bims-nenemi 2025-10-19 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–10–19
eighteen papers selected by
Marco Tigano, Thomas Jefferson University

POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.
Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.
Mycobacterial ESAT-6 triggers cGAS-STING pathway via the GSDMD-NT dependent mitochondria dysfunction.
MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
Ligase 3 prevents oxidative strand break-induced mitochondrial DNA loss but is not essential for replicative circularization.
Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).
Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.
Mitochondrial dysfunction alters early endosome trafficking via microtubule reorganization.
Modulation of mTOR Within Retinal Pigment Epithelium Affects Cell Viability and Mitochondrial Pathology.
Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.
SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.
Increased nucleotide metabolism alleviates Alzheimer's disease pathology.
Lactate-driven histone lactylation enhances GDF15 secretion in skeletal muscle under mtDNA mutation-induced mitochondrial stress.
FASTK post-transcriptional regulators - a 'FAST-tracK' in mitochondrial gene expression.
Detection methods for mitochondrial DNA heteroplasmy and their potential single-cell applications in cancer.
OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies.

Life Sci Alliance. 2025 Dec;pii: e202302563. [Epub ahead of print]8(12):

POLRMT overexpression increases mtDNA transcription without affecting steady-state mRNA levels.

Maria Miranda, Andrea Mesaros, Nathalie Scrima, Louise Pérard, Irina Kuznetsova, Martin Purrio, Ilian Atanassov, Aleksandra Filipovska, Arnaud Mourier, Nils-Göran Larsson, Inge Kühl.

POLRMT is the sole RNA polymerase in human mitochondria, where it generates primers for mitochondrial DNA (mtDNA) replication and transcribes the mtDNA to express genes encoding essential components of the oxidative phosphorylation (OXPHOS) system. Elevated POLRMT levels are found in several cancers and in mouse models with severe mitochondrial dysfunction. Here, we generated and characterized mice overexpressing Polrmt to investigate the physiological and molecular consequences of elevated POLRMT levels. Increasing POLRMT levels did not result in any pathological phenotype but led to increased exercise performance in male mice under stress conditions. Polrmt overexpression increased mtDNA transcription initiation, resulting in higher steady-state levels of the promoter-proximal L-strand transcript 7S RNA. Surprisingly, the abundance of mature mitochondrial RNAs was not affected by the elevated POLRMT levels. Furthermore, ubiquitous simultaneous overexpression of Polrmt and Lrpprc, which stabilizes mitochondrial messenger RNAs, did not increase steady-state levels of mitochondrial transcripts in the mouse. Our data show that POLRMT levels regulate transcription initiation, but additional regulatory steps downstream of transcription initiation and transcript stability limit OXPHOS biogenesis.

DOI: https://doi.org/10.26508/lsa.202302563
Curr Biol. 2025 Oct 15. pii: S0960-9822(25)01246-1. [Epub ahead of print]

Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.

Leeba A Chacko, Hidenori Nakaoka, Richard G Morris, Wallace F Marshall, Vaishnavi Ananthanarayanan.

  Mitochondria are not produced de novo in newly divided daughter cells but are inherited from the mother cell during mitosis. While mitochondrial homeostasis is crucial for living cells, the feedback responses that maintain mitochondrial volume across generations of dividing cells remain elusive. Here, using a microfluidic yeast "mother machine," we tracked several generations of fission yeast cells and observed that cell size and mitochondrial volume grew exponentially during the cell cycle. We discovered that while mitochondrial homeostasis relied on the "sizer" mechanism of cell size maintenance, mitochondrial function was a critical determinant of the timing of cell division; cells born with lower-than-average amounts of mitochondria grew slower and thus added more mitochondria before they divided. Thus, mitochondrial addition during the cell cycle was tailored to the volume of mitochondria at birth, such that all cells ultimately contained the same mitochondrial volume at cell division. Quantitative modeling and experiments with mitochondrial DNA-deficient rho0 cells additionally revealed that mitochondrial function was essential for driving the exponential growth of cells. Altogether, we demonstrate a central role for mitochondrial activity in dictating cellular growth rates and ensuring mitochondrial volume homeostasis.

