immune cells, highlight the translational potential of manipulating mitochondrial exchange, yet face challenges such as mitochondrial fragility, inefficient targeting, and immunogenicity. Deeper mechanistic insight into how mitochondrial transfer remodels redox signaling and metabolic adaptation will be essential for converting this biological process into next-generation organelle-level interventions for redox-driven disorders.

Keywords:  Extracellular vesicles (EVs); Immunometabolism; Mitochondrial therapeutics; Mitochondrial transfer; Tunneling nanotubes (TNTs)

DOI:  https://doi.org/10.1016/j.redox.2026.104019
Aging Med (Milton). 2025 Dec;8(6): 624-633

Research Progress on Idebenone in Neurodegenerative Diseases.

Yanqing Zhang, Yanhong Ren, Xiaoran Zhu, Tianhao Liu, Rundong Han, Yuqing Fang, Zhangning Zhao, Fei Mao, Yalin Wang, Xian Li, Xiuhua Li.

  In recent years, significant progress has been made in understanding the therapeutic potential of idebenone (IDE), a synthetic analogue of Coenzyme Q10, in neurodegenerative diseases (NDs). This review comprehensively examines the pharmacological properties of IDE and its emerging applications in various NDs, with particular emphasis on Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and Huntington's disease. We elucidate IDE's multifaceted neuroprotective mechanisms, including its potent antioxidant activity that reduces reactive oxygen species production, its ability to enhance mitochondrial bioenergetics, and its regulatory effects on cellular metabolism. Additionally, we critically evaluate current clinical research findings and discuss the translational potential of IDE in ND therapeutics. The accumulated evidence strongly supports IDE as a promising mitochondrial-targeted agent capable of mitigating disease symptoms and modifying disease progression in multiple neurodegenerative disorders. This review highlights both the current achievements and future directions for IDE-based interventions in ND treatment.

Keywords:  antioxidants; idebenone; mitochondria; neurodegenerative diseases; neuroprotection

DOI:  https://doi.org/10.1002/agm2.70047
Cell Rep. 2026 Jan 13. pii: S2211-1247(25)01581-5. [Epub ahead of print]45(1): 116809

Unveiling the neuroprotective power of mitochondrial transfer in orofacial inflammatory pain through ER membrane remodeling.

Chen Li, Yike Li, Fei Liu, Boyao Lu, Shiyang Ye, Dexin Zhu, Muyun Wang, Junyu Chen, Cheng Zhou, Chunjie Li, Yanyan Zhang, Jiefei Shen.

  Neuro-glial mitochondrial transfer critically sustains neuronal function in disease. While this transfer reshapes inflammatory microenvironments, its pathological mechanisms in peripheral inflammatory pain remain uncharacterized, impeding targeted interventions. Here, employing primary satellite glial cells (SGCs)-trigeminal ganglion neurons (TGNs) co-culture models, we demonstrate that, during acute inflammation, SGCs transfer functional mitochondria to injured TGNs via tunneling nanotubes and free mitochondrial uptake. Inflammatory stress impairs mitophagy, leading to dysfunctional mitochondrial accumulation and heightened neuronal hyperexcitability. Mitochondria from SGCs restore mitophagic flux and enhance mitochondrial-endoplasmic reticulum (ER) contact sites, thereby facilitating calcium exchange and homeostasis while reducing neuronal hyperexcitability. Critically, Atl1 knockout and overexpression mice models reveal that ATL1-driven ER restructuring initiates autophagosome formation during mitophagy and regulates early-stage autophagic progression. Taken together, our findings uncover a neuroprotective axis wherein glial mitochondrial donation safeguards neurons, directly nominating mitochondrial dynamics for therapeutic intervention in orofacial inflammatory pain.

Keywords:  ATL1; CP: cell biology; CP: neuroscience; endoplasmic reticulum; inflammatory pain; mitochondrial transplantation; mitophagy; trigeminal ganglion

DOI:  https://doi.org/10.1016/j.celrep.2025.116809
Hepatol Commun. 2026 Feb 01. pii: e0885. [Epub ahead of print]10(2):

Mitochondria-derived peptides in liver disease: Emerging regulators of hepatic metabolism and therapeutic targets.

