bims-mitmed 2025-11-23 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–11–23
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
Hypocitrullinemia as an Early Diagnostic Biomarker for MT-ATP6 Mitochondrial Diseases.
The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.
Mitochondrial transplantation restores mitochondrial content and function in SSBP1-related mitochondrial DNA depletion syndrome.
Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration.
Expanding research and care for Leigh syndrome: efforts of a patient-led advocacy organization.
Targeted deletions in human mitochondrial DNA engineered by Type V CRISPR-Cas12a system.
Friedreich Ataxia.
A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.
Mitochondria regulate the cell fate decisions of megakaryocyte-erythroid progenitors.
CRISPR/Cas9-mediated editing of MIC13 in human induced pluripotent stem cells: A model for mitochondrial hepato-encephalopathy.
SIRT4 positively regulates autophagy via ULK1, but independently of HDAC6 and OPA1.
Anatomical Associations Between Focal Mitochondrial Metabolism and Patterns of Neurodegeneration in Amyotrophic Lateral Sclerosis.
Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
Fontaine progeroid syndrome with neonatal mitochondrial disease.
Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.
Prime editing-installed suppressor tRNAs for disease-agnostic genome editing.
Measuring mitochondrial membrane potential.
Mitochondrial Respiratory Supercomplex Assembly Factor COX7RP Contributes to Lifespan Extension in Mice.
Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.
The metabolic engine of cognition: microglia-neuron interactions in health, ageing and disease.
Longitudinal transformation of mitochondrial metabolism during neurogenesis.
Novel role for PI3Kβ in placental function through regulation of system A amino acid transporter expression, associated with embryonic lethality.
Modulating mitochondrial metabolism: a neuroprotective mechanism for hypoxic-ischemic preconditioning.

Nat Commun. 2025 Nov 20. 16(1): 10222

An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.

Eloïse Marques, Stephen P Burr, Alva M Casey, Richard J Stopforth, Chak Shun Yu, Keira Turner, Dane M Wolf, Marisa Dilucca, Vincent Paupe, Suvagata Roy Chowdhury, Victoria J Tyrrell, Robbin Kramer, Yamini M Kanse, Chinmayi Pednekar, Chris A Powell, James B Stewart, Julien Prudent, Michael P Murphy, Michal Minczuk, Valerie B O'Donnell, Clare E Bryant, Patrick F Chinnery, Arthur Kaser, Alexander von Kriegsheim, Dylan G Ryan.

Impaired mitochondrial bioenergetics in macrophages promotes hyperinflammatory cytokine responses, but whether inherited mtDNA mutations drive similar phenotypes is unknown. Here, we profiled macrophages harbouring a heteroplasmic mitochondrial tRNAAla mutation (m.5019A>G) to address this question. These macrophages exhibit combined respiratory chain defects, reduced oxidative phosphorylation, disrupted cristae architecture, and compensatory metabolic adaptations in central carbon metabolism. Upon inflammatory activation, m.5019A>G macrophages produce elevated type I interferon (IFN), while exhibiting reduced pro-inflammatory cytokines and oxylipins. Mechanistically, suppression of pro-IL-1β and COX2 requires autocrine IFN-β signalling. IFN-β induction is biphasic: an early TLR4-IRF3 driven phase, and a later response involving mitochondrial nucleic acids and the cGAS-STING pathway. In vivo, lipopolysaccharide (LPS) challenge of m.5019A>G mice results in elevated type I IFN signalling and exacerbated sickness behaviour. These findings reveal that a pathogenic mtDNA mutation promotes an imbalanced innate immune response, which has potential implications for the progression of pathology in mtDNA disease patients.

DOI: https://doi.org/10.1038/s41467-025-65023-4
J Mol Neurosci. 2025 Nov 19. 75(4): 154

Hypocitrullinemia as an Early Diagnostic Biomarker for MT-ATP6 Mitochondrial Diseases.

Yingxue Li, Dongjuan Wang, Maobin Zhou, Haoxuan Sun, Siqi Hong, Li Jiang, Yi Guo.

