bims-nenemi 2025-07-13 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–07–13
twenty papers selected by
Marco Tigano, Thomas Jefferson University

Super-resolution microscopy of mitochondrial mRNAs.
Mitochondrial topoisomerases, nucleoid architecture and mtDNA repair in human disease.
FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.
Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.
D-RADA16 self-assembling peptide microneedle patches alleviate osteoarthritis inflammation by inhibiting mtDNA leakage-mediated cGAS-STING pathway.
Leber's hereditary optic neuropathy-associated ND1 3733G> C mutation ameliorates the mitochondrial quality control and cellular homeostasis.
The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence.
A molecular switch at the yeast mitoribosomal tunnel exit controls cytochrome b synthesis.
Combining phenomics with transcriptomics reveals cell-type-specific morphological and molecular signatures of the 22q11.2 deletion.
Organelles share the load.
ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
Understanding the mechanisms of mitochondrial rewiring during viral infections.
Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy.
PINK1 Loss of Function Selectively Alters the Mitochondrial-Derived Vesicle Pathway.
Multi-omics strategies to decode the molecular landscape of cellular senescence.
A Rare Molecular Diagnosis in a Patient With Hepatocerebral Syndrome Contributes to the Expansion of the Phenotypic Spectrum of POLG2-Related Mitochondrial Disorder.
Dynamin-like Proteins Combine Mechano-constriction and Membrane Remodeling to Enable Two-Step Mitochondrial Fission via a "Snap-through" Instability.
Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies.

Nat Commun. 2025 Jul 10. 16(1): 6391

Super-resolution microscopy of mitochondrial mRNAs.

Stefan Stoldt, Frederike Maass, Michael Weber, Sven Dennerlein, Peter Ilgen, Jutta Gärtner, Aysenur Canfes, Sarah V Schweighofer, Daniel C Jans, Peter Rehling, Stefan Jakobs.

Mitochondria contain their own DNA (mtDNA) and a dedicated gene expression machinery. As the mitochondrial dimensions are close to the diffraction limit of classical light microscopy, the spatial distribution of mitochondrial proteins and in particular of mitochondrial mRNAs remains underexplored. Here, we establish single-molecule fluorescence in situ hybridization (smFISH) combined with STED and MINFLUX super-resolution microscopy (nanoscopy) to visualize individual mitochondrial mRNA molecules and associated proteins. STED nanoscopy reveals the spatial relationships between distinct mRNA species and proteins such as the RNA granule marker GRSF1, demonstrating adaptive changes in mRNA distribution and quantity in challenged mammalian cells and patient-derived cell lines. Notably, STED-smFISH shows the release of mRNAs during apoptosis, while MINFLUX reveals the folding of the mRNAs into variable shapes, as well as their spatial proximity to mitochondrial ribosomes. These protocols are transferable to various cell types and open new avenues for understanding mitochondrial gene regulation in health and disease.

DOI: https://doi.org/10.1038/s41467-025-61577-5
J Cell Sci. 2025 Jul 01. pii: jcs263638. [Epub ahead of print]138(13):

Mitochondrial topoisomerases, nucleoid architecture and mtDNA repair in human disease.

Sangheeta Bhattacharjee, Benu Brata Das.

  DNA topoisomerases are essential for maintaining DNA topology, gene expression and the accurate transmission of genetic information. Mitochondria possess circular DNA (mtDNA), which, unlike nuclear chromosomes, lacks protective histones and exists in nucleoprotein complexes called nucleoids, which are vital for mtDNA stability. Although the mitochondrial genome encodes essential genes involved in ATP production via oxidative phosphorylation, it does not encode crucial mtDNA maintenance genes and depends entirely on nuclear-encoded proteins for mtDNA maintenance. These include nuclear-encoded topoisomerases (i.e. Top1mt, Top2α, Top2β and Top3α), which alleviate topological stress during mtDNA transcription and replication, and mitochondrial transcription factor A (TFAM), are crucial for ensuring proper nucleoid structure and mtDNA packaging. Furthermore, tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) participate in the repair of mtDNA damage associated with trapped topoisomerase-mtDNA complexes, which can compromise mtDNA integrity and contribute to neurodegeneration, cancer and premature aging. Drugs that stabilize these protein-DNA adducts (PDAs) to induce mtDNA damage and mitochondrial dysfunction are promising new strategies for cancer therapy. This Review explores the essential roles of mitochondrial topoisomerases, overviews mechanisms involved in mtDNA repair and discusses how mitochondrial fission and mitophagy are employed as a survival strategy for clearing damaged mtDNA.