Keywords:  S. pombe; fission yeast; growth kinetics; homeostasis; microfluidics; mitochondria; yeast mother machine

DOI:  https://doi.org/10.1016/j.cub.2025.09.046
Virulence. 2025 Dec;16(1): 2570001

Mycobacterial ESAT-6 triggers cGAS-STING pathway via the GSDMD-NT dependent mitochondria dysfunction.

Yang Yang, Jinxia Xu, Yanping Hu, Xinxin Zang, Yunjie Li, Ahui Xu, Hexiang Jiang, Jingyan Fan, Luqing Cui, Bei Huang, Fushan Shi, Houhui Song.

  Mycobacterium tuberculosis (Mtb) remains a global health threat due to its ability to subvert host immune responses. Emerging evidence suggests that Mtb infection induces the production of type I interferons (IFNs), during which cGAS directly binds to Mtb genomic DNA. Here, we demonstrate that ESAT-6, a secreted virulence factor of Mtb, potently induces type I interferon (IFN) responses through a cGAS/STING-dependent signaling axis. Genetic ablation and pharmacological inhibition of cGAS or STING abolished ESAT-6-induced IFN-β production. Mechanistically, ESAT-6 induces mitochondrial dysfunction, characterized by mitochondrial DNA (mtDNA) release and mitochondrial ROS (mtROS) production. Further investigation revealed that ESAT-6 triggers GSDMD cleavage, followed by the formation of GSDMD-NT. GSDMD-NT then translocates to mitochondria, disrupting their integrity and promoting mtDNA and mtROS release. GSDMD deficiency prevented ΔΨm loss, mtDNA/mtROS release, and IFN-β responses. Therefore, our findings establish a novel ESAT-6-GSDMD-mtDNA axis that drives type I IFN responses, providing critical insights into Mtb immune evasion strategies.

Keywords:  ESAT-6; GSDMD; Mtb; cGAS/STING; mitochondria damage

DOI:  https://doi.org/10.1080/21505594.2025.2570001
Nat Cell Biol. 2025 Oct;27(10): 1708-1724

MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.

Mai Nguyen, Jack J Collier, Olesia Ignatenko, Genevieve Morin, Vanessa Goyon, Alexandre Janer, Camila Tiefensee Ribeiro, Austen J Milnerwood, Sidong Huang, Michel Desjardins, Heidi M McBride.

Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson's disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death.

DOI: https://doi.org/10.1038/s41556-025-01774-y
Nucleic Acids Res. 2025 Oct 14. pii: gkaf1000. [Epub ahead of print]53(19):

Ligase 3 prevents oxidative strand break-induced mitochondrial DNA loss but is not essential for replicative circularization.

Genevieve Trombly, Afaf Milad Said, Alexei P Kudin, Kerstin Hallmann, Anano Kakabadze, Viktoriya Peeva, Kerstin Becker, Karl Köhrer, Gábor Zsurka, Wolfram S Kunz.

The mitochondrial isoform of LIG3 is proposed to catalyze both circularization of newly replicated mitochondrial DNA (mtDNA) and rejoining of free mtDNA strands in base excision and single-strand break repair. Inactivation of LIG3 has been reported to cause embryonic lethality in mice due to loss of mtDNA. Here, we applied genome editing to inactivate LIG3 in HEK 293 cells and observed only a moderate decrease of mtDNA copy numbers. BrdU incorporation experiments confirmed ongoing synthesis of intact supercoiled mtDNA. Using ultra-deep long-read sequencing of isolated mtDNA, we detected increased frequencies of single-strand and double-strand breaks clustering at sites with high GC-content, as well as hallmarks of accelerated degradation of linear mtDNA. This is likely due to the missing repair of intrinsic oxidative single-strand breaks, since the frequency of detected single-strand breaks was dependent on oxygen tension and on expression levels of enzymes involved in ROS (reactive oxygen species) defense. Exogenous oxidative challenge, that resulted in transient mtDNA damage in wild-type cells, caused dramatic mtDNA loss in LIG3-/- cell lines. Thus, our data provide evidence for the pivotal role of LIG3 in preventing mtDNA loss after oxidative damage and corroborate the hypothesis that oxidative strand break-induced mtDNA degradation is highly relevant for mtDNA turnover in vivo.

