bims-mitmed 2026-01-18 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–01–18
23 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial diseases.
Mitochondrial Disorder in a Child With Brainstem Lesions Mimicking Thiamine Deficiency.
Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.
Mitochondrial AR overactivation coupled with uterine decidual mitochondrial defects in PCOS-associated pregnancy loss.
The need to understand the underlying mechanisms associated with mitochondrial therapies in assisted reproduction before further clinical trials are performed.
Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study.
Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.
Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
Mitochondrial fission during mitophagy requires both inner and outer mitofissins.
SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington's disease models.
Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.
MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.
The nuclear and mitochondrial genomes need to tango. How is their dance synchronized during development?
Mapping brain growth and sex differences across prenatal to postnatal development.
A transposase-derived gene required for human brain development.
Brain organoid models of SZT2-related disease reveal an overproduction of outer radial glial cells through mTORC1 activation.
CHAMP1 is an essential regulator for human myoblast fusion and muscle development.
Mitochondrial transfer: a Janus-faced force in health and disease.
Mitochondrial uncoupler BAM15 ameliorates liver lipid metabolism disorders by activating the AMPK pathway.
Pollutant-regulated mitophagy: new perspectives in environmental toxicology.
AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.

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
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
J Endocrinol. 2026 Jan 14. pii: JOE-25-0287. [Epub ahead of print]

Mitochondrial AR overactivation coupled with uterine decidual mitochondrial defects in PCOS-associated pregnancy loss.

Yuehui Zhang, Min Hu, Linus R Shao, Lingjing Lu, Jing Han, Tingting Guo, Meng Jiang, Yao Wu, Han Han, Peng Cui, Mats Brännström, Amanda Nancy Sferruzzi-Perri, Håkan Billig.

  Nuclear androgen receptor (AR) dysregulation characterizes polycystic ovary syndrome (PCOS) pathophysiology and contributes to mitochondrial dysfunction-related adverse pregnancy outcomes. However, ARs also localize to mitochondria in many cell types, and mitochondrial dysfunction is implicated in the underlying pathogenesis of PCOS. In this study, human endometrial decidual basalis tissues and rat gravid uterine tissues were collected, and subcellular fractionation, Western blot, quantitative real-time polymerase chain reaction (qPCR), electron microscopy, and enzyme-linked immunosorbent assay (ELISA) were conducted. PCOS patients with early pregnancy exhibited increased expression of AR mRNA and mitochondrial AR protein in decidual basalis. Similar alterations of AR levels were also observed in gravid uterus of 5α-dihydrotestosterone (DHT)+insulin-exposed pregnant rats with fetal loss. In both PCOS patients and DHT+insulin-exposed pregnant rats, uterine mitochondria displayed disorganized cristae along with decreased uterine mitochondrial DNA (mtDNA) content, and reduced expression of mitochondrial morphogenesis (mito-morphosis) genes [sorting and assembly machinery component 50 (Samm50), coiled-coil helix coiled-coil helix domain-containing protein 3 (Chchd3), and dynamin-related protein 1 (Drp1)], and total adenosine triphosphate (ATP) levels. Additionally, there was dysregulated expression of mitochondrial fusion and fission, biogenesis, mitophagy, and mitochondrial ribosome protein (MRP) gene. In DHT+insulin-exposed pregnant rats, treatment with flutamide prevented fetal loss and partially rescued mitochondrial morphological abnormalities in uterine decidual stromal cells. In addition, flutamide normalized uterine Ar mRNA and mitochondrial AR protein expression; inner membrane mitochondrial protein (Immt), ras homolog enriched in brain protein (Rheb), and Mrp7 mRNA expression; and the Parkin: PTEM-induced putative kinase 1 (Pink1) ratio and restored total nicotinamide adenine dinucleotide (NAD) and ATP contents. Collectively, this work identifies mitochondrial AR in the uterus and implicates hyperandrogenism-induced, AR-dependent mitochondrial dysfunction in decidual stromal cells as a key mechanism underlying pregnancy loss in PCOS.

