bims-nenemi 2025-06-08 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–06–08
eleven papers selected by
Marco Tigano, Thomas Jefferson University

The antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
Cellular metabolic state controls mitochondrial RNA kinetics.
Mitochondrial tRNA processing defects reprogram mitochondrial and cellular homeostasis.
The low endoribonuclease activity and lack of rNMP preference of human mitochondrial topoisomerase 1 protect against ribonucleotide-dependent deletions.
Glucose restriction induces degeneration of neurons with mitochondrial DNA depletion by altering ER-mitochondria calcium transfer.
Mito-tempo ameliorates tubular injury of diabetic nephropathy via inhibiting mt-dsRNA release and PKR/eIF2α pathway activation.
Myocardial mitochondrial antiviral signaling protein promotes heart Ischemia-reperfusion injury via RIG-I signaling in mice.
Parkin-dependent ubiquitination of TAX1BP1 directs efficient autophagic removal of defective mitochondria.
Rescuing Ischemic Brain Injury by Rewiring Mitochondrial Electron Flow.
Single-cell RNA sequencing reveals distinct senotypes and a quiescence-senescence continuum at the transcriptome level following chemotherapy.
GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer's disease.

bioRxiv. 2025 May 19. pii: 2025.05.16.654477. [Epub ahead of print]

The antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.

Dominic A Ritacco, Hamna Shahnawaz, Antonia Oduguwa, Jacob Hawk, Brianna Vizcaino, Donna Farber, Ryan G Gaudet.

Lysosomal damage is an endogenous danger signal to the cell, but its significance for innate immunity and how specific signaling pathways are engaged by this stressor remain unclear. Here, we uncover an immune-inducible pathway that connects lysosomal damage to mitochondrial DNA (mtDNA) efflux and type I IFN production. Lysosomal damage elicits mitochondrial outer membrane permeabilization (MOMP) via BAK/BAX macropores; however, the inner mitochondrial membrane (IMM) prevents wholesale mtDNA release in resting cells. Priming with type II IFN (IFN-γ) induced the antibacterial effector apolipoprotein L-3 (APOL3), which upon transient lysosomal damage, targets mitochondria undergoing MOMP and selectively permeabilizes the IMM to enhance mtDNA release and activate cGAS/STING signaling. Biochemical and cellular reconstitution revealed that analogous to its bactericidal detergent-like mechanism, APOL3 solubilizes cardiolipin to permeabilize the IMM. Our findings illustrate how cells use an antibacterial protein to expedite the breakdown of endosymbiosis and facilitate a heightened response to injury and infection.

DOI: https://doi.org/10.1101/2025.05.16.654477
bioRxiv. 2025 May 27. pii: 2025.05.13.653903. [Epub ahead of print]

Cellular metabolic state controls mitochondrial RNA kinetics.

Sean D Reardon, Clarisa Bautista, Shannon C Cole, Julien Cicero, Tatiana V Mishanina.

Human mitochondrial genome encodes essential genes for the oxidative phosphorylation (OXPHOS) complexes. These genes must be transcribed and translated in coordination with nuclear-encoded OXPHOS components to ensure correct stoichiometry during OXPHOS complex assembly in the mitochondria. While much is known about nuclear gene regulation during metabolic stresses like glucose deprivation, little is known about the accompanying transcriptional response in mitochondria. Using microscopy, roadblocking qPCR, and transcriptomics, we studied mitochondrial transcription in cells subjected to glucose deprivation, which is known to cause nuclear transcription downregulation and to activate the integrated stress response (ISR). We found that glucose deprivation stabilizes mitochondrial RNAs and slows mitochondrial transcription, effects that are quickly reversed with glucose reintroduction. Although transcriptomics revealed strong upregulation of the ISR, mitochondrial RNA stabilization was not upregulated by pharmacological activation of the ISR, but was promoted by inhibition of glycolysis, unveiling a direct connection between metabolism and regulation of mitochondrial gene expression.

DOI: https://doi.org/10.1101/2025.05.13.653903
J Biol Chem. 2025 Jun 03. pii: S0021-9258(25)02184-2. [Epub ahead of print] 110334

Mitochondrial tRNA processing defects reprogram mitochondrial and cellular homeostasis.