Themis Thoudam, Ge Zeng, Hui Gao, Yanchao Jiang, Nazmul Huda, Zhihong Yang, Jing Ma, Suthat Liangpunsakul.

  Mitochondria-derived peptides (MDPs) are bioactive molecules encoded by small open reading frames within mitochondrial DNA (mtDNA). Humanin, the first MDP to be discovered, functions as a cytoprotective factor, protecting cells from stress-induced apoptosis. Subsequent discoveries expanded this family to include Mitochondrial Open-reading-frame of the Twelve S rRNA-c (MOTS-c), a key regulator of metabolic homeostasis and stress adaptation, and the Small Humanin-Like Peptides (SHLP1-6), which modulate mitochondrial bioenergetics and insulin sensitivity. MDPs play critical roles in liver homeostasis by maintaining mitochondrial function and metabolic balance. Intracellularly, they modulate mitochondrial activity, oxidative stress, and apoptosis, promoting hepatocyte survival. Extracellularly, they act in autocrine, paracrine, or endocrine manners, engaging receptors or signaling pathways to regulate nuclear gene expression and metabolic adaptation. Emerging evidence highlights their relevance in metabolic dysfunction-associated steatotic liver disease (MASLD). Humanin exerts hepatoprotective effects by inhibiting apoptosis and modulating lipid metabolism. MOTS-c activates AMPK, regulates nuclear gene expression, suppresses fibrotic and inflammatory signaling, and restores mitochondrial function in MASLD and fibrosis models. SHLPs, particularly SHLP2, enhance mitochondrial function and insulin sensitivity, supporting glucose homeostasis and mitigating oxidative stress. Collectively, MDPs establish a novel paradigm in mitochondrial signaling, extending mtDNA function beyond energy production. This review summarizes current insights into MDP biology and highlights its emerging therapeutic potential in chronic liver disease.

Keywords:  Humanin; Mitochondrial Open-reading-frame of the Twelve S rRNA-c; SHLPs; liver disease; mitochondria-derived peptides; mitochondrial DNA

DOI:  https://doi.org/10.1097/HC9.0000000000000885
Int J Biol Sci. 2026 ;22(2): 731-749

Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex.

Nai-Jia Xue, Yi Liu, Zhi-Hao Lin, Wen-Hao Huang, Feng Zhang, Ran Zheng, Xiao-Li Si, Lu-Yan Gu, Yi Fan, Jia-Li Pu, Bao-Rong Zhang.

  Disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) and calcium homeostasis has been implicated in the pathogenesis of Parkinson's disease (PD). Parkin, a PD-associated E3 ubiquitin ligase, has been shown to regulate MAM integrity and calcium dynamics. However, the mechanisms of Parkin recruitment and its substrate specificity have not been well understood. This investigation has demonstrated that loss of Parkin enhances ER-mitochondria associations and leads to excessive calcium flux in MAM, resulting in abnormal mitochondrial permeability transition pore (mPTP) opening and decreased cell viability. Further, Parkin physically interacts with IP3R-Grp75-VDAC1 complex at ER-mitochondria contact sites, where it is recruited by IP3R-mediated calcium flux and mitophagy. More importantly, Parkin deficiency leads to the accumulation of IP3R levels, particularly in MAM region. In addition, Parkin fine-tunes the stability of the complex and ubiquitinates IP3R for degradation via the ubiquitin-proteasomal system, ensuring suitable calcium transfer. Taken together, our study reveals a novel role of Parkin in regulating ER-mitochondria contacts, providing insights into PD pathogenesis and potential therapeutic strategies targeting MAMs.