  MT-ATP6 mitochondrial diseases are a group of disorders inherited from the maternal lineage caused by pathogenic variants in the MT-ATP6 gene, which encodes the a subunit of mitochondrial complex V (ATP synthase) in the electron transport chain. In this study, statistical analysis of 69 mitochondrial disease patients with complete blood metabolic screening at our center demonstrated that hypocitrullinemia exhibited 58% sensitivity (7/12) and 100% specificity (57/57) for diagnosing MT-ATP6 mitochondrial diseases. For detecting the m.8993T > G variant, the diagnostic sensitivity reached 78% (7/9) with maintained 100% specificity (60/60). Among the 7 patients with hypocitrullinemia, one had mtDNA large segment deletion syndrome involving MT-ATP6, and the other 6 had MT-ATP6 mitochondrial diseases due to the m.8993T > G variant. Hypocitrullinemia was initially detected in 3 patients during newborn screening and persisted in follow-up evaluations. A literature review identified 42 cases with MT-ATP6 variants exhibiting hypocitrullinemia, of whom 21 were diagnosed with decreased citrulline during newborn screening. We propose that hypocitrullinemia may serve as an early, characteristic serum biomarker for MT-ATP6 mitochondrial diseases, particularly aiding in the early diagnosis of the m.8993T > G variant. It also exhibits high specificity for diagnosing MT-ATP6 mitochondrial diseases and the m.8993T > G variant. Timely interventions, such as proactive diagnosis of pathogenic variants and administration of mitochondrial cofactors and citrulline, can mitigate the risk of decompensation and improve long-term prognosis.

Keywords:   MT-ATP6 ; Biomarker; Hypocitrullinemia; Leigh syndrome; m.8993T > G

DOI:  https://doi.org/10.1007/s12031-025-02440-6
Mitochondrion. 2025 Nov 16. pii: S1567-7249(25)00096-0. [Epub ahead of print] 102099

The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.

Jakob D Busch, Thomas Schöndorf, Dusanka Milenkovic, Xinping Li, Rolf Wibom, Joana F Silva-Rodrigues, Roberta Filograna, Camilla Koolmeister, Nils-Göran Larsson, Diana Rubalcava-Gracia.

  The mitochondrial cytochrome c oxidase (COX, complex IV), a multi-subunit protein complex, plays a crucial role in cellular respiration by reducing oxygen to water and simultaneously pumping protons to enable oxidative phosphorylation (OXPHOS). Thus, defects in its assembly can directly affect cellular energy homeostasis. COX20 is an essential chaperone for the core subunit COX2. In human cultured cells, TMEM177 was found to stabilize COX20 and maintain balanced COX2 levels. In mice, TMEM177 was also identified as an interactor of mitochondrial ribosomes. To understand the function of TMEM177 in vivo, we generated Tmem177 knockout mice. Here, we analyze how TMEM177 loss affects mitochondrial gene expression, as well as the activity and assembly of OXPHOS complexes. We found that a small proportion of the knockout mice died perinatally, while surviving knockout mice tended to gain less weight. TMEM177 depletion moderately reduced COX20 levels, but OXPHOS complexes were preserved. Moreover, Tmem177 and Surf1 double knockout mice were born asymptomatic. In conclusion, TMEM177 fine-tunes complex IV assembly by stabilizing COX20 in vivo. Our findings refine the current model of complex IV assembly in mammals.

Keywords:  Cytochrome c oxidase; Mitochondria; Mitoribosomes; OXPHOS; mtDNA

DOI:  https://doi.org/10.1016/j.mito.2025.102099
BMB Rep. 2025 Nov 20. pii: 6418. [Epub ahead of print]

Mitochondrial transplantation restores mitochondrial content and function in SSBP1-related mitochondrial DNA depletion syndrome.

Dohee Kim, Seo-Eun Lee, JuHyuen Cha, Jun Ho Lee, Young Cheol Kang, Sang-Yeon Lee.

This study examined therapeutic potential of mitochondrial transplantation using PN-101, a mitochondria preparation derived from human umbilical cord mesenchymal stem cells (UCMSCs), to address SSBP1-related mitochondrial DNA (mtDNA) depletion syndrome. Patient-derived fibroblasts harboring a heterozygous SSBP1 mutation (c.272G＞A:p.Arg91Gln) were treated with PN-101. Its successful uptake and integration into these cells were confirmed. Subsequent analyses revealed that PN-101 treatment significantly increased mtDNA copy numbers in a time- and dose-dependent manner, elevated the expression of key oxidative phosphorylation proteins, and enhanced overall mitochondrial bioenergetics. Taken together, these results provide strong evidence that mitochondrial transplantation holds promise as a therapeutic strategy for primary mitochondrial diseases, including those involving SSBP1 mutations.
Nat Metab. 2025 Nov 20.

Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration.