DOI: https://doi.org/10.1093/nar/gkaf1000
Biochim Biophys Acta Mol Basis Dis. 2025 Oct 10. pii: S0925-4439(25)00418-1. [Epub ahead of print]1872(2): 168070

Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.

Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Marta Zaninello, Esther Barth, Matteo Veronese, Richard Rodenburg, Elena I Rugarli, Susanne Brodesser, Susanne Arnold, Ulrich Brandt.

  Inherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, how molecular causes ultimately present as a clinical phenotype is poorly understood. To address this conundrum starting from the molecular defect, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45P retained 30-40 % of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by ∼20 kJ∙mol-1 in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.

Keywords:  Active/deactive transition; Complex I; Complexome profiling; Mitochondria; Mitochondrial disease; mtDNA

DOI:  https://doi.org/10.1016/j.bbadis.2025.168070
Mol Genet Metab. 2025 Oct 08. pii: S1096-7192(25)00252-5. [Epub ahead of print]146(3): 109260

Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).

Xueyang Pan, Yue Wang, Ning Liu, Xi Luo, V Reid Sutton, William J Craigen, Qin Sun.

  Large deletions in multi-copy mitochondrial DNA (mtDNA) are associated with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), and Pearson syndrome (PS), collectively referred to as single large-scale mtDNA deletion syndromes (SLSMDSs). These deletions are typically sporadic and heteroplasmic, yet the relationship between heteroplasmy levels and disease severity remains uncertain, particularly for low level deletions, making pathogenicity assessment challenging. To evaluate the functional impact of mtDNA deletions in muscle, we retrospectively analyzed 1104 consecutive clinical cases with both mtDNA sequencing and mitochondrial electron transport chain (ETC) enzyme assays performed on the same muscle specimen. Fifteen cases (1.4 %) carried a single large mtDNA deletion and exhibited clinical features consistent with the CPEO/KSS spectrum. Of these, seven showed ETC deficiencies despite low deletion heteroplasmy levels (<10 % in all cases). Four had enzyme deficiencies defined to a single complex, while three had deficiencies in multiple complexes. Complex IV was most frequently impaired, whereas nuclear-encoded complex II activity remained normal in all samples. Notably, the pattern of ETC impairment did not fully correlate with the specific mitochondrial genes disrupted by the deletions. These findings demonstrate that mitochondrial dysfunction can occur at mtDNA deletion heteroplasmy levels far below conventional pathogenic thresholds. This highlights the diagnostic relevance of low-level mtDNA deletions and supports the integration of molecular and functional testing in accurate SLSMDS diagnosis.

Keywords:  Chronic progressive external ophthalmoplegia (CPEO); ETC complex enzymatic assay; Heteroplasmy; Kearns-Sayre syndrome (KSS); Mitochondrial electron transport chain (ETC); Single large-scale mtDNA deletion syndrome (SLSMDS); mtDNA deletion; mtDNA next-generation sequencing (NGS)

DOI:  https://doi.org/10.1016/j.ymgme.2025.109260
Sci Adv. 2025 Oct 17. 11(42): eadx8662

Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.