Keywords:  DNA repair; Mitochondria; Mitochondrial DNA; Neurological diseases; TDP1; TFAM; Topoisomerase 1

DOI:  https://doi.org/10.1242/jcs.263638
Nucleic Acids Res. 2025 Jul 08. pii: gkaf665. [Epub ahead of print]53(13):

FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.

Hana Antonicka, Ana Vučković, Woranontee Weraarpachai, Seungwoo Hong, Michele Brischigliaro, Ahram Ahn, Antoni Barrientos, Hauke S Hillen, Eric A Shoubridge.

The first post-transcriptional step in mammalian mitochondrial gene expression, required for the synthesis of the 13 polypeptides encoded in mitochondrial DNA (mtDNA), is endonucleolytic cleavage of the primary polycistronic transcripts. Excision of the mtDNA-encoded transfer RNAs (tRNAs) releases most mature RNAs; however, processing of three noncanonical messenger RNAs (mRNAs) not flanked by tRNAs (CO1, CO3, and CYB) requires FASTKD5. To investigate the molecular mechanism involved, we created knockout human cell lines to use as assay systems. The absence of FASTKD5 produced a severe OXPHOS assembly defect due to the inability to translate two unprocessed noncanonical mRNAs and predicted altered folding patterns specifically at the 5'-end of the CO1 coding sequence. Structural features 13-15 nt upstream of the CO1 and CYB cleavage sites suggest FASTKD5 recognition mechanisms. Remarkably, a map of essential FASTKD5 amino acid residues revealed RNA substrate specificity; however, a key, putative active site residue was required for processing all three noncanonical pre-RNAs. Mutating this site did not significantly alter the binding of any client RNA substrate. A reconstituted in vitro system showed that wild-type, but not mutant, FASTKD5, was able to cleave client substrates correctly. These results establish FASTKD5 as the missing piece of biochemical machinery required to completely process the primary mitochondrial transcript.

DOI: https://doi.org/10.1093/nar/gkaf665
J Cell Sci. 2025 Jul 01. pii: jcs263701. [Epub ahead of print]138(13):

MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.

Michal Wasilewski, Karthik Mohanraj, Maciej Zakrzewski, Remigiusz A Serwa, Agnieszka Chacinska.

  Most mitochondrial proteins are imported through the actions of the presequence translocase of the inner membrane, the TIM23 complex, which requires energy in the form of the electrochemical potential of the inner membrane and ATP. Conversions of energy in mitochondria are disturbed in mitochondrial disorders that affect oxidative phosphorylation. Despite the widely accepted dependence of protein import into mitochondria on mitochondrial bioenergetics, effects of mitochondrial disorders on biogenesis of the mitochondrial proteome are poorly characterized. Here, we describe molecular tools that can be used to explore mitochondrial protein import in intact cells, the mitoRUSH assay, and a novel method based on labeling of nascent proteins with an amino acid analog and click chemistry. Using these orthogonal approaches, we discovered that defects in the electron transport chain and manipulating the expression of TIMM23, as well as the TIMM17A or TIMM17B paralogs, in human cells are associated with a decrease in protein import into mitochondria. We postulate that in the absence of a functional electron transfer chain, the mechanisms that support electrochemical potential of the inner membrane and ATP production are insufficient to sustain the import of proteins to mitochondria.

Keywords:  Bioenergetics; Mitochondria; Mitochondrial diseases; Protein import; TIM23; Translocase; mitoRUSH

DOI:  https://doi.org/10.1242/jcs.263701
Cell Rep. 2025 Jul 01. pii: S2211-1247(25)00693-X. [Epub ahead of print] 115922

Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.

Ichiro Katahira, Nina Liebrand, Michal Gorzkiewicz, Niklas Paul Klahm, Džiuljeta Abromavičiūtė, Julia Werner, Karina Stephanie Krings, Sarah Orywol, Tobias Lautwein, Karl Köhrer, Diran Herebian, Ertan Mayatepek, Max Anstötz, Ann Kathrin Bergmann, Arun Kumar Kondadi, Haifeng C Xu, Aleksandra A Pandyra, Takumi Kobayashi, Dirk Brenner, Thomas Floss, Ulrich Kalinke, Andreas S Reichert, Philipp A Lang.

