bims-nenemi 2025-02-09 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–02–09
nine papers selected by
Marco Tigano, Thomas Jefferson University

Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance.
RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release.
Activating AMPK improves pathological phenotypes due to mtDNA depletion.
Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans.
Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders.
The unusual suspect: A novel role for intermediate filament proteins in mitochondrial morphology.
Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.

EMBO Rep. 2025 Jan 31.

Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance.

Akshaya Seshadri, Anjana Badrinarayanan.

  Mitochondrial DNA (mtDNA) replication is essential for mitochondrial function. This is carried out by a dedicated DNA polymerase gamma, with 5'-3' polymerase and 3'-5' proofreading/ exonuclease activity. Perturbations to either property can have pathological consequences. Predominant sources for replication stress are DNA lesions, such as those induced by oxidative damage. How mtDNA lesions affect the polymerase activity and mtDNA stability in vivo is not fully understood. To address this, we induce mtDNA-specific damage in S. cerevisiae. We observe that mtDNA damage results in significant mtDNA loss. This loss occurs independent of cell cycle progression or cell division, suggesting an active mechanism for damaged mtDNA clearance. We implicate the 3'-5' exonuclease activity of the mtDNA polymerase in this clearance, with rates of loss being affected by cellular dNTP levels. Overall, our findings reveal context-dependent, selective regulation of two critical but opposing functions of polymerase gamma to ensure mitochondrial genome integrity.

Keywords:  DNA Replication; Mip1; PolG; Proofreading; mtDNA Damage

DOI:  https://doi.org/10.1038/s44319-025-00380-1
Mol Cell. 2025 Feb 04. pii: S1097-2765(25)00079-6. [Epub ahead of print]

RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release.

Sujin Kim, Stephanie Tan, Jayoung Ku, Tria Asri Widowati, Doyeong Ku, Keonyong Lee, Kwontae You, Yoosik Kim.

DOI: https://doi.org/10.1016/j.molcel.2025.01.029
FEBS J. 2025 Feb 07.

Activating AMPK improves pathological phenotypes due to mtDNA depletion.

Gustavo Carvalho, Tran V H Nguyen, Bruno Repolês, Josefin M E Forslund, W M Ruchitha Rukmal Wijethunga, Farahnaz Ranjbarian, Isabela C Mendes, Choco Michael Gorospe, Namrata Chaudhari, Micol Falabella, Mara Doimo, Sjoerd Wanrooij, Robert D S Pitceathly, Anders Hofer, Paulina H Wanrooij.

  AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that also plays a role in preserving mitochondrial function and integrity. Upon a disturbance in the cellular energy state that increases AMP levels, AMPK activity promotes a switch from anabolic to catabolic metabolism to restore energy homeostasis. However, the level of severity of mitochondrial dysfunction required to trigger AMPK activation is currently unclear, as is whether stimulation of AMPK using specific agonists can improve the cellular phenotype following mitochondrial dysfunction. Using a cellular model of mitochondrial disease characterized by progressive mitochondrial DNA (mtDNA) depletion and deteriorating mitochondrial metabolism, we show that mitochondria-associated AMPK becomes activated early in the course of the advancing mitochondrial dysfunction, before any quantifiable decrease in the ATP/(AMP + ADP) ratio or respiratory chain activity. Moreover, stimulation of AMPK activity using the specific small-molecule agonist A-769662 alleviated the mitochondrial phenotypes caused by the mtDNA depletion and restored normal mitochondrial membrane potential. Notably, the agonist treatment was able to partially restore mtDNA levels in cells with severe mtDNA depletion, while it had no impact on mtDNA levels of control cells. The beneficial impact of the agonist on mitochondrial membrane potential was also observed in cells from patients suffering from mtDNA depletion. These findings improve our understanding of the effects of specific small-molecule activators of AMPK on mitochondrial and cellular function and suggest a potential application for these compounds in disease states involving mtDNA depletion.

Keywords:  AMPK; AMP‐activated protein kinase; mitochondrial DNA depletion; polymerase ɣ

DOI:  https://doi.org/10.1111/febs.70006
bioRxiv. 2025 Jan 23. pii: 2025.01.22.634344. [Epub ahead of print]

Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans.

Avijit Mallick, Yunguang Du, Theresa Ramalho, Rui Li, Levi Ali, Sookyung Kim, Lihua Julie Zhu, Cole M Haynes.

