bims-nenemi 2025-06-15 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–06–15
thirteen papers selected by
Marco Tigano, Thomas Jefferson University

Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
Myeloid-specific TFAM deficiency drives mitochondrial DNA stress and exacerbates allergic airway inflammation.
Mitochondrial fusion controls the development of specialized mitochondrial structure and metabolism in rod photoreceptor cells.
Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
Membranes arrest the coarsening of mitochondrial condensates.
Induction of Cytoplasmic dsDNA and cGAS-STING Immune Signaling After Exposure of Breast Cancer Cells to X-ray or High-Energetic Carbon Ions.
Mitochondrial RNA/RIG-I promotes Caspase-1/GSDMD-mediated inflammation in sepsis-associated acute kidney injury.
Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism.
Short- and Long-Term Endothelial Inflammation Have Distinct Effects and Overlap with Signatures of Cellular Senescence.
Mitochondrial presequences harbor variable strengths to maintain organellar function.
Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC.
Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.
Mitochondrial fumarate inhibits Parkin-mediated mitophagy.

Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]

Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.

Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.

  Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.

Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells

DOI:  https://doi.org/10.1016/j.cell.2025.05.020
bioRxiv. 2025 May 27. pii: 2025.05.27.654580. [Epub ahead of print]

Myeloid-specific TFAM deficiency drives mitochondrial DNA stress and exacerbates allergic airway inflammation.

Jackie Nguyen, Courtney Van, Manjula Karpurapu, Jiyoung Kim, Tae Jin Lee, Ji Young Yoo, Navjot Pabla, John W Christman, Sangwoon Chung.

Asthma is the most prevalent chronic inflammatory lung disease in adolescents and young adults, characterized by persistent airway inflammation and remodeling. Increasing evidence indicates that activated lung macrophages play a significant role in the initiation, intensity, progression, and resolution of allergic airway inflammation. However, the underlying mechanisms regulating macrophage-mediated inflammation in asthma remain incompletely understood. Our previous work revealed increased mitochondrial DNA (mtDNA) depletion and mitochondrial damages in the lungs of asthmatic mice, implicating mitochondrial dysfunction in disease pathogenesis. Given that mitochondrial transcription factor A (TFAM) is essential for mtDNA maintenance and integrity, we hypothesized that TFAM has a fundamental role in regulating mtDNA stress and downstream inflammtroy response in asthma. Using myeloid-specific TFAM knockout (TFAM fl/fl LysMcre, TFAM KO) mice subjected to allergens sensitization and challenge, we observed pronounced mitochondrial dysfunction and accentuated asthmatic inflammation. This was accompanied by elevated expression of asthma-associated mediators, including il-13, muc5a/c, muc5b, and ccl17. In addition, TFAM deficiency was associated with increased eosinophilia and and cytosolic mtDNA release, contributing to exacerbated airway pathology. Together, we have identified a critical role of TFAM in myeloid cells that contributes to asthmatic airway inflammation. These results suggest that therapeutic restoration of TFAM function may offer a novel strategy to mitigate mitochondrial stress, reduce airway inflammation, and improve outcomes in patients with moderate to severe asthma.

DOI: https://doi.org/10.1101/2025.05.27.654580
bioRxiv. 2025 May 26. pii: 2025.05.21.655403. [Epub ahead of print]

Mitochondrial fusion controls the development of specialized mitochondrial structure and metabolism in rod photoreceptor cells.

Michael Landowski, Ryo Hagimori, Purnima Gogoi, Vijesh J Bhute, Sakae Ikeda, Tetsuya Takimoto, Akihiro Ikeda.