  Virus-infected cells often exhibit dramatic cellular changes accompanied by altered mitochondrial function. The contribution of factors shaping the inner mitochondrial membrane (IMM) and cristae architecture to viral replication is insufficiently understood. Single-cell transcriptomics applying vesicular stomatitis virus infection suggests involvement of factors determining IMM architecture following infection. Consistently, inhibition of the F1FO adenosine triphosphate (ATP) synthase reduces viral replication, which is associated with oligomerization of this complex and altered IMM structure. Moreover, deletion of mitochondrial contact site and cristae organizing system (MICOS) complex by targeting MIC60 results in reduced viral replication. Generation of Mic60inv/invCD11c-Cre+ mice uncovers reduced crista junctions and viral replication in bone marrow-derived dendritic cells. Consequently, reduced viral replication in CD11c-expressing cells limits prolonged immune activation. Altogether, by linking the F1FO ATP synthase and the MICOS complex to viral replication and immune activation, we describe links between the mitochondrial structure-metabolism and the immune response against viral infection.

Keywords:  BMDC; CP: Cell biology; CP: Microbiology; MIC60; MICOS; immunometabolism; innate immunity; inner mitochondrial membrane; itaconate; mitochondria; viral infection

DOI:  https://doi.org/10.1016/j.celrep.2025.115922
PLoS Genet. 2025 Jul 07. 21(7): e1011773

Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.

Leonor Miller-Fleming, Wing Hei Au, Laura Raik, Pedro Rebelo-Guiomar, Jasper Schmitz, Ha Yoon Cho, Aron Czako, Alexander J Whitworth.

Mitochondria perform essential metabolic functions and respond rapidly to changes in metabolic and stress conditions. As the majority of mitochondrial proteins are nuclear-encoded, intricate post-transcriptional regulation is crucial to enable mitochondria to adapt to changing cellular demands. The eukaryotic Clustered mitochondria protein family has emerged as an important regulator of mitochondrial function during metabolic shifts. Here, we show that the Drosophila melanogaster and Saccharomyces cerevisiae Clu/Clu1 proteins form dynamic, membraneless, mRNA-containing granules adjacent to mitochondria in response to metabolic changes. Yeast Clu1 regulates the translation of a subset of nuclear-encoded mitochondrial proteins by interacting with their mRNAs while these are engaged in translation. We further show that Clu1 regulates translation by interacting with polysomes, independently of whether it is in a diffuse or granular state. Our results demonstrate remarkable functional conservation with other members of the Clustered mitochondria protein family and suggest that Clu/Clu1 granules isolate and concentrate ribosomes engaged in translating their mRNA targets, thus, integrating metabolic signals with the regulation of mitochondrial protein synthesis.

DOI: https://doi.org/10.1371/journal.pgen.1011773
Int J Biol Macromol. 2025 Jul 04. pii: S0141-8130(25)06322-6. [Epub ahead of print] 145767

D-RADA16 self-assembling peptide microneedle patches alleviate osteoarthritis inflammation by inhibiting mtDNA leakage-mediated cGAS-STING pathway.

Ao Zhou, Yongle Wu, Yuzhang An, Jiaxin Kuang, Jianchuan Shu, Wen Dong, Yuchen Tang, Qiufu Wang, Rong Gao, Zhenming Hu, Kai Li, Fangzhou Song.

  Mitochondrial DNA (mtDNA) leakage and its activated cGAS-STING signaling pathway play a critical role in chronic inflammation of osteoarthritis (OA). However, how to effectively suppress mtDNA leakage and maintain joint homeostasis remains a huge challenge. This study proposes a synergistic strategy that combines the bioactive, extracellular matrix (ECM)-mimicking properties of D-RADA16 self-assembling peptides with the minimally invasive, localized delivery capabilities of a dissolvable microneedle patch (MNP). The resulting D-RADA16@MNP system forms a nanofibrous ECM-like microenvironment that promotes mitochondrial stability, limits mtDNA leakage, and modulates cGAS-STING-mediated inflammation. Compared with conventional intra-articular injections or NSAID therapy, D-RADA16@MNP enables precise, sustained, and patient-friendly transdermal delivery to inflamed joints. This synergistic interaction between the ECM-mimicking scaffold and the transdermal microneedle platform gives rise to a localized "cell safe-house" effect, which stabilizes the mitochondrial microenvironment, reduces mtDNA leakage, and suppresses inflammatory signaling. This study not only expands the biomedical application of D-form self-assembling peptides, but also provides a promising direction for the treatment of chronic inflammatory joint diseases.