Sarmistha Mukherjee, Ricardo A Velázquez Aponte, Caroline E Perry, Won Dong Lee, Kevin A Janssen, Marc Niere, Gabriel K Adzika, Mu-Jie Lu, Hsin-Ru Chan, Xiangyu Zou, Beishan Chen, Nicole Bye, Teresa Xiao, Jin-Seon Yook, Oniel Salik, David W Frederick, Ryan B Gaspar, Khanh V Doan, James G Davis, Joshua D Rabinowitz, Douglas C Wallace, Nathaniel W Snyder, Shingo Kajimura, Xiaolu A Cambronne, Mathias Ziegler, Joseph A Baur.

Nicotinamide adenine dinucleotide (NAD+) precursor supplementation shows metabolic and functional benefits in rodent models of disease and is being explored as potential therapeutic strategy in humans. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down the mechanisms of action. Here we show that the rate of liver regeneration is closely associated with the concentration of NAD+ in hepatocyte mitochondria. We find that the mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1). The heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, whereas the hepatocyte-specific overexpression of SLC25A51 is sufficient to enhance liver regeneration comparably to the effect of systemic NAD+ precursor supplements. This benefit is observed even though NAD+ levels are increased only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.

DOI: https://doi.org/10.1038/s42255-025-01408-5
Res Involv Engagem. 2025 Nov 20. 11(1): 137

Expanding research and care for Leigh syndrome: efforts of a patient-led advocacy organization.

Sophia Zilber, Melinda Burnworth, Titilola Afolabi, Jonathan R Brestoff, Michal Minczuk, Alejandro Rodriguez Luis, Qinglan Ling, Alessandro Prigione, Isabella Tolle, Ibrahim Elsharkawi, Ethan Perlstein, Danielle Boyce, Simon Johnson, Kasey Woleben.



Keywords:  Gene therapy; Leigh syndrome; Mitochondrial disease; Patient advocacy; Rare disease

DOI:  https://doi.org/10.1186/s40900-025-00808-x
NAR Mol Med. 2025 Apr;2(2): ugaf021

Targeted deletions in human mitochondrial DNA engineered by Type V CRISPR-Cas12a system.

Natalia Nikitchina, Anne-Marie Heckel, Nikita Shebanov, Ilya Mazunin, Ivan Tarassov, Nina Entelis.

Mutations in mitochondrial DNA (mtDNA) contribute to various neuromuscular diseases, with severity depending on heteroplasmy level when mutant and wild-type mtDNA coexist within the same cell. Developing methods to model mtDNA dysfunction is crucial for experimental therapies. Here, we adapted the Type V CRISPR-AsCas12a system, which recognizes AT-rich PAM sequences, for targeted editing of human mtDNA. We demonstrated that mitochondrial targeting sequence (MTS) from Neurospora crassa ATPase subunit 9 efficiently addressed the AsCas12a effector nuclease into human mitochondria. When programmed with two CRISPR RNAs (crRNAs) targeting distant regions of mtDNA, the mito-AsCas12a can cleave mtDNA, enabling generation of deletions in cultured human cells. Next generation sequencing of the deletions boundaries confirmed mtDNA ligation after the cleavage by the mitoCRISPR-AsCas12a system. Therefore, we provide experimental data proving that a CRISPR system has potential to be used for precise mtDNA manipulation, offering a promising tool for generating predefined deletions in mtDNA and creating cellular models of mitochondrial disorders.

DOI: https://doi.org/10.1093/narmme/ugaf021
Pediatr Neurol. 2025 Nov 01. pii: S0887-8994(25)00321-2. [Epub ahead of print]174 148-154

Friedreich Ataxia.

S H Subramony, David R Lynch.

  With the introduction of potential new therapy for Friedreich ataxia, the disorder has taken on a new importance in the world of pediatric neurology. Originally described more than 150 years ago, large scale clinical studies have defined diagnostic criteria and the underlying mutation as a biallelic, unstable expansion of an intronic guanine adenine adenine repeat in chromosome 9. In this review, we summarize the clinical features, routine management, pathophysiology, and emerging therapies for this devastating disease. The recent approval of omaveloxolone makes recognition of Friedreich ataxia and its treatment essential for all pediatric neurologists.

Keywords:  Epigenetic; Gene therapy; Mitochondrion; Neurodegeneration; Neurodevelopment; Protein replacement antioxidant

DOI:  https://doi.org/10.1016/j.pediatrneurol.2025.10.020
EMBO J. 2025 Nov 20.

A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.

Julia A Thayer, Jennifer D Petersen, Xiaoping Huang, Luiza M Gruel Budet, James Hawrot, Daniel M Ramos, Shiori Sekine, Yan Li, Michael E Ward, Derek P Narendra.

  Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage via a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the presequence translocase-associated import motor (PAM), blocked progression of PINK1 import through the translocase of the inner membrane (TIM23), causing it to remain bound to the translocase of the outer membrane (TOM). Ablation of TIM23 was sufficient to arrest PINK1 within TOM, irrespective of MMP. Meanwhile, TOM (including subunit TOMM5) was required for PINK1 retention on the mitochondrial surface. The energy state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Together, our findings point to a convergent mechanism of PINK1-Parkin activation by mitochondrial damage: loss of MMP stalls PINK1 import during its transfer from TOM to TIM23.

Keywords:  Autophagy; Glycolysis; Parkinson’s Disease; Unfolded Protein Response

DOI:  https://doi.org/10.1038/s44318-025-00604-z
Stem Cell Reports. 2025 Nov 20. pii: S2213-6711(25)00324-8. [Epub ahead of print] 102720

Mitochondria regulate the cell fate decisions of megakaryocyte-erythroid progenitors.

Eunkyu Sung, Shohei Murakami, Masanobu Morita, Tomoaki Ida, Takaaki Akaike, Hozumi Motohashi.

  Recent studies highlight the critical role of mitochondria in hematopoiesis, especially in stem cell function and erythroid maturation. To explore mitochondrial contributions to cell lineage commitment of hematopoietic progenitors, we utilized Cars2-mutant mice, an ideal model for this purpose. CARS2, a mitochondrial isoform of cysteinyl-tRNA synthetase, has cysteine persulfide synthase (CPERS) activity. Our new mouse model, with reduced CPERS activity, showed that the Cars2 mutation led to mitochondrial inhibition and anemia by suppressing erythroid commitment in megakaryocyte-erythroid progenitors (MEPs). This suppression was reproduced using mitochondrial electron transport chain inhibitors. We identified two distinct MEP populations based on the mitochondrial content: mitochondria-rich MEPs favored erythroid differentiation, while the mitochondria-poor MEPs favored megakaryocyte differentiation. These findings reveal critical contributions of mitochondria to the MEP lineage selection, acting as a "mitochondrial navigation" for lineage commitment.

Keywords:  CARS2; MEP; differentiation; erythropoesis; megakaryocyte; megakaryocyte-erythroid progenitor; mitochondria; mouse; persulfide; sulfur metabolism

DOI:  https://doi.org/10.1016/j.stemcr.2025.102720
Stem Cell Res. 2025 Nov 10. pii: S1873-5061(25)00220-X. [Epub ahead of print]89 103870

CRISPR/Cas9-mediated editing of MIC13 in human induced pluripotent stem cells: A model for mitochondrial hepato-encephalopathy.

Haribaskar Ramachandran, Alexander Becker, Jochen Dobner, Barbara Hildebrandt, Felix Distelmaier, Andrea Rossi, Ruchika Anand.

MIC13 is essential for cristae formation and functions as a key component of the large mitochondrial multi subunit MICOS complex. Mutations in MIC13 causes severe mitochondrial disease called mitochondrial hepato-encephalopathy. In this study, we describe the generation of a human induced pluripotent stem cell (iPSC) line carrying a patient-specific MIC13 mutation, introduced using a CRISPR/Cas knock-in approach. The resulting iPSC line will provide a valuable model to study the pediatric severe mitochondrial disease and to determine the pathological mechanisms as well as to facilitate the identification of potential therapeutic targets in the future.

DOI: https://doi.org/10.1016/j.scr.2025.103870
FEBS Open Bio. 2025 Nov 20.

SIRT4 positively regulates autophagy via ULK1, but independently of HDAC6 and OPA1.

Isabell Lehmkuhl, Khawar Amin, Lydia Gabriel, Nils Hampel, Afshin Iram, Julia Hesse, Constanze Wiek, Jasmin Thuy Vy Nguyen, Helmut Hanenberg, Jürgen Scheller, M Reza Ahmadian, Björn Stork, Doreen M Floss, Roland P Piekorz.