Mitochondria are dynamic organelles that undergo continuous morphological changes, yet exhibit unique, cell-type-specific structures. In rod photoreceptor cells of the retina, these structures include elongated mitochondria in the inner segments and a distinct, large, circular mitochondrion in each presynaptic terminal. The mechanisms underlying the establishment and maintenance of these specialized mitochondrial morphologies, along with their functional significance, are not well understood. Here, we investigate the roles of mitochondrial fusion proteins mitofusin 1 (MFN1) and mitofusin 2 (MFN2) in shaping these structures and maintaining photoreceptor cell health. Rod photoreceptor cell-specific ablation of MFN1 and MFN2 resulted in mitochondrial fragmentation by one month of age, suggesting that mitochondrial fusion is essential for the development of photoreceptor cell-specific mitochondrial structures. Notably, the layer structures of the retina examined by light microscopy appeared unaffected at this age. Following this time period, significant photoreceptor cell degeneration occurred by three months of age. Furthermore, we showed that impaired mitochondrial fusion perturbed the balance of proteins involved in glycolysis, oxidative phosphorylation (OXPHOS), and β-oxidation, highlighting the critical role of mitochondrial fusion in ensuring the proper levels of proteins necessary for optimal energy metabolism. Additionally, we identified upregulation of cellular stress pathways such as endoplasmic reticulum (ER) stress and unfolded protein response (UPR), which arise in response to energy deprivation, and cytoprotective biosynthetic pathways mediated by CCAAT/enhancer-binding protein gamma (C/EBPγ) and mammalian target of rapamycin complex 1 (mTORC1) signaling. In summary, our findings indicate that mitochondrial fusion through MFN1 and MFN2 is vital for the development of unique mitochondrial structures and proper energy production, underscoring the fundamental importance of mitochondrial dynamics in photoreceptor cell function and survival.
Significance Statements: Rod photoreceptor cells exhibit unique mitochondrial morphologies and high energy requirements. In this report, we examined how these unique mitochondrial structures are established and their biological significance. We identified that mitochondrial fusion is essential for the development of characteristic mitochondrial morphologies in rod photoreceptor cells. Furthermore, we demonstrated that impaired mitochondrial fusion disrupts the equilibrium of proteins associated with OXPHOS, glycolysis, and β-oxidation, ultimately leading to an imbalance in cellular energy homeostasis. Our findings also revealed activation of cellular stress pathways, including ER stress and the UPR, which are likely triggered by energy depletion. Additionally, we identified activation of cytoprotective biosynthetic pathways that are engaged to preserve cellular homeostasis and function.

DOI: https://doi.org/10.1101/2025.05.21.655403
bioRxiv. 2025 May 28. pii: 2025.05.25.655566. [Epub ahead of print]

Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.

Rahul Gupta, Timothy J Durham, Grant Chau, Md Mesbah Uddin, Wenhan Lu, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.

One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences from ∼750,000 individuals. Our analyses reveal a simple, two-step mechanism: first, individual cells randomly accumulate low levels of "cryptic" mtDNA mutations; then, when a cell clone proliferates, the cryptic mtDNA variants are carried as passenger mutations and become detectable in whole blood. Four lines of evidence support this model: (1) the mutational spectrum of age-accumulating mtDNA variants is consistent with a well-established model of mtDNA replication errors, (2) these mutations are found primarily at low levels of heteroplasmy and do not show evidence of positive selection, (3) high mtDNA mutation burden tends to co-occur in samples harboring somatic driver mutations for clonal hematopoiesis (CH), and (4) nuclear GWAS reveals that germline variants predisposing to CH (such as those near TERT , TCL1A , and SMC4 ) also increase mtDNA mutation burden. We propose that the high copy number and high mutation rate of mtDNA make it a particularly sensitive blood-based marker of CH. Importantly, our work helps to mechanistically unify three prominent signatures of aging: common germline variants in TERT , clonal hematopoiesis, and observed mtDNA mutation accrual.

DOI: https://doi.org/10.1101/2025.05.25.655566
bioRxiv. 2025 Jun 08. pii: 2025.06.06.658068. [Epub ahead of print]

Membranes arrest the coarsening of mitochondrial condensates.

Sanjaya V B D Aththawala Gedara, Surya Teja Penna, Marina Feric.