Keywords:  IP3R; Parkin; calcium; mitochondria-associated ER membrane; ubiquitination

DOI:  https://doi.org/10.7150/ijbs.121759
bioRxiv. 2026 Jan 09. pii: 2026.01.09.698677. [Epub ahead of print]

Suppressive Genetic Interactions Between Haploinsufficient Mitochondrial Genes Encoded in the 22q11.2 Microdeletion Locus Define Brain and Cardiac Phenotypes.

Meghan Wynne, Stephanie A Zlatic, Austin S Park, Amanda Crocker, Hadassah Mendez-Vazquez, Eliana Liporace, Avanti Gokhale, Cristy Tower-Gilchrist, Maxine Robinette, Ryan H Purcell, Gary J Bassell, Erica Werner, Jennifer Q Kwong, Victor Faundez.

Genomic copy number variations, such as the 22q11.2 microdeletion syndrome, cause pleiotropic disorders that affect diverse organ systems and disrupt neurodevelopment. Deletions of the 22q11.2 locus reduce the dosage of up to 46 protein coding genes, raising questions about the identity of haploinsufficient genes and their genetic interactions contributing to 22q11.2 phenotypes. Here, we dissect functional and molecular relationships between two genes encoded within the 22q11.2 locus: the mitochondrial ribosomal protein gene MRPL40 and the mitochondrial citrate transporter SLC25A1. We show that a MRPL40 null mutation disrupts mitochondrial translation, impairs respiration, and affects multiple components of the SLC25A1 interactome including factors required for lipid metabolism, mitochondrial ribosome subunits, and the mitochondrial RNA processing machinery. In silico coessentiality network analysis revealed correlated and anticorrelated fitness interactions linking MRPL40 and SLC25A1 to mitochondrial translation, intermediate carbon metabolism, and interferon signaling. We determined that Mrpl40 -null mutations are embryonic lethal in mice, but Mrpl40 -/+ mice are viable and displayed embryonic cardiac development and adult behavioral phenotypes. Similarly, Slc25a1 +/- animals showed embryonic cardiac developmental defects but lacked the adult behavioral phenotypes observed in Mrpl40 -/+ mice. Surprisingly, transheterozygotic Slc25a1 +/- ; Mrpl40 -/+ mice suppressed or mitigated cardiac development, behavioral, and brain transcriptome phenotypes observed in single heterozygotic animals. These results reveal that MRPL40 and SLC25A1 are haploinsufficient genes within the 22q11.2 locus that genetically and biochemically interact to define tissue development and physiology. Our findings provide a framework for understanding the complexity and type of gene dosage interactions within the 22q11.2 deletion syndrome locus.

DOI: https://doi.org/10.64898/2026.01.09.698677
BMC Genomics. 2026 Jan 16.

MitoCommun: a database for decoding mitochondrial communication networks.

Xueyan Wu, Danlei Chen, Jitong Feng, Xueying Bu, Shengbo Wu, Jianjun Qiao.



Keywords:  Intercellular crosstalk; Mitochondria; Mitochondrial-nuclear interaction; Organelle communication; Signaling networks; Signaling transduction

DOI:  https://doi.org/10.1186/s12864-026-12549-6
Nat Commun. 2026 Jan 15. 17(1): 547

Development of a split-toxin CRISPR screening platform to systematically identify regulators of human myoblast fusion.

Haifeng Zhang, Renjie Shang, Zheng Zhang, Min Zhou, Anne Bigot, Yanqing Cai, Yanran Zhao, Yushu Wang, Aaryahi Deshmukh, Elena Kudryashova, Dmitri S Kudryashov, Cuiyu He, Vincent Mouly, Pengpeng Bi.