  The sirtuin SIRT4 has been implicated in the control of autophagy and mitochondrial quality control via mitophagy. However, the role of SIRT4 in regulating autophagy/mitophagy induced by different stressors is unclear. Here, we show that cells expressing SIRT4(H161Y), a catalytically inactive, dominant-negative mutant of SIRT4, fail to upregulate LC3B-II. These cells also exhibit a reduced autophagic flux upon treatment with different inducers of mitophagy/autophagy, that is, CoCl2-triggered pseudohypoxia, CCCP (carbonyl cyanide 3-chlorophenylhydrazone)/oligomycin-mediated respiratory chain inhibition, or rapamycin treatment. Interestingly, SIRT4(H161Y) expression upregulated protein levels of HDAC6, which is involved in mitochondrial trafficking and autophagosome-lysosome fusion, and inhibited the conversion of OPA1-L to OPA1-S, which is associated with increased mitochondrial fusion and decreased mitophagy. Both HDAC6 and OPA1 are SIRT4 interactors. However, the pharmacological inhibition of HDAC6 using Tubacin or of OPA1 using MYLS22 did not restore the stress-induced upregulation of LC3B-II levels upon autophagy/mitophagy treatment in SIRT4(H161Y)-expressing cells. Remarkably, inhibition of autophagosome-lysosome fusion and thus disruption of late autophagic flux by BafA1 treatment also failed to restore LC3B-II levels upon autophagy/mitophagy treatment, suggesting an inhibitory effect of SIRT4(H161Y) on the initiation/early phase of autophagy. Consistent with this, we demonstrate that SIRT4(H161Y) promotes the phosphorylation of ULK1 at S638 and S758 (mTORC1 targets), both of which mediate an important inhibitory regulation of autophagy initiation. Thus, our data suggest a positive regulatory function of SIRT4 in the ULK1-dependent early regulation/initiation of stress-induced autophagic flux, presumably via modulation of AMPK/mTORC1 signaling.

Keywords:  HDAC6; LC3; OPA1; SIRT4; ULK1; autophagy

DOI:  https://doi.org/10.1002/2211-5463.70164
Ann Neurol. 2025 Nov 21.

Anatomical Associations Between Focal Mitochondrial Metabolism and Patterns of Neurodegeneration in Amyotrophic Lateral Sclerosis.

Marlene Tahedl, We Fong Siah, Efstratios Karavasilis, Jennifer C Hengeveld, Mark A Doherty, Russell L McLaughlin, Orla Hardiman, Ee Ling Tan, Foteini Christidi, Jana Kleinerova, Peter Bede.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) has a very specific neuroimaging signature, but the molecular underpinnings of the strikingly selective anatomic involvement have not elucidated to date. Accordingly, a large neuroimaging study was conducted with 258 participants to evaluate associations between patterns of neurodegeneration and focal metabolic metrics.
METHODS: Structural and diffusivity alterations were systematically evaluated in a genetically stratified cohort. Voxelwise associations between neurodegeneration and physiological mitochondrial indices were systematically evaluated over the entire brain and also examined in specific regions.
RESULTS: Significant topological associations were identified between physiological mitochondria tissue density, nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome c oxidase (COX), mitochondrial respiratory capacity (MRC), tissue respiratory capacity (TRC), and propensity to focal atrophy in ALS. Anatomic correlations between mitochondrial metrics and morphometric change were particularly strong in GGGGCC hexanucleotide repeat carriers in C9orf72. Diffusivity analyses also confirmed associations between brain metabolism and microstructural degeneration. Higher focal mitochondria tissue density was associated with higher likelihood of frontal, temporal, cerebellar, opercular, thalamic, cingulum, putamen, corpus callosum, and corona radiata degeneration. Uncinate fasciculus degeneration was associated with higher Complex I, II, COX, and TRC activity. Topological associations were readily replicated in an external validation cohort.
INTERPRETATION: Our data indicate that brain regions with high metabolic activity are particularly vulnerable to neurodegeneration in ALS. Anatomic associations between physiological cerebral metabolism and patterns of neurodegeneration implicate mitochondrial dysfunction in the pathophysiology of ALS. Although mitochondrial dysfunction may not be the primary etiological factor, it may represent a shared bottleneck of multiple converging molecular and genetic pathways, offering a potential opportunity for meaningful pharmacological intervention. ANN NEUROL 2025.

DOI: https://doi.org/10.1002/ana.78099
Int Rev Immunol. 2025 Nov 17. 1-30

Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.

Thao Hoang Nhu Le, Van Thi Tuong Nguyen.

  Mitochondria serve as the powerhouses of living cells, supplying energy and essential building blocks for cellular activities. The immune system exhibits a dynamic and active characteristic within the body, wherein immune cells are constantly activated and primed for pathogens without causing harmful effects on the self-body. These characteristics necessitate that immune cells function effectively and correctly, supported by a sufficient energy supply and metabolism from the mitochondria. Mitochondrial dysfunction leads to immune dysregulation, resulting in inappropriate inflammation, autoimmunity, immunodeficiency, and hypersensitive responses, all of which contribute to the development of illness and disease. Recent studies on mitochondrial transfer in immune cells indicate that mitochondrial replacement could emerge as a promising tool for rectifying immune cell function. This review will emphasize the role of mitochondria in various immune cell types and explore how mitochondrial dysfunction can result in pathogenesis in different conditions. We also discuss the potential application of mitochondrial transfer and transplantation to- and from immune cells in the context of health and disease.