Gao Zhu, Yunfan He, Xincheng Li, Yun Xiao, Huisen Zhan, Maoli Duan, Min-Xin Guan.

Mitochondrial tRNA processing defects have been associated with some clinical presentations including deafness. Especially, a deafness-linked m.7516delA mutation impaired the 5' end processing of RNA precursors and mitochondrial translation. In this study, we investigated the mechanism by m.7516delA mutation induced-deficiencies mitigate organellular and cellular integrity. The m.7516delA mutation downregulated the expression of nucleus encoding subunits and upregulated assemble factors of complex IV and altered the assembly and activities of oxidative phosphorylation (OXPHOS) complexes. The impairment of OXPHOS alleviated mitochondrial quality control processes, including the imbalanced mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology. The m.7516delA mutation upregulated both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing levels of Parkin, BNIP3, NIX and MFN2-ubiquitination and altering interaction between MFN2 and MUL1 or Parkin, to facilitate the degradation of severely damaged mitochondria. Strikingly, the m.7516delA mutation activated integrated stress response (ISR) pathway, evidenced by upregulation of GCN2, P-GCN2, p-eIF2α, CHOP, ATF4 and elevating the nucleus-location of ATF5 to minimizes the damages in defective mitochondria. Both activation of ISR and PINK1/Parkin mitophagy pathways ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into underlying aberrant RNA processing-induced dysfunctions reprogrammed organelles and cellular integrity.

DOI: https://doi.org/10.1016/j.jbc.2025.110334
Nucleic Acids Res. 2025 Jun 06. pii: gkaf475. [Epub ahead of print]53(11):

The low endoribonuclease activity and lack of rNMP preference of human mitochondrial topoisomerase 1 protect against ribonucleotide-dependent deletions.

Cyrielle P J Bader, Erika Miyazaki-Kasho, Josefin M E Forslund, Aiswarya Dash, Malgorzata Wessels, Paulina H Wanrooij.

The incorporation of ribonucleotides (rNMPs) into the nuclear genome leads to severe genomic instability, including strand breaks and short 2-5 bp deletions at repetitive sequences. Curiously, the detrimental effects of rNMPs are not observed for the human mitochondrial genome (mtDNA) that typically contains several rNMPs per molecule. Given that the nuclear genome instability phenotype is dependent on the activity of the nuclear topoisomerase 1 enzyme (hTOP1), and mammalian mitochondria contain a distinct topoisomerase 1 paralog (hTOP1MT), we hypothesized that the differential effects of rNMPs on the two genomes may reflect divergent properties of the two cellular topoisomerase 1 enzymes. Here, we characterized the endoribonuclease activity of hTOP1MT and found it to be less efficient than that of its nuclear counterpart, a finding that was partly explained by its weaker affinity for its DNA substrate. Moreover, while hTOP1 and yeast TOP1 were able to cleave at an rNMP located even outside of the consensus cleavage site, hTOP1MT showed no such preference for rNMPs. As a consequence, hTOP1MT was inefficient at producing the short rNMP-dependent deletions that are characteristic of TOP1-driven genome instability. These findings help explain the tolerance of rNMPs in the mitochondrial genome.

DOI: https://doi.org/10.1093/nar/gkaf475
Mol Psychiatry. 2025 Jun 03.

Glucose restriction induces degeneration of neurons with mitochondrial DNA depletion by altering ER-mitochondria calcium transfer.

Lingyan Zhou, Feixiang Bao, Jiajun Zheng, Yingzhe Ding, Jiahui Xiao, Jian Zhang, Yongpeng Qin, Liang Yang, Yi Wu, Qi Meng, Manjiao Lu, Qi Long, Lingli Hu, Chong Li, Haitao Wang, Shijuan Huang, Linpeng Li, Junwei Wang, Wuming Wang, Gang Lu, Wai-Yee Chan, Dajiang Qin, Gong Chen, Xingguo Liu.