Mitochondria contain double membranes that enclose their contents. Within their interior, the mitochondrial genome and its RNA products are condensed into ~100 nm sized (ribo)nucleoprotein complexes. How these endogenous condensates maintain their roughly uniform size and spatial distributions within membranous mitochondria remains unclear. Here, we engineered an optogenetic tool (mt-optoIDR) that allowed for controlled formation of synthetic condensates upon light activation in live mitochondria. Using live cell super-resolution microscopy, we visualized the nucleation of small, yet elongated condensates (mt-opto-condensates), which recapitulated the morphologies of endogenous mitochondrial condensates. We decoupled the contribution of the double membranes from the environment within the matrix by overexpressing the dominant negative mutant of a membrane fusion protein (Drp1K38A). The resulting bulbous mitochondria had significantly more dynamic condensates that coarsened into a single, prominent droplet. These observations inform how mitochondrial membranes can limit the growth and dynamics of the condensates they enclose, without the need of additional regulatory mechanisms.

DOI: https://doi.org/10.1101/2025.06.06.658068
Adv Radiat Oncol. 2025 Jun;10(6): 101783

Induction of Cytoplasmic dsDNA and cGAS-STING Immune Signaling After Exposure of Breast Cancer Cells to X-ray or High-Energetic Carbon Ions.

Cristina Totis, Nicole B Averbeck, Burkhard Jakob, Maik Schork, Gaia Volpi, Dennis F Hintze, Marco Durante, Claudia Fournier, Alexander Helm.

Purpose: Radiation therapy can trigger activation of the cyclic GMP-AMP synthase (cGAS)- Stimulator of interferon genes (STING) axis via cytoplasmic dsDNA fragment induction. The activation of cGAS-STING initiates innate immune signaling mediated by interferon type I that can contribute to eradicate the malignancy. The effect was shown to depend on the fractionation scheme employed. We hypothesized that the innate immune response can also depend on radiation quality because densely ionizing radiation, such as carbon ions, have different effects on DNA lesion quality.
Methods and Materials: We exposed an in vitro 4T1 breast cancer model to either photons or carbon ions and measured the clonogenic survival of cells with the colony-forming assay. The occurrence of cytosolic dsDNA fragments was assessed via immunofluorescence, whereas the expression and release of interferon-β by quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Bulk RNA sequencing was used to investigate global radiation-induced changes in gene expression.
Results: We show here that carbon ions induced a significantly higher yield of cytosolic dsDNA fragments per unit dose as compared to photons. The higher efficiency also translated in expression and release of interferon-β by the tumor cells. The rate of cytoplasmic dsDNA foci as well as interferon-β release increased with doses up to 20 Gy and no differences for a fractionation scheme (3 × 8 Gy) were found as compared to the single high doses (20 or 24 Gy) of photons.
Conclusions: In conclusion, we found that the release of interferon-β after radiation increases with the radiation dose up to 20 Gy and that carbon ions have the potential to elicit a strong innate immune signaling.

DOI: https://doi.org/10.1016/j.adro.2025.101783
Immunobiology. 2025 Jun 04. pii: S0171-2985(25)00219-0. [Epub ahead of print]230(4): 153085

Mitochondrial RNA/RIG-I promotes Caspase-1/GSDMD-mediated inflammation in sepsis-associated acute kidney injury.

Jie Jiao, Xuan Fang, Lisha Ma, Ruiqin Shen, Dongmei Li, Hao Luo, Aiping Xu, Zhaojun Xia, Sheng Jin, YunXia Shao, Mengya Wang, Decui Shao.

  Mitochondria play a decisive role in the pathological mechanisms of acute kidney injury (AKI). However, the specific mechanisms by which mitochondria regulate inflammation in AKI remain elusive. We aimed to investigate the role of mitochondrial RNA (mtRNA) and retinoic acid-inducible gene I (RIG-I) in sepsis-induced renal injury. To establish an AKI mouse model, intraperitoneal injection of lipopolysaccharide was used. Meanwhile, NRK-52E cells were treated with lipopolysaccharide, ATP, and Nigericin (LAN). Western blotting and immunohistochemistry analyses revealed an upregulation of RIG-I expression in AKI samples. Depolarization of mitochondrial membrane potential and elevation of cytoplasmic mtRNA were observed after LAN treatment. RNA immunoprecipitation demonstrated a direct binding interaction between mtRNA and RIG-I. Additionally, mtRNA was shown to induce mitochondrial membrane potential depolarization, an effect that could be mitigated by RIG-I knockdown. It was observed that Caspase-1 and ASC associating with RIG-I through co-immunoprecipitation. The mitochondrial damage induced by LAN, along with the upregulation of caspase-1, cleaved caspase-1, GSDMD, and cleaved GSDMD, were mitigated by the knockdown of RIG-I. Additionally, GSDMD knockout attenuates lipopolysaccharide-induced renal injury and reduces the level of IL-1β and TNF-α in murine models. Our research indicates that the pathological processes of AKI are driven by mtRNA/RIG-I-mediated Caspase-1/GSDMD, leading to inflammation.