Muscle defects are common in human developmental disorders and often cause severe functional impairment. These defects arise from intricate tissue crosstalk and rare genetic mutations, underscoring the need to systematically identify cell-autonomous mechanisms regulating human myogenesis. Here we show a rationally designed, high-throughput genetic screening platform that integrates human myoblast models, customized CRISPR libraries, and a split-toxin strategy that enables quantitative selection of fusion-defective myocytes. Leveraging this platform, our initial screen uncovers a large group of hits essential for human myoblast fusion. The majority of these hits converge into 23 protein complexes. Notably, mutations in 41 screen hits are associated with human diseases marked by abnormal skeletal-muscle morphology. Applying a new single-cell CRISPR & RNA-seq approach, we show that majority of these hits control human myoblast fusion as well as influence early-stage myogenic differentiation. This work establishes a scalable approach to identify cell-autonomous regulators of human muscle differentiation and fusion.

DOI: https://doi.org/10.1038/s41467-025-67583-x
NAR Mol Med. 2026 Jan;3(1): ugaf042

The nuclear and mitochondrial genomes need to tango. How is their dance synchronized during development?

Justin C St John.

For quite some time, knowledge about mitochondria and the mitochondrial genome has been primarily limited to energy production. However, there is now increasing evidence that they have many important roles in cell function and that synergy between the nuclear and mitochondrial genomes is an essential prerequisite to developmental outcome. This review describes the mitochondrial genome and its contribution to overall cellular genomic content; and discusses mitochondrial DNA (mtDNA) inheritance. mtDNA homoplasmy and heteroplasmy are defined and distinctions between pathogenic and non-pathogenic rearrangements are drawn; how they are transmitted; and their effects on oocyte quality and developmental outcomes. This is followed by analysis of mtDNA replication and changes in mtDNA copy number during development; why they need to happen; and how they influence developmental outcomes. Changes to nuclear DNA methylation events are then discussed in the context of changes to mtDNA replication throughout development. This leads to the concept of 'genomic balance', which defines how cells at any stage of development require adjustments to both genomes to ensure successful cellular function and development; and how this process can be perturbed by some of the more invasive assisted reproductive technologies designed to treat infertility and mtDNA disease.

DOI: https://doi.org/10.1093/narmme/ugaf042
Biochem Pharmacol. 2026 Jan 14. pii: S0006-2952(26)00040-7. [Epub ahead of print] 117709

DNMT1 knockdown mitigates sepsis-induced myocardial dysfunction by preventing TFAM-mediated mitochondrial DNA cytosolic escape and subsequent cGAS-STING to regulate macrophage M2 polarization.

Min Li, Yang Liu, Kuo Qu, Yu Zhang, Hailing Yang.

  Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication of sepsis and correlates with high mortality. The study investigated the effect of inhibiting DNA methyltransferase 1 (DNMT1) on SIMD and its potential mechanism. In this study, an SIMD mouse model was established using lipopolysaccharide (LPS). Two weeks before modeling, mice were intraperitoneally injected with the DNMT1 inhibitor decitabine or Vehicle. Pretreatment with the DNMT1 inhibitor decitabine in SIMD mice improved survival, cardiac function, and reduced cardiomyocyte apoptosis. In LPS-stimulated RAW264.7 macrophages, DNMT1 knockdown promoted M2 polarization while suppressing M1 polarization, and reduced apoptosis in cardiomyocytes cultured with conditioned media. Mechanistically, DNMT1 depletion upregulated mitochondrial transcription factor A (TFAM) by reducing DNA methylation modification, which alleviated mitochondrial dysfunction and limited mitochondrial DNA (mtDNA) release into the cytosol. This subsequently inactivated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. TFAM downregulation reversed the improvement in mitochondrial function achieved by DNMT1 knockdown, while cGAS upregulation averted DNMT1 knockdown-inhibited mtDNA cytosolic escape-mediated cGAS-STING. In vivo validation confirmed this mechanism. Collectively, DNMT1 regulates mitochondrial dysfunction and cytosolic mtDNA release by modulating TFAM promoter DNA methylation, thereby activating the cGAS-STING pathway, further influencing macrophage polarization and cardiomyocyte apoptosis, and ultimately exacerbating SIMD.