Sofia La Vecchia, Saurav Doshi, Petros Antonoglou, Tanima Kundu, Wafa Al Santli, Kleopatra Avrampou, Matthew T Witkowski, Anna Pellattiero, Federico Magrin, Kristina Ames, Amit Verma, Kira Gritsman, Xiaoyang Su, Andrea Mattarei, Iannis Aifantis, Luca Scorrano, Christina Glytsou.

Acute myeloid leukemia (AML) is the most prevalent and deadliest adult leukemia. Its frontline treatment uses the BH3 mimetic venetoclax to trigger mitochondria-dependent apoptosis. However, drug resistance nearly always develops, calling for therapies to circumvent it. Advanced microscopy and genome-wide CRISPRi screen analyses pinpointed mitochondrial adaptations primarily mediated by the master regulator of cristae shape optic atrophy 1 (OPA1) as critical for BH3 mimetics resistance. Resistant AML cells up-regulate OPA1 to modify their mitochondrial structure and evade apoptosis. MYLS22 and Opitor-0, two specific and nontoxic OPA1 inhibitors, promote apoptotic cristae remodeling and cytochrome c release, synergizing with venetoclax in AML cells and xenografts derived from AML patients ex vivo and in vivo. Mechanistically, OPA1 loss renders AML cells dependent on glutamine and sensitizes them to ferroptosis by activating ATF4-regulated integrated stress responses. Overall, our data clarify how OPA1 up-regulation allows AML cells' metabolic flexibility and survival and nominates specific OPA1 inhibitors as efficacious tools to overcome venetoclax resistance in leukemia.

DOI: https://doi.org/10.1126/sciadv.adx8662
Life Sci Alliance. 2026 Jan;pii: e202403020. [Epub ahead of print]9(1):

Mitochondrial dysfunction alters early endosome trafficking via microtubule reorganization.

Anjali Vishwakarma, Lilia Chihki, Kiran Todkar, Mathieu Ouellet, Marc Germain.

Mitochondria are essential for bioenergetics and cellular processes including cell differentiation and immunity; alterations in these processes cause a wide range of muscular and neurological pathologies. Although these pathologies have traditionally been associated with ATP deficits, mitochondrial dysfunction also leads to reactive oxygen species (ROS) generation, inflammation, and alterations in the function of other organelles. Although the negative impact of mitochondrial dysfunction on lysosomal activity is established, the relationship between mitochondria and the rest of the endocytic compartment remains poorly understood. Here, we show that inhibiting mitochondrial activity through genetic and chemical approaches causes early endosome (EE) perinuclear aggregation and impairs cargo delivery to lysosomes. This impairment is due to ROS-mediated alterations in microtubule architecture and centrosome dynamics. Antioxidants can rescue these EE defects, underlying the pivotal role of mitochondria in maintaining cellular activities through ROS regulation of microtubule networks. Our findings highlight the significance of mitochondria beyond ATP production, emphasizing their critical involvement in endocytic trafficking and cellular homeostasis. These insights emphasize mitochondria's critical involvement in cellular activities and suggest novel targets for therapies to mitigate the effects of mitochondrial dysfunction.

DOI: https://doi.org/10.26508/lsa.202403020
Int J Mol Sci. 2025 Sep 26. pii: 9442. [Epub ahead of print]26(19):

Modulation of mTOR Within Retinal Pigment Epithelium Affects Cell Viability and Mitochondrial Pathology.

Gloria Lazzeri, Michela Ferrucci, Paola Lenzi, Maria Anita Giambelluca, Francesca Biagioni, Carla Letizia Busceti, Alessandro Frati, Francesco Fornai.