Keywords:  Acute kidney injury; Caspase-1; Mitochondrial RNA; RIG-I; Sepsis

DOI:  https://doi.org/10.1016/j.imbio.2025.153085
PNAS Nexus. 2025 Jun;4(6): pgaf178

Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism.

Carlotta Giorgi, Femke J Aan, Natalija Glibetic, Daniela Ramaccini, Lorenzo Modesti, Veronica A M Vitto, Vanessa Montoya-Uribe, Austin Corpuz, Sonia Missiroli, Inês Simões, Yaiza Potes, Mariusz R Wieckowski, Joe W Ramos, Paolo Pinton, Michelle L Matter.

  The integrin effector, PTRH2, associates with mitochondria in adherent cells where its function has not been elucidated (Jan Y, et al. 2004. A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors. Cell. 116:751-762; Griffiths GS, et al. 2011. Bit-1 mediates integrin-dependent cell survival through activation of the NF{kappa}B pathway. J Biol Chem. 286:14713-14723). PTRH2 loss-of-function mutations cause multisystem disease in children through an unknown mechanism. We sought to determine the role of mitochondrial PTRH2. We used immunoprecipitation/mass spectrometric proteomics to identify PTRH2 interacting partners: TRABID (a deubiquitinase [DUB]) and respiratory complex I NADH: ubiquinone oxidoreductase core subunit 5 (mt-ND5). We show for the first time that mitochondrial PTRH2 regulates TRABID's ability to deubiquitylate mt-ND5. In cells lacking PTRH2 expression, mt-ND5 stability is significantly increased due to aberrant TRABID-mediated deubiquitylation of mt-ND5. This increase in mt-ND5 stability promotes complex I activity and ATP production, which under stress conditions leads to mitochondrial Ca2+ overload. Reexpression of mitochondrial PTRH2 blocks TRABID-mediated mt-ND5 deubiquitylation, resulting in mt-ND5 polyubiquitylation and proteasomal degradation. Inhibiting complex I or TRABID activity rescued PTRH2 loss-of-function mutant patient cells from mitochondrial Ca2+ overload under stress. Immunostaining analysis of ptrh2+/+ and ptrh2-/- mouse skeletal muscle revealed a negative relationship between PTRH2 and mt-ND5, confirming a regulatory role for PTRH2 in controlling mt-ND5 stability. Taken together, mitochondrial PTRH2 is a regulator of metabolic homeostasis that, when lost, promotes mitochondrial Ca2+ overload when cells are exposed to stress signals. Targeting mt-ND5 stability through PTRH2-mediated regulation of TRABID's DUB function provides a novel mechanistic approach to inhibit mitochondrial Ca2+ overload in diseases that occur due to dysregulated mitochondria.

Keywords:  PTRH2; TRABID; metabolism; mitochondrial Ca2+ overload; mt-ND5

DOI:  https://doi.org/10.1093/pnasnexus/pgaf178
Cells. 2025 May 30. pii: 806. [Epub ahead of print]14(11):

Short- and Long-Term Endothelial Inflammation Have Distinct Effects and Overlap with Signatures of Cellular Senescence.

Barbora Belakova, José Basílio, Manuel Campos-Medina, Anna F P Sommer, Adrianna Gielecińska, Ulrike Resch, Johannes A Schmid.