Keywords:  androgen receptor; gravid uterus; mito-morphosis; mitochondrial function; polycystic ovary syndrome; pregnancy loss

DOI:  https://doi.org/10.1530/JOE-25-0287
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
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
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
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
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
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
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
Cell Commun Signal. 2026 Jan 15.

SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington's disease models.

Cristina Trujillo-Del Río, Seda Koyuncu, Julia Tortajada-Pérez, Mar Collado-Pérez, Ana Pilar Gómez-Escribano, Carlos Mora, Christian Neri, Agustín Lahoz, Marta Roca, José María Millán, Yolanda Sanz, David Vilchez, Andrea Del Valle Carranza, Rafael P Vázquez-Manrique.

Huntington's disease (HD) is a neurodegenerative disorder caused by mutations in the huntingtin gene resulting in an extended polyglutamine (polyQ) stretch in the protein, which is prone to aggregation and toxicity. In addition to a proteostasis imbalance, growing evidence highlights the role of mitochondrial dysfunction in HD progression. Here we explore the role of SIR-2.3/SIRT4, a mitochondrial sirtuin, in polyQ-expanded peptides and mutant huntingtin (mHTT) toxicity using C. elegans and mammalian models. Notably, loss of sir-2.3 function results in neuronal protection mediated by AMPK activation and enhanced autophagy. These neuroprotective effects require the transcription factors DAF-16/FOXO and NHR-49, which regulate autophagy and metabolism. To explore the translational potential of these findings, we used soft ATP synthase inhibitors to mimic sir-2.3 ablation, successfully reducing mHTT-induced neuronal toxicity. These results identify the SIRT4-AMPK axis as a critical regulator linking mitochondrial metabolism, autophagy, and neuronal homeostasis in HD. These findings not only advance our understanding of HD pathogenesis but also offer promising therapeutic targets for restoring proteostasis and neuronal resilience capacity against neurodegenerative diseases.

DOI: https://doi.org/10.1186/s12964-026-02655-z
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
Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00002-X. [Epub ahead of print]

MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.

Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede, Amalie Hertz Daugaard, Josefine H Schmidt, Stine Ringholm, Manal Merimi, Fatima Raad Al-Obaidi, Amanda Takamiya Kristoffersen, Egija Zole, Birgitte Regenberg, Rasmus Kjøbsted, Jørgen Wojtaszewski, Ylva Hellsten, Henriette Pilegaard.

Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments/augmented muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTs-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.01.002
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
Sci Rep. 2026 Jan 15.

Mapping brain growth and sex differences across prenatal to postnatal development.

Yumnah T Khan, Alex Tsompanidis, Marcin A Radecki, Carrie Allison, Meng-Chuan Lai, Richard A I Bethlehem, Simon Baron-Cohen.



Keywords:  Brain development; Brain growth; MRI; Neonatal; Prenatal; Sex differences

DOI:  https://doi.org/10.1038/s41598-025-33981-w
Sci Adv. 2026 Jan 16. 12(3): eadv7530

A transposase-derived gene required for human brain development.

Luz Jubierre Zapater, Sara A Lewis, Rodrigo Lopez Gutierrez, Makiko Yamada, Elias Rodriguez-Fos, Merce Planas-Felix, Daniel Cameron, Phillip Demarest, Anika Nabila, Helen S Mueller, Junfei Zhao, Paul Bergin, Casie Reed, Tzippora Chwat-Edelstein, Alex Pagnozzi, Caroline Nava, Emilie Bourel-Ponchel, Patricia Cornejo, Ali Dursun, R Köksal Özgül, Halil Tuna Akar, Henry Houlden, Huma Arshad Cheema, Muhammad Nadeem Anjum, Giovanni Zifarelli, Peter Bauer, Miriam Essid, Hanene Benrhouma, Meriem Ben Hafsa, Ichraf Kraoua, Carolina I Galaz-Montoya, Alex Proekt, Xiaolan Zhao, Nicholas D Socci, Matthew Hayes, Yves Bigot, Raul Rabadan, Reza Maroofian, David Torrents, Claudia L Kleinmann, Michael C Kruer, Miklos Toth, Alex Kentsis.