The mitochondrial unfolded protein response (UPR mt ) is regulated by the bZIP protein ATFS-1 which promotes mitochondrial protein homeostasis (proteostasis) and mitochondrial biogenesis in Caenorhabditis elegans . Upon mitochondrial perturbation, the ATFS-1-dependent transcriptional program promotes gene expression, leading to mitochondrial recovery. Conversely, atfs-1 -deletion worms harbor dysfunctional mitochondria, are developmentally impaired, and short-lived. However, atfs-1 -deletion worms develop to adults suggesting the presence of other signaling pathways that promote mitochondrial function and biogenesis in the absence of atfs-1 . We hypothesized that additional transcription factors regulate, or promote, mitochondrial function in the absence of atfs-1 . Here, we screened for transcription factors that could reduce the decline in mitochondrial function in the atfs-1 mutants when inhibited. Here, we demonstrate that inhibition of the nuclear hormone receptor NHR-180 re-establishes a functional mitochondrial network in atfs-1(null) worms, increases mtDNA content, and improves the developmental rate of wildtype worms. NHR-180 increases transcription of genes required for cytosolic protein synthesis in response to mitochondrial perturbation. Inhibition of the S6 kinase homolog, rsks-1 , in atfs-1(null) worms leads to a recovery of the mitochondrial network and mtDNA content consistent with nhr-180 regulating expression of protein synthesis components. Consistent with the observations in C. elegans , S6 kinase inhibition also increased mitochondrial biogenesis in mammalian atf5 -knockout cells that harbor severely impaired mitochondria. Intriguingly, nhr-180 or S6 kinase inhibition also rescues mitochondrial dysfunction caused by mutations in multiple genes required for oxidative phosphorylation. Combined, these studies suggest that increased protein synthesis contributes to the mitochondrial dysfunction caused by perturbations in OXPHOS gene expression and suggest a relatively straightforward approach to reducing the impact of mitochondrial dysfunction.

DOI: https://doi.org/10.1101/2025.01.22.634344
Science. 2025 Feb 06. eadf2034

Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.

Emily M Walker, Gemma L Pearson, Nathan Lawlor, Ava M Stendahl, Anne Lietzke, Vaibhav Sidarala, Jie Zhu, Tracy Stromer, Emma C Reck, Jin Li, Elena Levi-D'Ancona, Mabelle B Pasmooij, Dre L Hubers, Aaron Renberg, Kawthar Mohamed, Vishal S Parekh, Irina X Zhang, Benjamin Thompson, Deqiang Zhang, Sarah A Ware, Leena Haataja, Nathan Qi, Stephen C J Parker, Peter Arvan, Lei Yin, Brett A Kaufman, Leslie S Satin, Lori Sussel, Michael L Stitzel, Scott A Soleimanpour.

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.

DOI: https://doi.org/10.1126/science.adf2034
J Neuroinflammation. 2025 Feb 07. 22(1): 34

Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders.

Guangming Zhang, Huayuan Wei, Anliu Zhao, Xu Yan, Xiaolu Zhang, Jiali Gan, Maojuan Guo, Jie Wang, Fayan Zhang, Yifang Jiang, Xinxing Liu, Zhen Yang, Xijuan Jiang.

  Mitochondrial dysfunction is a pivotal instigator of neuroinflammation, with mitochondrial DNA (mtDNA) leakage as a critical intermediary. This review delineates the intricate pathways leading to mtDNA release, which include membrane permeabilization, vesicular trafficking, disruption of homeostatic regulation, and abnormalities in mitochondrial dynamics. The escaped mtDNA activates cytosolic DNA sensors, especially cyclic gmp-amp synthase (cGAS) signalling and inflammasome, initiating neuroinflammatory cascades via pathways, exacerbating a spectrum of neurological pathologies. The therapeutic promise of targeting mtDNA leakage is discussed in detail, underscoring the necessity for a multifaceted strategy that encompasses the preservation of mtDNA homeostasis, prevention of membrane leakage, reestablishment of mitochondrial dynamics, and inhibition the activation of cytosolic DNA sensors. Advancing our understanding of the complex interplay between mtDNA leakage and neuroinflammation is imperative for developing precision therapeutic interventions for neurological disorders.

Keywords:  DNA sensors; Innate immunity; Neuroinflammation; Neurological disorders; mtDNA leakage

DOI:  https://doi.org/10.1186/s12974-025-03363-0
Mitochondrion. 2025 Feb 03. pii: S1567-7249(25)00005-4. [Epub ahead of print] 102008

The unusual suspect: A novel role for intermediate filament proteins in mitochondrial morphology.