Keywords:  Immunology; immunometabolism; mesenchymal stem cells; metabolism; mitochondria transfer

DOI:  https://doi.org/10.1080/08830185.2025.2577986
Hum Genome Var. 2025 Nov 21. 12(1): 26

Fontaine progeroid syndrome with neonatal mitochondrial disease.

Mitsuhiko Riko, Daiki Kawamoto, Kentaro Hirayama, Tomoya Tsuchihashi, Takayuki Suzuki, Takuya Sugimoto, Yasushi Okazaki, Kei Murayama, Daisuke Tokuhara.

Fontaine progeroid syndrome (FPS) is a rare condition characterized by abnormalities in SLC25A24. Some instances of FPS have been reported to be fatal early in life. Here we present the first case of mitochondrial disease diagnosed with FPS in Japan. The diagnosis was based on the presence of the heterozygous known pathogenic variant of SLC25A24, NM_013386.5: c.649C>T and decreased activity of mitochondrial respiratory chain enzyme activity.

DOI: https://doi.org/10.1038/s41439-025-00331-1
J Transl Med. 2025 Nov 19. 23(1): 1321

Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.

Cristina Algieri, Salvatore Nesci, Francesca Oppedisano.

  Mitochondria, in addition to their classic role in energy production, have emerged as central hubs in the regulation of innate immunity. Under conditions of cellular stress, mitochondrial dysfunction triggers the release of mitochondrial DNA (mtDNA) into the cytosol or extracellular space, activating potent inflammatory pathways such as cGAS-STING, NLRP3 and TLR9. mtDNA release, driven by factors such as oxidative damage, membrane permeabilization, and various cell death pathways, is involved in immune surveillance and the pathogenesis of various diseases. At the same time, this downstream event leads to profound reorganization of immune cell metabolism, influencing functional polarization and inflammatory outcomes. This review presents the mitochondrion as an interface between metabolism, immunity, immunometabolites, and danger signalling. We explore the molecular mechanisms of mtDNA release, its conversion into immune signals, and its impact on metabolism in immune cells. Translational implications for pathologies such as neurodegenerative, autoimmune, and neoplastic diseases are also discussed. Deciphering the interconnection between mitochondrial stress, mtDNA release, and immunometabolic rewiring could open new avenues for the treatment of complex diseases and drive innovation in immunotherapy and regenerative medicine.

Keywords:  Complex diseases; Immunity; Inflammation; Metabolism; Mitochondria

DOI:  https://doi.org/10.1186/s12967-025-07392-4
Nature. 2025 Nov 19.

Prime editing-installed suppressor tRNAs for disease-agnostic genome editing.

Sarah E Pierce, Steven Erwood, Keyede Oye, Meirui An, Nicholas Krasnow, Emily Zhang, Aditya Raguram, Davis Seelig, Mark J Osborn, David R Liu.

Precise genome-editing technologies such as base editing1,2 and prime editing3 can correct most pathogenic gene variants, but their widespread clinical application is impeded by the need to develop new therapeutic agents for each mutation. For diseases that are caused by premature stop codons, suppressor tRNAs (sup-tRNAs) offer a more general strategy. Existing approaches to use sup-tRNAs therapeutically, however, require lifelong administration4,5 or show modest potency, necessitating potentially toxic overexpression. Here we present prime editing-mediated readthrough of premature termination codons (PERT), a strategy to rescue nonsense mutations in a disease-agnostic manner by using prime editing to permanently convert a dispensable endogenous tRNA into an optimized sup-tRNA. Iterative screening of thousands of variants of all 418 human tRNAs identified tRNAs with the strongest sup-tRNA potential. We optimized prime editing agents to install an engineered sup-tRNA at a single genomic locus without overexpression and observed efficient readthrough of premature termination codons and protein rescue in human cell models of Batten disease, Tay-Sachs disease and cystic fibrosis. In vivo delivery of a single prime editor that converts an endogenous mouse tRNA into a sup-tRNA extensively rescued disease pathology in a model of Hurler syndrome. PERT did not induce detected readthrough of natural stop codons or cause significant transcriptomic or proteomic changes. Our findings suggest the potential of disease-agnostic therapeutic genome-editing approaches that require only a single composition of matter to treat diverse genetic diseases.