Keywords:  Microneedle patch; Osteoarthritis; Self-assembling peptide; cGAS-STING pathway; mtDNA leakage

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145767
J Biol Chem. 2025 Jul 08. pii: S0021-9258(25)02314-2. [Epub ahead of print] 110464

Leber's hereditary optic neuropathy-associated ND1 3733G> C mutation ameliorates the mitochondrial quality control and cellular homeostasis.

Meiheriayi Yasheng, Yanchun Ji, Yunfan He, Qiuzi Yi, Huanhuan Zhang, Wenqi Shan, Kai Wang, Juanjuan Zhang, Ya Li, Feilong Meng, Minglian Zhang, Jun Qin Mo, Shihui Wei, Min-Xin Guan.

Leber's hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying LHON-linked mtDNA mutations, especially their impact on mitochondrial and cellular integrity, is not well understood. Recently, the ND1 3733G>C (p.E143Q) mutation was identified in three Chinese pedigrees with suggestively maternal inheritance of LHON. In this study, we investigated the pathogenic mechanism of m.3733G>C mutation using cybrids generated by fusing mtDNA-less ρ0 cells with enucleated cells from a Chinese patient carrying the m.3733G>C mutation and control subject. Molecular dynamics simulations showed that p.E143Q mutation destabilized these interactions between residues E143 and S110/Y114, or between S141 and W290 in the ND1. Its impact of ND1 structure and function was further evidenced by reduced levels of ND1 in mutant cells. The m.3733G>C mutation caused defective assembly and activity of complex I, respiratory deficiency, diminished mitochondrial ATP production, and increased production of mitochondrial ROS in the mutant cybrids carrying the m.3733G>C mutation. These mitochondrial dysfunctions regulated mitochondrial quality control via mitochondrial dynamics and mitophagy. The m.3733G>C mutation-induced dysfunction yielded elevating mitochondrial localization of DRP1, decreasing network connectivity and increasing fission with abnormal morphologies. Furthermore, the m.3733G>C mutation downregulated ubiquitin-dependent mitophagy pathway, evidenced by decreasing the levels of Parkin and Pink, but not ubiquitin-independent mitophagy pathway. The m.3733G>C mutation-induced deficiencies reshaped the cellular homeostasis via impairing autophagy process and promoting intrinsic apoptosis. Our findings provide new insights into pathophysiology of LHON arising from the m.3733G>C mutation-induced mitochondrial dysfunctions and reprograming organellular and cellular homeostasis.

DOI: https://doi.org/10.1016/j.jbc.2025.110464
Elife. 2025 Jul 07. pii: RP101984. [Epub ahead of print]13

The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence.

Fan Zhang, Yuan Wang, Luyang Zhang, Chunjie Wang, Deping Chen, Haibo Liu, Ren Xu, Cole M Haynes, Jae-Hyuck Shim, Xianpeng Ge.

  The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, the elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway, such as in lysosomal storage diseases. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.

Keywords:  CHMP5; bone; cell biology; cell senescence; endolysosomal pathway; medicine; mouse; musculoskeletal disease; skeletal stem cell

DOI:  https://doi.org/10.7554/eLife.101984
Nucleic Acids Res. 2025 Jul 08. pii: gkaf634. [Epub ahead of print]53(13):

A molecular switch at the yeast mitoribosomal tunnel exit controls cytochrome b synthesis.

Andreas Carlström, Joseph B Bridgers, Mary Couvillion, Abeer Prakash Singh, Ignasi Forné, Axel Imhof, L Stirling Churchman, Martin Ott.