Keywords:  Cyclic GMP-AMP synthase; DNA methyltransferase 1; Mitochondrial DNA; Mitochondrial transfer; Sepsis-induced myocardial dysfunction; Stimulator of interferon genes

DOI:  https://doi.org/10.1016/j.bcp.2026.117709
Nat Commun. 2026 Jan 15.

Assembling unregulated DNA segments bypasses synthesis screening: regulate fragments as select agents.

Rey Edison, Shay Toner, Kevin M Esvelt.

DOI: https://doi.org/10.1038/s41467-025-67955-3
Nat Commun. 2026 Jan 15. 17(1): 546

CHAMP1 is an essential regulator for human myoblast fusion and muscle development.

Haifeng Zhang, Min Zhou, Zheng Zhang, Zhaoning Wang, Ruifeng Shi, Yushu Wang, Xiaolin Wei, Renjie Shang, Jianwen Li, Cuiyu He, Jin Xie, Yarui Diao, Pengpeng Bi.

Human skeletal muscle comprises myofibers formed by fusion of thousands of myoblasts. This process depends on tightly regulated, muscle-specific fusogens, but its genetic control remains poorly understood. Here, we identify CHAMP1 (Chromosome Alignment Maintaining Phosphoprotein 1) as essential for human myoblast fusion in vitro and in vivo. Genomic and protein-interaction assays reveal a noncanonical role for CHAMP1 as a MyoD cofactor that directly activates expression of the key muscle fusogen Myomaker. As established in prior clinical reports, CHAMP1 mutations in patients cause developmental delay, hypotonia, and muscle weakness. Consistently, patient-derived cells show fusion defects that can be fully rescued by restoring Myomaker expression. Structure and function analyses identify C2H2-type zinc-finger motifs on CHAMP1 protein that are both necessary and sufficient for MyoD interaction and Myomaker expression. These findings highlight a cell-autonomous role for CHAMP1 in muscle development and disease and point to therapeutic avenues for treating CHAMP1-related muscle development defects.

DOI: https://doi.org/10.1038/s41467-025-67584-w
Cerebellum. 2026 Jan 13. 25(1): 9

Juvenile-Onset Cerebrotendinous Xanthomatosis with Novel Compound Heterozygous CYP27A1 Mutations: Case Series and Literature Review.

Kefang Du, Chunrong Wang, Linlin Wan, Zhao Chen, Hongyu Yuan, Qian Jiang, Xiao Dong, Daji Chen, Riwei Ouyang, Xiafei Long, Xiaokang Wu, Xinying Xiao, Ruqing He, Rong Qiu, Hong Jiang.

  Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive neurometabolic disorder characterized by multisystem involvement and marked clinical heterogeneity. Pathogenic variants in the CYP27A1 gene, encoding mitochondrial sterol-27-hydroxylase, disrupt bile acid synthesis, leading to pathological accumulation of cholestanol in neural tissues, tendons, and other organs. This study aimed to characterize two novel CTX cases with compound heterozygous variants in the CYP27A1 gene through integrated clinical-genetic analysis, and to systematically synthesize current evidence on CTX through a literature review. Molecular investigations employed a tiered sequencing strategy: whole-exome sequencing (WES) for variant discovery, third-generation sequencing for variant screening of WES-negative samples, and Sanger sequencing for familial segregation validation. We present two Chinese juvenile-onset CTX cases demonstrating characteristic multisystem involvement, including both extraneural manifestations and progressive neurological deterioration. Genetic investigations revealed three CYP27A1 variants: the previously unreported c.845 - 46_881del83, the splicing variant c.1477-2 A > C, and a novel nonsense variant c.487 C > T in exon 3. Both probands exhibited compound heterozygosity, sharing the c.845 - 46_881del83 variant alongside distinct second alleles (c.1477-2 A > C and c.487 C > T, respectively). Then, a literature review synthesizes current evidence on clinical manifestations, genotypic patterns, and therapeutic approaches in CTX. This study expands the CYP27A1 mutational spectrum with two novel variants and validates the diagnostic utility of long-read sequencing (LRS) in resolving complex autosomal recessive cerebellar ataxia (ARCA) cases. The synthesis of clinical and literature evidence underscores the need for early recognition of CTX's heterogeneous presentations.