  The relevance of well-structured mitochondria in sustaining the integrity of the retinal pigment epithelium (RPE) is increasingly evident. Conversely, altered mitochondria are a culprit of age-related macular degeneration (AMD), which is influenced by the activity of mechanistic target of rapamycin (mTOR). In the present manuscript, the mitochondrial status of RPE cells was investigated by light and electron microscopy following the administration of various doses of compounds, which modulate mTOR. The study combines MitoTracker dyes and mitochondrial immunohistochemistry with in situ mitochondrial morphometry. Various doses of 3-methyladenine (3-MA), curcumin, and rapamycin were administered alone or in combination. The activity of autophagy and mTOR was quantified following each treatment. Administration of 3-MA led to activation of mTOR, which was associated with severe cell death, altered membrane permeability, and altered ZO-1 expression. In this condition, mitochondrial mass was reduced, despite a dramatic increase in damaged mitochondria being reported. The decrease in healthy mitochondria was concomitant with alterations in key mitochondria-related antigens such as Tomm20, Pink1, and Parkin. Specific mitochondrial alterations were quantified through in situ ultrastructural morphometry. Both curcumin and rapamycin counteract mTOR activation and rescue mitochondrial status, while preventing RPE cell loss and misplacement of decreased ZO-1 expression. Mitigation of mTOR may protect mitochondria in retinal degeneration.

Keywords:  MitoTracker Green; MitoTracker Red; PINK1; Parkin; Tomm20; ZO-1; autophagy; curcumin; mitochondrial morphology; mitochondrial ultrastructure; rapamycin

DOI:  https://doi.org/10.3390/ijms26199442
EMBO Mol Med. 2025 Oct 15.

Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.

Ang Li, Sen Huang, Shu-Qin Cao, Jinyi Lin, Linping Zhao, Feng Yu, Miaodan Huang, Lele Yang, Jiaqi Xin, Jing Wen, Lingli Yan, Ke Zhang, Maoyuan Jiang, Weidong Le, Peng Li, Yong U Liu, Dajiang Qin, Jiahong Lu, Guang Lu, Hanming Shen, Xiaoli Yao, Evandro F Fang, Huanxing Su.

  Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.

Keywords:  Amyotrophic Lateral Sclerosis; Drug Screening; Isoginkgetin; Mitophagy; PINK1-Parkin

DOI:  https://doi.org/10.1038/s44321-025-00323-2
Mol Cell. 2025 Oct 10. pii: S1097-2765(25)00703-8. [Epub ahead of print]

SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.

Marilia M Dias, Martin S King, Engy Shokry, Sergio Lilla, Nikki Paul, Peter Thomason, Sara Zanivan, David Sumpton, Edmund R S Kunji, Thomas MacVicar.

  Methylated amino acids accumulate upon the degradation of methylated proteins and are implicated in diverse metabolic and signaling pathways. Disturbed methylated amino acid homeostasis is associated with cardiovascular disease and renal failure. Mitochondria are core processing hubs in conventional amino acid metabolism, but how they interact with methylated amino acids is unclear. Here, we reveal that the orphan mitochondrial solute carrier 25A45 (SLC25A45) is required for the mitochondrial uptake of methylated amino acids. SLC25A45 binds with dimethylarginine and trimethyllysine but has no affinity for unmethylated arginine and lysine. A non-synonymous mutation of human SLC25A45 (R285C) stabilizes the carrier by limiting its proteolytic degradation and associates with altered methylated amino acids in human plasma. Metabolic tracing of trimethyllysine in cancer cells demonstrates that SLC25A45 drives the biosynthesis of the key amino acid derivative, carnitine. SLC25A45 is therefore an essential mediator of compartmentalized methylated amino acid metabolism.

Keywords:  SLC25; carnitine; metabolism; metabolite transport; methylated amino acids; mitochondria; solute carriers

DOI:  https://doi.org/10.1016/j.molcel.2025.08.018
Front Cell Dev Biol. 2025 ;13 1650462

Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.

Karis B D'Alessandro, Enrico Zampese, Jenna L E Blum, Britta Kuusik, Alec Palmiotti, Shawn M Davidson, Colleen R Reczek, D James Surmeier, Navdeep S Chandel.