Irene M G M Hemel, Carlijn Steen, Simon L I J Denil, Gökhan Ertaylan, Martina Kutmon, Michiel Adriaens, Mike Gerards.

  Mitochondrial dynamics is crucial for cellular homeostasis. However, not all proteins involved are known. Using a protein-protein interaction (PPI) approach, we identified ITPRIPL2 for involvement in mitochondrial dynamics. ITPRIPL2 co-localizes with intermediate filament protein vimentin, supported by protein simulations. ITPRIPL2 knockdown reveals mitochondrial elongation, disrupts vimentin processing, intermediate filament formation, and alters vimentin-related pathways. Interestingly, vimentin knockdown also leads to mitochondrial elongation. These findings highlight ITPRIPL2 as vimentin-associated protein essential for intermediate filament structure and suggest a role for intermediate filaments in mitochondrial morphology. Our study demonstrates that PPI analysis is a powerful approach for identifying novel mitochondrial dynamics proteins.

Keywords:  Intermediate filaments; Mitochondria; Mitochondrial dynamics; Network analysis; Protein-protein interactions

DOI:  https://doi.org/10.1016/j.mito.2025.102008
bioRxiv. 2025 Jan 23. pii: 2025.01.20.633997. [Epub ahead of print]

Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.

Sara Wong, Katherine R Bertram, Nidhi Raghuram, Thomas Knight, Adam L Hughes.

Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
Significance Statement: Mitochondrial-derived compartments are multilamellar structures that sequester protein and lipids of the outer mitochondrial membrane in response to metabolic and membrane perturbations, but it is largely unknown how membrane fluidity influences this pathway.Increased levels of unsaturated phospholipids may disrupt the TOM complex, a large multi-subunit complex on the outer mitochondrial membrane, to promote the formation of mitochondrial-derived compartments, while increased levels of saturated phospholipids inhibits formation of mitochondrial-derived compartments.These findings reveal a link between phospholipid composition and protein stress in driving mitochondrial-derived compartment biogenesis, and thus mitochondrial quality control.

DOI: https://doi.org/10.1101/2025.01.20.633997
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251316350

Mitochondrial-ER Contact Sites and Tethers Influence the Biosynthesis and Function of Coenzyme Q.

Noelle Alexa Novales, Hadar Meyer, Yeynit Asraf, Maya Schuldiner, Catherine F Clarke.

  Coenzyme Q (CoQ) is an essential redox-active lipid that plays a major role in the electron transport chain, driving mitochondrial ATP synthesis. In Saccharomyces cerevisiae (yeast), CoQ biosynthesis occurs exclusively in the mitochondrial matrix via a large protein-lipid complex, the CoQ synthome, comprised of CoQ itself, late-stage CoQ-intermediates, and the polypeptides Coq3-Coq9 and Coq11. Coq11 is suggested to act as a negative modulator of CoQ synthome assembly and CoQ synthesis, as its deletion enhances Coq polypeptide content, produces an enlarged CoQ synthome, and restores respiration in mutants lacking the CoQ chaperone polypeptide, Coq10. The CoQ synthome resides in specific niches within the inner mitochondrial membrane, termed CoQ domains, that are often located adjacent to the endoplasmic reticulum-mitochondria encounter structure (ERMES). Loss of ERMES destabilizes the CoQ synthome and renders CoQ biosynthesis less efficient. Here we show that deletion of COQ11 suppresses the respiratory deficient phenotype of select ERMES mutants, results in repair and reorganization of the CoQ synthome, and enhances mitochondrial CoQ domains. Given that ER-mitochondrial contact sites coordinate CoQ biosynthesis, we used a Split-MAM (Mitochondrial Associated Membrane) artificial tether consisting of an ER-mitochondrial contact site reporter, to evaluate the effects of artificial membrane tethers on CoQ biosynthesis in both wild-type and ERMES mutant yeast strains. Overall, this work identifies the deletion of COQ11 as a novel suppressor of phenotypes associated with ERMES deletion mutants and indicates that ER-mitochondria tethers influence CoQ content and turnover, highlighting the role of membrane contact sites in regulating mitochondrial respiratory homeostasis.

Keywords:  ER-mitochondrial encounter structure; artificial tether; coenzyme Q; mitochondria

DOI:  https://doi.org/10.1177/25152564251316350