Keywords:   CYP27A1 gene; 27-hydroxylase; Cerebrotendinous xanthomatosis; Mutation

DOI:  https://doi.org/10.1007/s12311-025-01955-3
bioRxiv. 2026 Jan 09. pii: 2026.01.08.698025. [Epub ahead of print]

Early multi-omic signatures and machine learning models predict cardiomyocyte differentiation efficiency and enable robust hPSC differentiation to cardiomyocytes.

Austin K Feeney, Aaron D Simmons, Elizabeth F Bayne, Yanlong Zhu, Mason R Pentes, Paulo F Cobra, Jianhua Zhang, Timothy J Kamp, Ying Ge, Sean P Palecek.

Protocols for generating cardiomyocytes (CMs) from human pluripotent stem cells (hPSCs) have existed for nearly two decades, yet manufacturing variability in terminal cell identity continues to limit clinical translation. To uncover the origin of fate divergence during hPSC-CM differentiation, we performed temporal transcriptomics, proteomics, and metabolomics of high and low efficiency differentiations. We identified significant early multi-omic divergence between differentiation batches and key pathways underlying fate divergence at critical differentiation stages included Wnt, MAPK, and glucose metabolism. Machine learning models trained on early candidate gene markers predicted hPSC-CM purity better than models using canonical cardiac development markers. Lastly, multi-omic insights informed perturbations, including Wnt and MAPK inhibition, which produced higher CM purities and yields. Our results showcase multi-omic analysis coupled with machine learning models as a powerful tool to identify cell fate determinants and enable robust manufacturing of complex cell products such as hPSC-derived cell therapies.
Teaser: Multi-omic analysis of hPSC-CM differentiation efficiency reveals early predictive features and enables robust differentiation.

DOI: https://doi.org/10.64898/2026.01.08.698025
Science. 2026 Jan 15. 391(6782): eadq9006

Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.

Danhui Liu, Chuanli Zhou, Xiaochen Wang, Zhou Luo, Ruiyao Xu, Shanshan Huo, Lina Guo, Xuemei Luo, Shuhan Yang, Arielle Click, Janiece Vancil, Paola Barajas, Victor Mijares, Hamid Baniasadi, Nan Yan, Jan Rehwinkel, Dustin C Hancks, Elizabeth H Chen, Shuang Liang, Zhenyu Zhong.

Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome hyperactivation and excessive interleukin (IL)-1β production in macrophages by disrupting SAM and HD domain-containing protein 1 (SAMHD1), a deoxynucleoside triphosphate (dNTP) hydrolase crucial for nucleotide balance. This caused aberrant accumulation of dNTPs, which can be transported into mitochondria, and initiated mitochondrial DNA (mtDNA) neosynthesis, which increased the presence of oxidized mtDNA and triggered NLRP3 hyperactivation. Deletion of SAMHD1 promoted NLRP3 hyperactivation in cells isolated from zebrafish, mice, and humans. SAMHD1-deficient mice showed elevated circulating IL-1β, insulin resistance, and metabolic dysfunction-associated steatohepatitis. Blocking dNTP mitochondrial transport prevented NLRP3 hyperactivation in macrophages from obese patients and SAMHD1-deficient mice. Our study revealed that obesity by inhibiting SAMHD1 rewired macrophage nucleotide metabolism, thereby triggering NLRP3 inflammasome hyperactivation to drive disease progression.

DOI: https://doi.org/10.1126/science.adq9006
PLoS Comput Biol. 2026 Jan 12. 22(1): e1013885

Overcoming the widespread flaws in the annotation of vertebrate selenoprotein genes in public databases.

Max Ticó, Emerson Sullivan, Roderic Guigó, Marco Mariotti.