  Dysfunction of mitochondrial complex I (MCI) has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Here, we report the effect of expressing MitoLbNOX, a mitochondrial-targeted version of the bacterial enzyme LbNOX, which increases regeneration of NAD+ in the mitochondria to maintain the NAD+/NADH ratio, in dopaminergic neurons with impaired MCI (MCI-Park mice). MitoLbNOX expression did not ameliorate the cellular or behavioral deficits observed in MCI-Park mice, suggesting that alteration of the mitochondrial NAD+/NADH ratio alone is not sufficient to compensate for loss of MCI function in dopaminergic neurons.

Keywords:  NAD+; Parkinson’s disease; dopaminergic neurons; mitochondrial complex I; neurodegeneration; neurometabolism

DOI:  https://doi.org/10.3389/fcell.2025.1650462
Cell Death Dis. 2025 Oct 16. 16(1): 724

Increased nucleotide metabolism alleviates Alzheimer's disease pathology.

Yizhou Yu, Michael B Miller, August Yue Huang, Bryan Wei Zhi Tan, Ivana Celardo, Nuno Santos Leal, Samantha H Y Loh, L Miguel Martins.

Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD remain unclear. Here, we combine in silico methods from single-cell genomics of patients with AD with experimental validation in a Drosophila model of AD to elucidate the DNA repair processes in AD. We show that the levels of poly(ADP‒ribose) polymerase 1 (PARP1), which mediates multiple DNA damage repair pathways, are increased in the brains of patients with AD. We found that higher PARP1 levels in neurons from patients with AD are linked to increased disease risk and a greater burden of somatic mutations. Nucleotide imbalance can increase the frequency of somatic mutations upon activation of DNA repair processes. Using a fly model of AD, we identified a metabolic signature in AD animals characterised by decreased levels of phosphorylated nucleotides. Enhancing nucleotide metabolism via dietary supplementation or genetic manipulation protects against AD pathology in animals. Finally, Mendelian randomisation revealed that higher expression of human deoxyguanosine kinase (DGUOK) is linked to a lower risk of developing AD. Our results suggest that enhancing nucleotide metabolism could improve DNA repair and serve as an adjunct therapy to delay AD progression.

DOI: https://doi.org/10.1038/s41419-025-08066-1
Sci Bull (Beijing). 2025 Sep 29. pii: S2095-9273(25)00992-2. [Epub ahead of print]

Lactate-driven histone lactylation enhances GDF15 secretion in skeletal muscle under mtDNA mutation-induced mitochondrial stress.

Yan Lin, Busu Li, Jiayin Wang, Weiyue Si, Xingyu Zhuang, Ying Zhao, Wei Jiang, Wei Wang, Dongdong Wang, Fuchen Liu, Ruonan Duan, Yuying Zhao, Yunfan Yang, Jian-Sheng Kang, Xiaorong Zhang, Linpeng Li, Xingguo Liu, Chuanzhu Yan, Kunqian Ji.

DOI: https://doi.org/10.1016/j.scib.2025.09.052
Biochem Soc Trans. 2025 Oct 16. pii: BST20253089. [Epub ahead of print]

FASTK post-transcriptional regulators - a 'FAST-tracK' in mitochondrial gene expression.

Justin Van Riper, Bridget J Corsaro, Monica C Pillon.

  Fas-activated serine/threonine kinase (FASTK) proteins comprise one of the largest families of mitochondrial post-transcriptional regulators. Members are classified based on their conserved C-terminus, which shows homology with the PD-(D/E)XK superfamily of endoribonucleases. However, it is still uncertain which of these FASTK members are catalytic. The six human FASTK homologs rely on their RNA-binding activity to regulate distinct stages of mitochondrial gene expression, including early processing of nascent RNA, 3'-end messenger RNA (mRNA) maturation, ribosomal RNA (rRNA) modification, mRNA stability, and translation. Genetic and genomic studies have highlighted the crucial role of FASTK proteins in balancing the mitochondrial transcriptome and controlling oxidative phosphorylation. However, until recently, the molecular mechanisms governing their RNA metabolic activities have remained elusive. New biochemical and structural advances have provided molecular insights into the architecture and regulation of FASTK proteins. Here, we summarize the current understanding of the FASTK family's specialized roles in gene regulation, with an emphasis on mitochondrial mRNA metabolism by the proteins FASTK, FASTK domain-containing protein 4 (FASTKD4), and FASTKD5. Additionally, we leverage recent experimental structures and artificial intelligence-based prediction models to explore the molecular organization of FASTK proteins and highlight the family's signature C-terminus, a region essential for their RNA-binding activity.