Mitochondrial DNA (mtDNA) mutations and/or depletion are implicated in epilepsy and many neurodegenerative diseases. However, systematic investigation into how mtDNA alterations relate to epilepsy and neural degeneration is needed. Here, we established a mouse model in which mtDNA depletion is induced by the Herpes Simplex Virus Type 1 (HSV-1) protein UL12.5 in the brain led to an epileptic phenotype characterized by abnormal electroencephalography (EEG) patterns and increased neural excitability in hippocampus. We also found that UL12.5 mediated mtDNA depletion in neurons in vitro (rho-) causes epilepsy-like abnormal EEG. Caloric restriction (CR) or glucose restriction (GR) is a strategy proven to reduce epileptic activity, however GR mimetic 2-deoxy-D-glucose (2-DG), induced degeneration in mtDNA depleted neurons. Mechanistically, mtDNA depletion increased mitochondria-endoplasmic reticulum (ER) contacts, facilitating GR-induced mitochondrial calcium overload. Rho- neurons did not show changes in mitochondrial motility or membrane potential. Our study revealed an unexpected axis of mtDNA depletion, ER-mitochondrial contacts, and calcium overload in the rho- neuron model. Fasting-induced GR causes early motor dysfunction, accelerates epilepsy progression, and worsens neurodegeneration in UL12.5 mice. Importantly, the IP3R inhibitor 2-APB blocks the neurodegeneration induced by fasting. This is the first description of animal and neuronal models of mitochondrial epilepsy. Our findings with these models suggest that GR may not be a viable clinical intervention in patients with mtDNA depletion.

DOI: https://doi.org/10.1038/s41380-025-03069-y
Free Radic Biol Med. 2025 May 31. pii: S0891-5849(25)00735-X. [Epub ahead of print]237 147-159

Mito-tempo ameliorates tubular injury of diabetic nephropathy via inhibiting mt-dsRNA release and PKR/eIF2α pathway activation.

Tongyue Duan, Liya Sun, Yiyun Xi, Chenrui Li, Qing Zhao, Lujun Xu, Ming Yang, Chongbin Liu, Li Xiao, Tuo Deng, Lin Sun.

   BACKGROUND: Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus linked to the overproduction of mitochondrial reactive oxygen species (mtROS). The mitochondria-targeted antioxidant Mito-tempo (MT) can reduce tubular damage in DN. It's known that mitochondrial double-stranded RNA (mt-dsRNA) can be released into the cytoplasm, leading to inflammation and apoptosis in disease states. However, it remains unclear whether MT prevents renal injury in DN by reducing mtROS production and subsequently mt-dsRNA release.
METHODS: Type 1 DN model (STZ-induced mice) and type 2 DN model (db/db mice), as well as the high glucose (HG) induced human proximal tubular epithelial cells (HK-2 cells) were performed in vivo and in vitro experiments, respectively. Polynucleotide phosphorylase (PNPase) siRNA was transiently transfected into HK-2 cells to overexpress mt-dsRNA, and C16 was used to inhibit protein kinase R (PKR) phosphorylation. Mitochondrial damage, oxidative stress and apoptosis indicators, the localization and expression of mt-dsRNA, and downstream pathways changes were examined.
RESULTS: Treatment of MT to DN mice significantly reduced renal pathological changes. In addition, mt-dsRNA expression significantly decreased in tubular cells of DN mice treated with MT, along with oxidative stress, cell apoptosis and phosphorylated PKR/eukaryotic translation initiation factor 2 subunit alpha (eIF2α) reduced. Similar results were found in HK-2 cells treated with HG and MT, while mt-dsRNA release from the mitochondria to the cytoplasm and cell apoptosis were decreased, but cell apoptosis was further amplified by PNPase siRNA and partially blocked by C16.
CONCLUSION: These data suggest that mitochondria-targeted antioxidant MT reduces mtROS overproduction and prevents tubular injury in DN by inhibiting mt-dsRNA release and PKR/eIF2α pathway activation.

Keywords:  Diabetic nephropathy; Mito-tempo; Tubular injury; mt-dsRNA; mtROS

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.431
Nat Commun. 2025 Jun 02. 16(1): 5101

Myocardial mitochondrial antiviral signaling protein promotes heart Ischemia-reperfusion injury via RIG-I signaling in mice.