Mitochondrial gene expression needs to be balanced with cytosolic translation to produce oxidative phosphorylation complexes. In yeast, translational feedback loops involving lowly expressed proteins called translational activators help to achieve this balance. Synthesis of cytochrome b (Cytb or COB), a core subunit of complex III in the respiratory chain, is controlled by three translational activators and the assembly factor Cbp3-Cbp6. However, the molecular interface between the COB translational feedback loop and complex III assembly is yet unknown. Here, using protein-proximity mapping combined with selective mitoribosome profiling, we reveal the components and dynamics of the molecular switch controlling COB translation. Specifically, we demonstrate that Mrx4, a previously uncharacterized ligand of the mitoribosomal polypeptide tunnel exit, interacts with either the assembly factor Cbp3-Cbp6 or with the translational activator Cbs2. These reciprocal interactions determine whether the translational activator complex with bound COB messenger RNA (mRNA) can interact with the mRNA channel exit on the small ribosomal subunit for translation initiation. Organization of the feedback loop at the tunnel exit therefore orchestrates mitochondrial translation with respiratory chain biogenesis.

DOI: https://doi.org/10.1093/nar/gkaf634
Nat Commun. 2025 Jul 09. 16(1): 6332

Combining phenomics with transcriptomics reveals cell-type-specific morphological and molecular signatures of the 22q11.2 deletion.

Matthew Tegtmeyer, Dhara Liyanage, Yu Han, Kathryn B Hebert, Ruifan Pei, Gregory P Way, Pearl V Ryder, Derek Hawes, Callum Tromans-Coia, Beth A Cimini, Anne E Carpenter, Shantanu Singh, Ralda Nehme.

Neuropsychiatric disorders remain difficult to treat due to complex and poorly understood mechanisms. NeuroPainting is a high-content morphological profiling assay based on Cell Painting and optimized for human stem cell-derived neural cell types, including neurons, progenitors, and astrocytes. The assay quantifies over 4000 features of cell structure and organelle organization, generating a dataset suitable for phenotypic screening in neural models. Here, we show that, in studies of the 22q11.2 deletion-a strong genetic risk factor for schizophrenia-we observe cell-type-specific effects, particularly in astrocytes, including mitochondrial disruption, altered endoplasmic reticulum organization, and cytoskeletal changes. Transcriptomic analysis shows reduced expression of cell adhesion genes in deletion astrocytes, consistent with post-mortem brain data. Integration of RNA and morphology data suggests a link between adhesion gene dysregulation and mitochondrial abnormalities. These results illustrate how combining image-based profiling with gene expression analysis can reveal cellular mechanisms associated with genetic risk in neuropsychiatric disease.

DOI: https://doi.org/10.1038/s41467-025-61547-x
Science. 2025 Jul 10. 389(6756): 130-131

Organelles share the load.

Marc Fransen.

Peroxisome-mitochondria contact sites manage mitochondrial oxidative stress.

DOI: https://doi.org/10.1126/science.adz0109
Science. 2025 Jul 10. 389(6756): 157-162

ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.

Laura F DiGiovanni, Prabhsimran K Khroud, Ruth E Carmichael, Tina A Schrader, Shivneet K Gill, Kyla Germain, Robert Y Jomphe, Christoph Wiesinger, Maxime Boutry, Maki Kamoshita, Daniel Snider, Garret Stubbings, Rong Hua, Noel Garber, Christian Hacker, Andrew D Rutenberg, Roman A Melnyk, Johannes Berger, Michael Schrader, Brian Raught, Peter K Kim.

Maintenance of mitochondrial redox homeostasis is of fundamental importance to cellular health. Mitochondria harbor a host of intrinsic antioxidant defenses, but the contribution of extrinsic, nonmitochondrial antioxidant mechanisms is less well understood. We found a direct role for peroxisomes in maintaining mitochondrial redox homeostasis through contact-mediated reactive oxygen species (ROS) transfer. We found that ACBD5 and PTPIP51 form a contact between peroxisomes and mitochondria. The percentage of these contacts increased during mitochondrial oxidative stress and helped to maintain mitochondrial health through the transfer of mitochondrial ROS to the peroxisome lumen. Our findings reveal a multiorganelle layer of mitochondrial antioxidant defense-suggesting a direct mechanism by which peroxisomes contribute to mitochondrial health-and broaden the scope of known membrane contact site functions.

DOI: https://doi.org/10.1126/science.adn2804
J Gen Virol. 2025 Jul;106(7):

Understanding the mechanisms of mitochondrial rewiring during viral infections.

Marta Lopez-Nieto, Nicolas Locker.