  This study investigates the interplay between cellular senescence and inflammation in human umbilical vein endothelial cells (HUVECs). We employed RNA sequencing to analyze gene expression changes in HUVECs subjected to replicative- or radiation-stress-induced senescence, and we compared these profiles with those of cells under acute or chronic TNFα-mediated inflammation. Our findings reveal that both senescence types exhibited significant upregulation of genes associated with epithelial- (or endothelial) mesenchymal transition (EMT) and inflammatory pathways, indicating a shared molecular response. Notably, chronic inflammation led to a pronounced EMT signature, while acute inflammation primarily activated classical inflammatory responses. Experimental validation confirmed reduced proliferation and increased secretion of pro-inflammatory cytokines (IL-6 and IL-8) in senescent and chronically inflamed cells and substantiated the upregulation of EMT marker genes. Additionally, we observed impaired wound healing capacity in senescent and chronically inflamed cells, highlighting the functional consequences of these cellular states. Our study underscores the critical role of inflammation in exacerbating senescence-related changes, contributing to the understanding of age-related cardiovascular pathologies. These insights may inform future therapeutic strategies aimed at mitigating the effects of aging and inflammation on endothelial function and cardiovascular health.

Keywords:  acute inflammation; chronic inflammation; gene set enrichment analysis; mesenchymal transition; molecular signatures; proliferation; senescence; transcriptomics; wound healing

DOI:  https://doi.org/10.3390/cells14110806
bioRxiv. 2025 May 29. pii: 2025.05.26.655807. [Epub ahead of print]

Mitochondrial presequences harbor variable strengths to maintain organellar function.

Youmian Yan, Baigalmaa Erdenepurev, Ian Collinson, Natalie M Niemi.

Hundreds of mitochondrial-destined proteins rely on N-terminal presequences for organellar targeting and import. While generally described as positively charged amphipathic helices, presequences lack a consensus motif and thus likely promote the import of proteins into mitochondria with variable efficiencies. Indeed, the concept of presequence "strength" critically underlies biological models such as stress sensing, yet a quantitative analysis of what dictates "strong" versus "weak" presequences is lacking. Furthermore, the extent to which presequence strength affects mitochondrial function and cellular fitness remains unclear. Here, we capitalize on the high-throughput and kinetic nature of the MitoLuc mitochondrial protein import assay to quantify multiple aspects of presequence strength. We find that select presequences, including those that regulate the mitochondrial unfolded protein response (UPR mt ), are sufficient to impart differential import efficiencies during mitochondrial uncoupling. Surprisingly, we find that presequences beyond those classically associated with stress signaling promote highly variable import efficiency in stressed and basal (i.e., non-stressed) conditions in vitro, suggesting that presequence strength may influence a broader array of processes than currently appreciated. We exploit this variability to demonstrate that only presequences that promote robust import in vitro can fully rescue defects in respiratory growth in Complex IV-deficient yeast, suggesting that presequence strength dictates metabolic potential. Collectively, our findings demonstrate that presequence strength can describe numerous metrics, such as total imported protein, maximal import velocity, or sensitivity to uncoupling, suggesting that the annotation of presequences as "weak" versus "strong" requires more nuanced characterization than is typically performed. Importantly, we find that such variability in presequence strength meaningfully affects cellular fitness in processes beyond stress signaling, suggesting that organisms may broadly exploit presequence strength to fine-tune mitochondrial import and thus organellar homeostasis.

DOI: https://doi.org/10.1101/2025.05.26.655807
Nat Commun. 2025 Jun 10. 16(1): 5136

Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC.

Songlei Liu, Li Li, Fan Zhang, Mariana Garcia-Corral, Katharina Meyer, Patrick R J Fortuna, Björn van Sambeek, Evan Appleton, Alex H M Ng, Parastoo Khoshakhlagh, Yuancheng Ryan Lu, James Cameron, Ricardo N Ramirez, Yuting Chen, Chun-Ting Wu, Jeremy Y Huang, Yuqi Tan, George Chao, John Aach, Elaine T Lim, Jenny M Tam, Soumya Raychaudhuri, George M Church.