Zhenyu Kang, Mengling Yang, Yue Liu, Yang Gui, Yalan Dong, Haifeng Zhou, Zili Zhang, Mingyue Li, Heng Fan, Zheng Li, Junjie Lu, Junyi Li, Rui Zhu, Chengyu Yin, Boyi Liu, Feng Jiang, Kun Huang, Alexey Sarapultsev, Fangfei Li, Ge Zhang, Ling Zhao, Yanyi Wang, Yunjia Ning, Xiang Cheng, Sarajo K Mohanta, Changjun Yin, Shanshan Luo, Andreas J R Habenicht, Desheng Hu.

Myocardial ischemia-reperfusion injury (MIRI) is a life-threatening complication of myocardial infarcts, with inner mitochondrial membrane protein dysfunction involved in MIRI-induced heart injury. The role of outer mitochondrial membrane protein mitochondrial antiviral signaling protein (MAVS) is unknown. Here, we show that MAVS expression increases in infarcted myocardium of male wild-type mice. Global MAVS-knock-out or myocardial-specific MAVS knockdown protects male mice from acute and chronic MIRI. MIRI induces double-stranded RNA in affected myocardium, activating intracellular retinoic acid-inducible gene I (RIG-I) signaling, which leads to MAVS aggregation and subsequent non-canonical downstream signaling. MAVS aggregates recruit tumor necrosis factor-associated factor family 6 (TRAF6) and transforming growth factor-β-activated kinase 1 (TAK1), the activating mitogen-activated protein kinase (MAPK) pathway and apoptosis. MAVS-knock-out reduces c-jun-NH2 terminal kinase (JNK) phosphorylation and apoptosis. JNK inhibition protects against MIRI in wild-type male mice, whereas JNK agonist impairs protection in MAVS-knock-out male mice. MIRI activates RIG-I/MAVS pathway and subsequently triggers the TAK1/TRAF6 complex, leading to the activation of the MAPK/JNK signaling cascade. This sequential activation cascade may serve as a potential therapeutic target for MIRI.

DOI: https://doi.org/10.1038/s41467-025-60123-7
bioRxiv. 2025 May 19. pii: 2025.05.16.654474. [Epub ahead of print]

Parkin-dependent ubiquitination of TAX1BP1 directs efficient autophagic removal of defective mitochondria.

Anna Lechado-Terradas, Bianca Lemke, Katharina I Zittlau, Boris Macek, Philipp J Kahle.

In stressed cells, the recessive Parkinson disease (PD) associated gene products PINK1 and parkin mediate the autophagic removal of damaged mitochondria (mitophagy). Upon mitochondrial membrane potential disruption, PINK1 phosphorylation activates the ubiquitin ligase parkin which ubiquitinates various mitochondrial protein substrates. These feed-forward modifications on the mitochondria surface attract ubiquitin-binding autophagy receptors that target ubiquitinated mitochondria to autophagosomes and indirectly contribute to phagophore elongation. Investigating post-translational protein modifications during this process, we detected transient ubiquitination of K549 within the third coiled-coil domain (CC3) of TAX1BP1 in HeLa cells expressing WT but not catalytically inactive parkin. Parkin-dependent ubiquitination did not target TAX1BP1 to proteasomal degradation but was rather indicative of a regulatory modification. In cells with the full complement of autophagy receptors, TAX1BP1 plays only a minor role in mitophagy. However, when expressed as a sole autophagy receptor, both WT and ubiquitination deficient TAX1BP1 were capable of promoting mitophagy, albeit mitochondria degradation was slightly delayed under mutant conditions. Use of the lysosomal inhibitor bafilomycin A indicated classical autophagolysosomal targeting of damaged mitochondria mediated by WT TAX1BP1. However, for the ubiquitination-deficient TAX1BP1, we observed an increased prevalence of enlarged endolysosomal vesicles carrying accumulated TAX1BP1-positive autophagosomes filled with mitochondrial material. Thus, while ubiquitination of the CC3 domain of TAX1BP1 is not essential for complete mitophagy, the lack of CC3 in TAX1BP1 reroutes the degradation flux to a less efficient endolysosmal degradative pathway. Interestingly, the PD gene product VPS35, becomes prominently engaged in this alternative mitophagy pathway.