Vertebrate brain development is associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. DNA transposable elements could contribute to somatic genome rearrangements; however, their contributions to brain development are largely unknown. PiggyBac transposable element derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase-derived gene with DNA remodeling activities in human cells. Here, we show that PGBD5 contributes to normal brain development in mice and humans, and its deficiency causes disorder of intellectual disability, movement disorders, and epilepsy. In mice, Pgbd5 is required for the developmental induction of postmitotic DNA breaks and recurrent somatic brain genome rearrangements. In the cerebral cortex, loss of Pgbd5 leads to aberrant neuronal gene expression, including of specific types of glutamatergic neurons, which partly explains the features of PGBD5 deficiency in humans. Thus, PGBD5 is a transposase-derived gene required for brain development in mammals.

DOI: https://doi.org/10.1126/sciadv.adv7530
Sci Rep. 2026 Jan 14.

Brain organoid models of SZT2-related disease reveal an overproduction of outer radial glial cells through mTORC1 activation.

Emi Sato, Yuji Nakamura, Masanori Fujimoto, Issei S Shimada, Toshihiko Iwaki, Daisuke Ieda, Yutaka Negishi, Ayako Hattori, Yoichi Kato, Shinji Saitoh.

  Biallelic loss-of-function variants of Seizure Threshold 2 (SZT2) cause neurodevelopmental diseases with developmental delay, epilepsy, and macrocephaly. SZT2 forms the KICSTOR complex, which represses the mechanistic target of rapamycin complex 1 (mTORC1) amino acid-sensitive pathway. SZT2 dysfunction is thought to cause abnormal activation of the mTOR pathway, underlying the pathogenesis of SZT2-related diseases. We previously reported constitutive activation of mTORC1 in lymphoblastoid cell lines derived from patients with SZT2-related disease. However, the impact of SZT2 dysfunction on human brain development remains unclear. In this study, we examined the effects of SZT2 dysfunction on brain development using human brain organoids. We generated pluripotent stem cell-derived brain organoids and found a significantly greater number of outer radial glial cells (oRGCs) in the subventricular zone-like layer (SVZ) of SZT2 mutant (MT) brain organoids compared to control (WT) brain organoids. The number of upper-layer neurons, which generally originate from oRGCs, was also significantly greater in SZT2 MT brain organoids. Mechanistically, SZT2 MT brain organoids showed higher mTORC1 activity in the SVZ, where neural stem/progenitor cells amplify for cortical expansion in response to mTORC1 activity. Our data suggest that SZT2 dysfunction may cause macrocephaly through dysregulation of mTORC1 in early neural development.

Keywords:  Basal radial glia; Cerebral organoids; Developmental and epileptic encephalopathy 18 (DEE18); Neurogenesis; Outer radial glia

DOI:  https://doi.org/10.1038/s41598-026-35733-w
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
J Transl Med. 2026 Jan 16. 24(1): 76

Mitochondrial transfer: a Janus-faced force in health and disease.

Yuan Hu, Wenqin Zhou, Lin Chen.



Keywords:  Immune evasion; Infections; Intercellular communication; Mitochondrial transfer; Organelle therapy; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-025-07649-y
FEBS J. 2026 Jan 12.

Mitochondrial uncoupler BAM15 ameliorates liver lipid metabolism disorders by activating the AMPK pathway.

Zunhai Liu, Wentao Wang, Simeng Wang, Rui Lv, Chaowei Li, Chao Sun.