Differentiation of induced pluripotent stem cells (iPSCs) into specialized cell types is essential for uncovering cell-type specific molecular mechanisms and interrogating cellular function. Transcription factor screens have enabled efficient production of a few cell types; however, engineering cell types that require complex transcription factor combinations remains challenging. Here, we report an iterative, high-throughput single-cell transcription factor screening method that enables the identification of transcription factor combinations for specialized cell differentiation, which we validated by differentiating human microglia-like cells. We found that the expression of six transcription factors, SPI1, CEBPA, FLI1, MEF2C, CEBPB, and IRF8, is sufficient to differentiate human iPSC into cells with transcriptional and functional similarity to primary human microglia within 4 days. Through this screening method, we also describe a novel computational method allowing the exploration of single-cell RNA sequencing data derived from transcription factor perturbation assays to construct causal gene regulatory networks for future cell fate engineering.

DOI: https://doi.org/10.1038/s41467-025-59596-3
Am J Hum Genet. 2025 Jun 03. pii: S0002-9297(25)00188-0. [Epub ahead of print]

Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.

Hana Antonicka, Woranontee Weraarpachai, Katherine M Szigety, Robert Kopajtich, James B Gibson, Johan L K Van Hove, Marisa W Friederich, Piervito Lopriore, Christiane Neuhofer, Roxanne A Van Hove, Michel A Cole, Richard Reisdorph, James T Peterson, Katherine J Dempsey, Rebecca D Ganetzky, Michelangelo Mancuso, Holger Prokisch, Eric A Shoubridge.

  Using exome sequencing, we identified compound heterozygous variants of unknown significance in FASTKD5, a gene that codes for a mitochondrial protein essential for processing mRNAs at non-canonical cleavage sites in the primary mitochondrial transcript, in three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia. Among the three subjects, we identified three missense variants and two frameshift variants leading to a premature stop codon. Analysis of fibroblasts from two subjects showed reduced steady-state levels of FASTKD5 protein by immunoblot, reduced translation of the cytochrome c oxidase subunit 1, impaired assembly of complex IV, and a consequent decrease in cytochrome c oxidase enzymatic activity. The extent of these deficiencies appeared to correlate with the severity of the clinical phenotype. Expression of a wild-type FASTKD5 cDNA, but not cDNAs expressing the missense mutations, rescued all the molecular defects in the subjects' fibroblasts, demonstrating that the alleles are pathogenic. Two of the three identified missense mutations resulted in near complete loss of function, while one was hypomorphic, resulting from impaired protein stability. These cases of mitochondrial disease associated with bi-allelic variants in FASTKD5 add to a growing list of primary genetic mutations causing Leigh syndrome associated with complex IV deficiency.

Keywords:  FASTKD5; Leigh syndrome; RNA processing; cytochrome c oxidase deficiency; mitochondrial DNA; mitochondrial disease; mitochondrial gene expression; mitochondrial translation; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.ajhg.2025.05.007
Mol Cell. 2025 Jun 03. pii: S1097-2765(25)00460-5. [Epub ahead of print]

Mitochondrial fumarate inhibits Parkin-mediated mitophagy.

Su Jin Ham, Sunhoe Bang, Daihn Woo, Jae-Yoon Jo, Takwon Yoo, Eunju Yoon, Yeonju Kyoung, Daehyun Baek, Jong-Seo Kim, Jongkyeong Chung.

  Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby impeding PINK1-Parkin-mediated mitophagy. Notably, our investigation reveals that the succinatable cysteines in human Parkin are not conserved in invertebrates, including Drosophila. To assess the functional impact of Parkin succination, we generate Parkin knockin flies with succinatable cysteines. These flies exhibit robust Parkinson's disease (PD)-related phenotypes when exposed to elevated fumarate levels. Collectively, our findings underscore the significance of fumarate as an endogenous regulator of PINK1-Parkin-mediated mitophagy, offering insights into the intricate interplay between mitochondrial metabolic activities and PD pathology.

Keywords:  ANT1; PINK1; Parkinson's disease; VDAC1/2; fumarate; parkin; succination

DOI:  https://doi.org/10.1016/j.molcel.2025.05.021