  As intracellular parasites, viruses must hijack and often rewire organelles, signalling pathways and the bioenergetics machinery of the infected cell to replicate their genome, produce viral proteins and assemble new viral particles. Mitochondria are key eukaryotic organelles often referred to as the cell's powerhouse. They control many fundamental cellular processes, from metabolism and energy production to calcium homeostasis and programmed cell death. Importantly, mitochondrial membranes are also critical sites for the integration and amplification of antiviral innate immune responses. Overall, mitochondria are therefore both supporting the virus life cycle by sustaining energy production, metabolism and synthesis of macromolecules and part of the cell's first line of defence against viruses. This review summarizes recent findings on viral manipulations of mitochondria and their functions. We explore the evolving understanding of how mitochondrial dynamics is targeted to regulate innate immunity, evasion strategies used to avoid mitochondrial-associated mechanisms that impair replication and the role of mitochondrial functions such as generating reactive oxygen species or regulating the electron transport chain during infection. Overall, we provide a comprehensive view of how viruses modulate mitochondrial function to promote replication.

Keywords:  innate immunity; mitochondria; mitochondrial unfolded protein response (UPRmt)

DOI:  https://doi.org/10.1099/jgv.0.002128
Nature. 2025 Jul 09.

Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy.

Guangbin Shi, Claire Miller, Sota Kuno, Alejandro G Rey Hipolito, Salsabiel El Nagar, Giulietta M Riboldi, Megan Korn, Wyatt C Tran, Zixuan Wang, Lia Ficaro, Tao Lin, Quentin Spillier, Begoña Gamallo-Lana, Drew R Jones, Matija Snuderl, Soomin C Song, Adam C Mar, Alexandra L Joyner, Roy V Sillitoe, Robert S Banh, Michael E Pacold.

Decreased brain levels of coenzyme Q10 (CoQ10), an endogenously synthesized lipophilic antioxidant1,2, underpin encephalopathy in primary CoQ10 deficiencies3,4 and are associated with common neurodegenerative diseases and the ageing process5,6. CoQ10 supplementation does not increase CoQ10 pools in the brain or in other tissues. The recent discovery of the mammalian CoQ10 headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ10 headgroup precursor 4-hydroxybenzoate (4-HB)7, offers an opportunity to pharmacologically restore CoQ10 synthesis and mechanistically treat CoQ10 deficiencies. To test whether 4-HMA or 4-HB supplementation promotes CoQ10 headgroup synthesis in vivo, here we administered 4-HMA and 4-HB to Hpdl-/- mice, which model an ultra-rare, lethal mitochondrial encephalopathy in humans. Both 4-HMA and 4-HB were incorporated into CoQ9 and CoQ10 in the brains of Hpdl-/- mice. Oral treatment of Hpdl-/- pups with 4-HMA or 4-HB enabled 90-100% of Hpdl-/- mice to live to adulthood. Furthermore, 4-HB treatment stabilized and improved the neurological symptoms of a patient with progressive spasticity due to biallelic HPDL variants. Our work shows that 4-HMA and 4-HB can modify the course of mitochondrial encephalopathy driven by HPDL variants and demonstrates that CoQ10 headgroup intermediates can restore CoQ10 synthesis in vivo.

DOI: https://doi.org/10.1038/s41586-025-09246-x
FASEB Bioadv. 2025 Jul;7(7): e70030

PINK1 Loss of Function Selectively Alters the Mitochondrial-Derived Vesicle Pathway.

Charlotte L Collier, Colleen Ruedi, Naomi J Thorne, David A Tumbarello.

  Cell homeostasis and metabolic control require the efficient function of mitochondria and implementation of quality control pathways following damage. Cells have various discrete pathways of mitochondrial quality control (mitoQC) to maintain the healthy network. PINK1 and Parkin are two key players in mitoQC, most highly associated with the ubiquitin-dependent capture and degradation of whole mitochondria by autophagy. However, these proteins have alternative roles in repair routes directing locally damaged cargo to the lysosome, such as the mitochondrial-derived vesicle (MDV) pathway. We aimed to clarify the role of PINK1 and determine how its loss of function impacts mitochondrial dynamics and quality control. Results indicate PINK1 knockout (KO) has little impact on whole mitochondrial turnover in response to damage in SH-SY5Y cells, whereas both PINK1 and Parkin KO cells have healthy mitochondrial networks with efficient ATP production. However, TOM20 positive outer-membrane and damage-induced PDH-positive inner-membrane MDVs are elevated in PINK1 KO cells. Although, in contrast to Parkin KO, this is not due to a defect in trafficking to a LAMP1-positive compartment and may instead indicate increased damage-induced flux. In comparison, loss of Atg5-dependent mitophagy has no effect on whole mitochondrial turnover and only results in a limited elevation in inner-membrane MDVs in response to damage, indicating autophagy-independent mechanisms of whole mitochondrial turnover and a minor compensatory increase in damage-induced MDVs. Therefore, these data suggest PINK1 and Parkin are dispensable for whole mitochondrial turnover, but following their perturbation have disparate effects on the MDV pathway.