DOI: https://doi.org/10.1101/2025.05.16.654474
bioRxiv. 2025 May 23. pii: 2025.05.19.650489. [Epub ahead of print]

Rescuing Ischemic Brain Injury by Rewiring Mitochondrial Electron Flow.

Belem Yoval-Sánchez, Ivan Guerrero, Qiuying Chen, Sergei Sosunov, Fariha Ansari, Max Siragusa, Csaba Konrad, Zoya Niatsetskaya, Anna Stepanova, Anatoly A Starkov, Sergei Khruschev, Jordi Magrane, Arina A Nikitina, Oxana Bereshchenko, Ping Zhou, LiPing Zhou, Marten Szibor, Ilka Wittig, Giovanni Manfredi, Steven S Gross, Vadim Ten, Alexander Galkin.

Mitochondrial metabolic flux alterations are critical drivers of acute ischemia-reperfusion (IR) brain injury. Reverse electron transfer (RET), defined as the upstream flow of electrons from the quinone pool to complex I, is a major source of pathological reactive oxygen species (ROS) under stress conditions. Using an in vivo model of brain IR, we show that RET-supporting substrates - succinate and glycerol 3-phosphate - accumulate during oxygen deprivation. Rapid oxidation of these substrates by brain mitochondria upon reoxygenation drives massive ROS production, while also leading to over-reduction and dissociation of the complex I flavin mononucleotide (FMN) cofactor. The resulting FMN-deficient complex I becomes catalytically impaired, unable to oxidize NADH or to produce ROS. To mitigate RET and preserve complex I function, we used transgenic mice xenotopically expressing alternative oxidase (AOX). This enzyme bypasses complexes III and IV by directly oxidizing the reduced quinone pool and passing electrons onto molecular oxygen. AOX expression did not alter complex I abundance, supercomplexes assembly, or basal respiration rates, but effectively diverted electrons from the quinone pool, decreasing RET flux via complex I and limiting ROS generation during IR. This attenuation of RET preserved complex I FMN binding, suppressed oxidative stress, and conferred neuroprotection in vivo . Our findings reveal a novel strategy for rewiring mitochondrial electron flux to mitigate initial IR brain injury, highlighting modulation of the quinone pool by AOX as a potential therapeutic strategy for IR.

DOI: https://doi.org/10.1101/2025.05.19.650489
bioRxiv. 2025 May 14. pii: 2025.05.13.653730. [Epub ahead of print]

Single-cell RNA sequencing reveals distinct senotypes and a quiescence-senescence continuum at the transcriptome level following chemotherapy.

Brianna Fernandez, Victor Passanisi, Humza M Ashraf, Sabrina L Spencer.

Quiescence (reversible cell-cycle arrest) and senescence (irreversible arrest) are challenging to distinguish due to a lack of specific biomarkers, yet both arise simultaneously after chemotherapy. While senescence suppresses tumors by limiting proliferation and recruiting the immune system, quiescent cancer cells evade future therapies and may resume proliferation. Here, we pair time-lapse imaging of cell-cycle dynamics with single-cell RNA-sequencing after etoposide treatment to differentiate these states, linking heterogeneous cell-cycle phenotypes to the transcriptomic landscape. We identify diverse senescent types (senotypes) and link them to two arrest pathways - a gradual path arising after a standard mitosis-to-G0 transition, and a rarer but direct path driven by a mitotic slip. Using pseudotime trajectory analysis, we find that senescent phenotypes begin to manifest early and gradually along the first trajectory, even in shallow quiescent cells. These data support a model wherein, following chemotherapy, quiescence and senescence exist on a continuum of cell-cycle withdrawal at a transcriptome-wide level.

DOI: https://doi.org/10.1101/2025.05.13.653730
Mol Med. 2025 Jun 04. 31(1): 219

GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer's disease.

Xiaoqin Wang, Shijing Wu, Zhangjing Deng, Mengyu Yan, Dandan Wang, Maojun Yang, Fuxing Zhong, Jiaqi Song, Lihua Chen, Yingxi Chen, Qi Tian, Weihua Yu, Yang Lü.



Keywords:  Alzheimer’s disease; Apoptosis; Cyclophilin D; G protein-coupled receptor 43; Mitochondria; Neurons; Synapses

DOI:  https://doi.org/10.1186/s10020-025-01269-4