Genome annotations provide the essential framework for genomic analyses, capturing our current knowledge of gene structure and function as inferred from computational predictions and experimental evidence. Even as automated annotation pipelines become more sophisticated, their accuracy in representing unconventional gene expression events remains largely untested. Here, we address this gap by examining the most common form of translational recoding: the insertion of selenocysteine (Sec), a non-canonical amino acid incorporated into selenoproteins, oxidoreductase enzymes carrying essential roles in redox homeostasis. Sec insertion occurs in response to UGA, normally interpreted as stop codon, but recoded in selenoprotein mRNAs. Owing to the dual function of UGA, the identification of selenoprotein genes poses a challenge. We show that the vertebrate selenoprotein genes are widely misannotated in major public databases. Only 11% and 5% of selenoprotein genes are well annotated in Ensembl and NCBI GenBank, respectively, due to the lack of dedicated selenoprotein annotation pipelines. In most cases (81% and 84%), overlapping flawed annotations are present which lack the Sec-encoding UGA. In contrast, NCBI RefSeq employs a dedicated selenoprotein pipeline, yet with some shortcomings: its selenoprotein annotations are correct in 77% of cases, and most errors affect families with a C-terminal Sec residue. We argue that selenoproteins must be correctly annotated in public databases and that must occur via automated pipelines, to keep the pace with genome sequencing. To facilitate this task, we present a new version of Selenoprofiles, an homology based tool for selenoprotein prediction that produces predictions with accuracy comparable to manual curation, and can be easily deployed and integrated in existing annotation pipelines.

DOI: https://doi.org/10.1371/journal.pcbi.1013885
Nature. 2026 Jan 14.

Cancer might evade immune defences by stealing mitochondria.

Laura Dattaro.



Keywords:  Cancer; Immunology; Metabolism

DOI:  https://doi.org/10.1038/d41586-026-00123-9
bioRxiv. 2026 Jan 06. pii: 2026.01.05.697836. [Epub ahead of print]

Bedaquiline inhibits the ATP synthase leak channel and prevents glutamate-induced neuronal death.

Amrendra Kumar, Erin Smith, Ikram Mezghani, Subhash Eedarapalli, Yangyu Wu, Khondoker Adeba Ferdous, Emma Amjad, Han-A Park, Nelli Mnatsakanyan.

F O F 1 -ATP synthase is one of the most abundant proteins of the mitochondrial inner membrane and the primary enzyme responsible for ATP production in eukaryotic cells. Nevertheless, it was recently reported to play a prominent role in cell death by forming a large-conductance leak channel in the mitochondrial permeability transition pore (mPTP), making it a promising therapeutic target. Bedaquiline (BDQ), a member of the diarylquinoline class of drugs, was shown to selectively inhibit the catalytic activity of Mycobacterium tuberculosis ATP synthase with no effect on the mammalian enzyme. Here, we report a new role for BDQ as a potent inhibitor of the ATP synthase c-subunit leak channel in mammals. BDQ inhibited the single-channel activity of porcine heart ATP synthase in planar lipid bilayer recordings and prevented glutamate-induced cell death in primary hippocampal neurons. These findings reveal the potential new application of BDQ for treating mPTP-related diseases by targeting the ATP synthase c-subunit leak channel.
Why it matters: Bedaquiline (BDQ) is the only FDA-approved drug to treat pulmonary multidrug-resistant tuberculosis (TB), caused by the Mycobacterium tuberculosis . BDQ cures TB by specifically targeting mycobacterial ATP synthase and inhibiting ATP production. Recently, BDQ was also reported to bind to mammalian ATP synthase at the interface between the a and c-subunits and to inhibit its catalytic activity. However, the effect of BDQ on ATP synthase leak channel activity has not been explored. Here, we report that BDQ inhibits the ATP synthase c-subunit leak channel (ACLC) activity with an IC50 of ∼24 nM and prevents glutamate-induced neuronal death, suggesting a new therapeutic repurposing of BDQ for treating ACLC-related diseases.

DOI: https://doi.org/10.64898/2026.01.05.697836