Keywords:  Parkinson's; lysosome; membrane trafficking; mitochondria; mitochondrial quality control; vesicle transport

DOI:  https://doi.org/10.1096/fba.2024-00200
Ageing Res Rev. 2025 Jul 05. pii: S1568-1637(25)00170-9. [Epub ahead of print]111 102824

Multi-omics strategies to decode the molecular landscape of cellular senescence.

Manuela Giovanna Basilicata, Eduardo Sommella, Lucia Scisciola, Giovanni Tortorella, Marco Malavolta, Chiara Giordani, Michelangela Barbieri, Pietro Campiglia, Giuseppe Paolisso.

  Cellular senescence is a conserved cellular program characterized by a permanent cell cycle arrest triggered by a variety of stressors. Originally described as a tumor-suppressive mechanism, it is now recognized to exert pleiotropic and context-dependent functions, contributing to key physiological processes such as embryogenesis and tissue repair, as well as to processes associated with aging and the development of age-related diseases. Unlike normal cells, senescent cells remain metabolically active despite their non-dividing state. They significantly impact their environment through the Senescence-Associated Secretory Phenotype (SASP), a complex mix of cytokines, growth factors, and proteases. This secretory profile can promote tissue repair and regeneration but, if persistent, contributes to chronic inflammation, fibrosis, and tissue dysfunction. Two major pathways primarily regulate senescence: the p53/p21 and p16^INK4a^/Rb axes. These respond to stress signals like DNA damage, oxidative stress, and oncogenic activation, enforcing stable cell cycle arrest to prevent uncontrolled proliferation. However, as senescent cells accumulate over time, their ongoing SASP activity disrupts tissue homeostasis, driving inflammation and age-related diseases. Recent advances in multi-omics technologies, including metabolomics, proteomics, and lipidomics, have provided deeper insights into the complex molecular changes within senescent cells, revealing new biomarkers and potential therapeutic targets. These approaches offer a comprehensive understanding of cellular senescence, but challenges remain in distinguishing the causal relationships within these data and translating findings into clinical applications. This review integrates recent multi-omics discoveries, highlighting their potential to refine our understanding of senescence and support the development of targeted interventions to extend healthspan and combat age-related pathologies.

Keywords:  Aging mechanisms; Metabolic dysregulation; Multi-omics technologies; Senescence

DOI:  https://doi.org/10.1016/j.arr.2025.102824
Am J Med Genet A. 2025 Jul 09. e64177

A Rare Molecular Diagnosis in a Patient With Hepatocerebral Syndrome Contributes to the Expansion of the Phenotypic Spectrum of POLG2-Related Mitochondrial Disorder.

Vittoria Rossi, Dan Brooks, Hongzheng Dai, Elizabeth Mizerik, Karla Salazar, Daniel Davila-Williams, Yishay Ben-Moshe, Seema R Lalani, Sarah H Elsea, Charul Gijavanekar, Daryl A Scott, Keren Machol, Mir Reza Bekheirnia, Fernando Scaglia.

  POLG2 encodes an accessory subunit in DNA polymerase gamma that is required for mitochondrial DNA synthesis. Monoallelic pathogenic variants in POLG2 are associated primarily with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 4 (PEOA4, MIM #610131). We report a rare case of severe infantile hepatocerebral syndrome associated with biallelic variants in POLG2. The proband, a 5-week-old female infant, presented with seizures and acute liver failure. Extensive metabolic workup, including untargeted metabolomics analysis and elevated plasma growth differentiation factor 15, was suggestive of mitochondrial dysfunction. Rapid trio genome sequencing identified compound heterozygous variants, a likely pathogenic variant and a variant of uncertain significance in POLG2. This case expands the clinical phenotype associated with POLG2-related mitochondrial disease to include a severe hepatocerebral syndrome manifesting in early childhood. This case underscores the utility of integrated genomic and metabolomic analyses in diagnosing rare and complex mitochondrial disorders. These findings also emphasize the importance of considering POLG2-related mitochondrial disease in the differential diagnosis of infants presenting with liver failure and neurological symptoms and enhance our understanding of the phenotypic spectrum associated with this disorder.