DOI: https://doi.org/10.1038/s41586-025-09732-2
EMBO J. 2025 Nov 17.

Measuring mitochondrial membrane potential.

Oscar Tovar-Ferrero, Javier Rubio, Antonio Zorzano, Guillermo Martínez-Corrales, Marc Liesa.

DOI: https://doi.org/10.1038/s44318-025-00632-9
Aging Cell. 2025 Nov 18. e70294

Mitochondrial Respiratory Supercomplex Assembly Factor COX7RP Contributes to Lifespan Extension in Mice.

Kazuhiro Ikeda, Sachiko Shiba, Masataka Yokoyama, Masanori Fujimoto, Kuniko Horie, Tomoaki Tanaka, Satoshi Inoue.

  COX7RP is a critical factor that assembles mitochondrial respiratory chain complexes into supercomplexes, which is considered to modulate energy production efficiency. Whether COX7RP contributes to metabolic homeostasis and lifespan remains elusive. We here observed that COX7RP-transgenic (COX7RP-Tg) mice exhibit a phenotype characterized by a significant extension of lifespan. In addition, metabolic alterations were observed in COX7RP-Tg mice, including lower blood glucose levels at 120 min during the glucose tolerance test (GTT) without a significant difference in the area under the curve (AUC), as well as reduced serum triglyceride (TG) and total cholesterol (TC) levels. Moreover, COX7RP-Tg mice exhibited elevated ATP and nicotinamide adenine dinucleotide levels, reduced ROS production, and decreased senescence-associated β-galactosidase levels. Single-nucleus RNA-sequencing (snRNA-seq) revealed that senescence-associated secretory phenotype genes were downregulated in old COX7RP-Tg white adipose tissue (WAT) compared with old WT WAT, particularly in adipocytes. This study provides a clue to the role of mitochondrial respiratory supercomplex assembly factor COX7RP in resistance to aging and longevity extension.

Keywords:  lifespan; metabolism; mitochondria; supercomplex; white adipose tissue

DOI:  https://doi.org/10.1111/acel.70294
Mol Cell Biol. 2025 Nov 18. 1-16

Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.

Himangshu S Bose, William E Burak, Randy M Whittal.

  Cholesterol trafficking from the endoplasmic reticulum (ER) through the mitochondria-associated ER membrane (MAM) and finally to mitochondria is essential for mammalian survival. ER lipid raft-associated protein 2 (ERLIN2) scaffolds raft-like microdomains in the trans-Golgi network, endosomes, and plasma membrane. We found that ERLIN2 assists in rolling cholesterol trafficking-associated lipid vesicles by facilitating the intermediate folding of cholesterol trafficker steroidogenic acute regulatory protein (StAR) from the ER to MAM prior to delivery to the outer mitochondrial membrane. Each ERLIN2-StAR interaction is short. The absence of ERLIN2 ablates mitochondrial cholesterol transport. Over time, StAR association with ERLIN2 increases from the ER to MAM, thereby enhancing mitochondrial cholesterol transport. Thus, ERLIN2 is central for regulating mitochondrial cholesterol trafficking required for mitochondrial steroid metabolism.

Keywords:  Steroids; cholesterol; endoplasmic reticulum; mitochondria associated-ER membrane (MAM); pregnenolone; steroidogenic acute regulatory protein (StAR)

DOI:  https://doi.org/10.1080/10985549.2025.2583172
Nat Metab. 2025 Nov 21.

The metabolic engine of cognition: microglia-neuron interactions in health, ageing and disease.

Evridiki Asimakidou, Stefano Pluchino, Bianca Ambrogina Silva, Luca Peruzzotti-Jametti.

Cognitive impairment is associated with perturbations of fine-tuned neuroimmune interactions. At the molecular level, alterations in cellular metabolism can compromise brain function, driving structural damage and cognitive deficits. In this Review, we focus on the bidirectional interactions between microglia, the brain-resident immune cells and neurons to dissect the metabolic determinants of brain resilience and cognition. We first outline these metabolic pathways during development and adult life. Then, we delineate how these processes are perturbed in ageing, as well as in metabolic, neuroinflammatory and neurodegenerative disorders. By doing so, we provide a mechanistic understanding of the metabolic pathways relevant to cognitive function in health and disease, thus paving the way for novel therapeutic targets based on the emerging field of neuroimmunometabolism.

DOI: https://doi.org/10.1038/s42255-025-01409-4
Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2517961122

Longitudinal transformation of mitochondrial metabolism during neurogenesis.