Keywords:  FASTK; RAP domain; RNA; gene regulation; helix-turn-helix; mitochondria; nuclease

DOI:  https://doi.org/10.1042/BST20253089
Biochim Biophys Acta Rev Cancer. 2025 Oct 10. pii: S0304-419X(25)00214-8. [Epub ahead of print] 189472

Detection methods for mitochondrial DNA heteroplasmy and their potential single-cell applications in cancer.

Tianguang Cheng, Min Pan, Yi Qiao, Jing Tu.

  Mitochondrial DNA (mtDNA) is crucial for cellular metabolism, oxidative stress responses, and genomic stability, with mutations linked to cancer progression and therapeutic resistance. Mitochondrial heteroplasmy, the coexistence of wild-type and mutant mtDNA within a cell or across populations, plays a key role in mitochondrial dysfunction, tumor heterogeneity, and disease pathogenesis. Advances in single-cell technologies like quantitative PCR (qPCR), digital droplet PCR (ddPCR), next-generation sequencing (NGS), and long-read sequencing (TGS) have enabled precise mapping of heteroplasmic variants, providing insights into their role in cancer. This review evaluates current detection methods, discussing their strengths, limitations, and relevance to cancer research. We also explore the biological implications of heteroplasmy in cellular dynamics, nuclear mitochondrial DNA segments (NUMTs), and cancer pathogenesis, highlighting emerging technologies and future directions for studying mtDNA mutations at single-cell resolution in cancer. Ultimately, this review provides a critical synthesis of how single-cell mtDNA heteroplasmy analysis is reshaping our understanding of tumorigenesis and identifies key methodological and challenges that must be addressed to realize its full potential in precision oncology.

Keywords:  Cancer metabolism; Heteroplasmy; Mitochondrial DNA; Sequencing; Single cell

DOI:  https://doi.org/10.1016/j.bbcan.2025.189472
Commun Biol. 2025 Oct 16. 8(1): 1475

OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies.

Qinglong Wang, Yiqi Wang, Yi Da Douglas Jiang, Ryan Donahue, Gaby Cao, Weixuan Yan, Hong Guo, Zhenghui Li, Jenna Liang, Jin Hao, Yi Lu, Fengfeng Bei, Qianbin Wang, Feng Tian.

Optineurin (OPTN) is an adaptor protein that plays a crucial role in many cellular pathways, including NF-κB signaling, programmed cell death, and vesicular trafficking. OPTN dysfunction has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS). While mutations of OPTN seem to be predominantly loss-of-function in ALS, only gain-of-function mechanisms have been reported in POAG. Here, we demonstrate that OPTN knockout in the retina contributes to short-term astrogliosis, retinal ganglion cell (RGC) loss and long-term microglial activation. Moreover, OPTN loss of function does not exacerbate RGC death induced by ocular hypertension. Integrated bioinformatics and immunofluorescence analyses reveal that OPTN dysfunction leads to neuropeptide Y (NPY) downregulation and CHOP upregulation. Overexpression of wild-type OPTN in a hypertension glaucoma model prevents the RGC loss and attenuates microglial activation. Together, our findings highlight a neuroprotective role for OPTN as a key neuroimmune modulator.

DOI: https://doi.org/10.1038/s42003-025-08534-6