Keywords:   POLG2 ; liver failure; mitochondrial DNA replication; mitochondrial disorder; untargeted metabolomics analysis

DOI:  https://doi.org/10.1002/ajmg.a.64177
J Am Chem Soc. 2025 Jul 08.

Dynamin-like Proteins Combine Mechano-constriction and Membrane Remodeling to Enable Two-Step Mitochondrial Fission via a "Snap-through" Instability.

Haleh Alimohamadi, Elizabeth Wei-Chia Luo, Xiaoying Liu, Wasi Iqbal, Rena Yang, Shivam Gupta, Kelsey A Nolden, Taraknath Mandal, R Blake Hill, Liting Duan, Gerard C L Wong.

Mitochondrial fission is controlled by dynamin-like proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamin-like proteins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membranes to achieve fission while also remodeling membranes by inducing negative Gaussian curvature, which is essential for the completion of fission. Despite advances in optical and electron imaging technologies, the underlying mechanics of mitochondrial fission remain unclear due to the multiple times involved in the dynamics of mechanoenzyme activity, oligomer disassembly, and membrane remodeling. Here, we examine how multiscale phenomena in dynamin Drp1 synergistically influence membrane fission using a mechanical model calibrated with small-angle X-ray scattering structural data and informed by a machine learning analysis of the Drp1 sequence, and tested the concept using optogenetic mechanostimulation of mitochondria in live cells. We find that free dynamin-like proteins can trigger a "snap-through instability" that enforces a shape transition from an oligomer-confined cylindrical membrane to a drastically narrower catenoid-shaped neck within the spontaneous hemi-fission regime, in a manner that depends critically on the length of the confined tube. These results indicate how the combination of assembly and paradoxically disassembly of dynamin-like proteins can lead to diverse pathways to scission.

DOI: https://doi.org/10.1021/jacs.5c06352
Biogerontology. 2025 Jul 09. 26(4): 142

Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies.

Pei Wei, Xiaoyan Zhang, Chi Yan, Siyu Sun, Zhigang Chen, Fei Lin.

  Aging is an inherent phenomenon that is highly important in the pathological development of numerous diseases. Aging is a multidimensional phenomenon characterized by the progressive impairment of various cellular structures and organelle functions. The basis of human organ senescence is cellular senescence. Currently, with the increase in human life expectancy and the increasing proportion of the elderly population, the economic burden of diseases related to aging is becoming increasingly heavy worldwide, and an in-depth study of the mechanism of cellular aging is urgently needed. Aging, a multifactor-driven biological process, is closely related to mitochondrial dysfunction, which is the core pathological basis of a variety of age-related diseases. This article systematically reviews the molecular pathways by which mitochondrial dysfunction drives aging through multidimensional mechanisms such as metabolic reprogramming, epigenetic regulation, telomere damage, autophagy imbalance, and the senescence-associated secretory phenotype. Metabolic reprogramming promotes tumor progression and exacerbates energy metabolism disorders through abnormal activation of the PI3K/Akt/mTOR signaling pathways. The sirtuin family (such as SIRT1 and SIRT3) maintains mitochondrial homeostasis by regulating PGC-1α, FOXO3 and other targets. Telomere shortening directly inhibits mitochondrial biosynthesis through the p53-PGC-1α axis, leading to oxidative stress accumulation and a decline in organ function. The dual roles of autophagy (removing damaged mitochondria or inducing apoptosis) suggests that its homeostasis is essential for delaying aging. The SASP mediates the inflammatory microenvironment through the cGAS‒STING pathway, which is not only a marker of aging but also a driving force of disease progression. Future studies need to integrate multiomics techniques to analyze the interaction network between mitochondria and other organelles, such as the endoplasmic reticulum and lysosomes, and explore precise intervention strategies targeting sirtuins, AMPK and telomerase. Combined therapies targeting metabolic reprogramming or SASP inhibition are expected to provide new ideas for delaying aging and preventing age-related diseases.

Keywords:  Aging; Autophagy; Epigenetic regulation; Metabolic reprogramming; Mitochondria; Telomere dysfunction

DOI:  https://doi.org/10.1007/s10522-025-10273-4