  N5,N6-bis(2-Fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (BAM15) is a recently identified mitochondrial uncoupler with antitumor, anti-inflammatory, antioxidant and antiobesity properties. Although it has been shown that BAM15 has a high targeting ability to the liver, its capacity to improve liver metabolic disorders and the underlying mechanisms are not well understood. This study examined how BAM15 works in high-fat-diet (HFD) induced obese mice. Our results showed that compared with 2,4-Dinitrophenol (DNP) and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), BAM15 has a higher binding capacity and stronger activity in mediating proton uncoupling, and effectively promoted mitochondrial fusion, division, autophagy, and the tricarboxylic acid cycle. BAM15 improved hepatic lipid metabolism disorders by enhancing mitochondrial autophagy through activation of the 5'-AMP-activated protein kinase (AMPK) pathway. This indicates that BAM15 could be used to treat liver lipid metabolism issues and offers a solid theoretical foundation for managing lipid-related diseases.

Keywords:  AMPK pathway; BAM15; lipid metabolism; liver; mitophagy

DOI:  https://doi.org/10.1111/febs.70400
Apoptosis. 2026 Jan 10. 31(1): 24

Pollutant-regulated mitophagy: new perspectives in environmental toxicology.

Menglan Yan, Chunxia Huang, Shiqi Li, Wenjia Luo, Jiaqiang Wu, Xianhuan Zhou, Kangping Yang, Liang Yang.

  Environmental pollutants such as heavy metals, pesticides, air pollutants, and industrial chemicals pose serious threats to human health, in part by disrupting mitochondrial function. Mitophagy, a selective autophagic process that eliminates impaired mitochondria, is essential for maintaining mitochondrial and cellular homeostasis. Recent studies have shown that various pollutants can impair or dysregulate mitophagy, particularly through pathways such as PTEN-induced kinase 1 (PINK1)/Parkin-mediated mechanisms, leading to mitochondrial dysfunction, oxidative stress, inflammation, and ultimately contributing to diseases including neurodegeneration, cancer, and metabolic disorders. This review comprehensively summarizes the mechanisms by which different classes of environmental pollutants regulate mitophagy, the molecular signaling pathways involved, and the downstream effects on cellular health. Furthermore, this review also discusses current drugs and natural interventions that can alleviate pollutant-induced mitophagy dysfunction, such as melatonin, resveratrol, selenium, and stem cell therapy. By integrating the latest advances in environmental toxicology and mitochondrial biology, the review offers novel perspectives on the role of mitophagy in pollutant toxicity and highlights promising strategies for mitigating the adverse health effects of environmental exposures.

Keywords:  Disease; Environmental pollutants; Mitophagy; Toxicology

DOI:  https://doi.org/10.1007/s10495-025-02242-6
Nat Metab. 2026 Jan 12.

AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.

Tyler K T Smith, Logan K Townsend, William J Smiles, Jonathan S Oakhill, Morgan D Fullerton, Gregory R Steinberg.

The orchestration of cellular metabolism requires the integration of signals related to energy stores and nutrient availability through multiple overlapping mechanisms. AMP-activated protein kinase (AMPK) is a pivotal energy sensor that responds to reductions in adenylate charge; however, studies over the past decade have also positioned AMPK as a key integrator of nutrient-derived signals that coordinate metabolic function. This Review highlights recent advances in our understanding of how AMPK senses nutrients and regulates metabolic activity across tissues, timescales and cell types. These effects are mediated through the phosphorylation of substrates involved in metabolite trafficking, mitochondrial function, autophagy, transcription, ubiquitination, proliferation and cell survival pathways, including ferroptosis. Particular attention is given to the role of AMPK in the pathophysiology of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular and renal diseases, neurodegenerative disorders and cancer. Collectively, these findings reinforce AMPK as a central metabolic node that aligns cellular behaviour with energetic demand. Continued investigation into its nutrient-sensing mechanisms holds promise for identifying new strategies to restore metabolic balance in disease.

DOI: https://doi.org/10.1038/s42255-025-01442-3