Donghoon Lim, Sewon Park, Jong Seung Lee, Hyo Jin Gwon, Yunwoo Nam, Suhyuk Choi, Jongwon Kim, Yeonsu Kim, Geonwoo Park, Woo Yang Pyun, Hyun Woo Park, Seung-Woo Cho, Hyun S Ahn.

  Neural stem cells (NSCs) are valuable in the quest to conquer neurodegenerative diseases due to their capability to reconstruct the damaged neuronal networks. However, deep understanding of the intercellular signaling mechanism controlling the lineage and fate of the stem cells is required before potential clinical applications. Here, we applied nondestructive and label-free electrochemical methods for the longitudinal tracking of NSC respiratory metabolism. Sharp change in the oxygen utilization pattern was observed concomitant to stemness loss and onset of differentiation, suggesting metabolic reprogramming in the transition. Intra- and extracellular profiling of mitochondrial metabolites revealed molecular preference in the extracellular transport rates. Electrochemical emulation of the metabolite release pattern induced acceleration of neurite growth in nearby cells, suggesting paracrine signaling system mediated by mitochondrial metabolites.

Keywords:  intercellular signaling; neurogenesis; reactive oxygen species; scanning electrochemical microscopy

DOI:  https://doi.org/10.1073/pnas.2517961122
Cell Mol Life Sci. 2025 Nov 19. 82(1): 413

Novel role for PI3Kβ in placental function through regulation of system A amino acid transporter expression, associated with embryonic lethality.

Sarah E Conduit, Cindy X W Zhang, Wayne Pearce, Julie Guillermet-Guibert, Amanda N Sferruzzi-Perri, Bart Vanhaesebroeck.

  The placenta is essential for embryonic development, in part by mediating nutrient transfer from mother to embryo. Placental insufficiency is the most common cause of intrauterine growth restriction which has long-term health consequences lasting into adulthood. p110β is a class IA phosphoinositide 3-kinase (PI3K) catalytic subunit, a family of lipid kinases which are critical regulators of adult metabolism, immunity and embryonic and placental development. However, unlike the other class IA PI3K isoforms, the in vivo functions of p110β remain unclear. While homozygous p110β kinase-dead mice are mostly embryonically lethal, some survive into adulthood with no apparent phenotypes, other than reduced fertility. The mechanism(s) underlying this embryonic lethality remain unclear. Therefore, we performed an in-depth characterisation of p110β kinase-dead embryos, revealing a previously unrecognised role for p110β in controlling the expression of system A amino acid transporters. We show that homozygous p110β kinase-dead embryos are phenotypically normal, but growth-restricted and exhibit placental insufficiency. The placenta is small with a reduced nutrient storing junctional zone and downregulation of the system A amino acid transporters, required for maternal-to-embryo amino acid transfer. These data suggest defective amino acid transfer drives embryonic growth restriction and partial lethality of p110β kinase-dead embryos. This predominantly embryonic p110β phenotype is consistent with the notion that system A amino acid transporters are more critical during development than in adult physiology. The greater significance of p110β in development than in adult homeostasis may also help explain why p110β inhibitors, compared to inhibitors of other PI3K isoforms, are well-tolerated in adults.

Keywords:   PIK3CB ; Drug target; Inhibitor; Nutrient transporters; PI 3-kinase; Placenta

DOI:  https://doi.org/10.1007/s00018-025-05937-w
Cell Regen. 2025 Nov 16. 14(1): 45

Modulating mitochondrial metabolism: a neuroprotective mechanism for hypoxic-ischemic preconditioning.

Wenxin Li, Guo Shao, Ruifang Qi.

  Hypoxia-ischemia plays a role in the physiological and pathological processes of various diseases and presents a common challenge for humans under extreme environmental conditions. Neurons are particularly sensitive to hypoxia-ischemia, and prolonged exposure may lead to irreversible brain damage. The primary mechanisms underlying this damage include energy depletion, mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis. Mitochondria serve as primary organelles for adenosine triphosphate (ATP) production, and mitochondrial dysfunction plays a crucial role in mediating hypoxic pathophysiological processes. Hypoxic-ischemic preconditioning (H/IPC) is an endogenous cellular protective mechanism that reduces the damage caused by lethal hypoxic stressors. In this review, we summarize the potential role of H/IPC and its protective effects on mitochondrial quality control and function. This perspective offers a new approach for treating diseases caused by hypoxia-ischemia.

Keywords:  Hypoxia; Hypoxic/ischemic preconditioning; Ischemia; Mitochondrial; Neuroprotection

DOI:  https://doi.org/10.1186/s13619-025-00268-4