bims-mitdis 2025-01-05 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2025–01–05
28 papers selected by
Catalina Vasilescu, Helmholz Munich

Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70.
Beyond static snapshots: Mitochondria in action.
Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.
DLK-dependent axonal mitochondrial fission drives degeneration after axotomy.
Basic Science and Pathogenesis.
Basic Science and Pathogenesis.
Imaging phenotype reveals that disulfirams induce protein insolubility in the mitochondrial matrix.
Basic Science and Pathogenesis.
Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53.
Loss of Mfn1 but not Mfn2 enhances adipogenesis.
Molecular basis of human nuclear and mitochondrial tRNA 3' processing.
Mitochondrial dysfunction and Alzheimer's disease: pathogenesis of mitochondrial transfer.
Basic Science and Pathogenesis.
Mitochondrial Quality Control: A New Perspective in Skeletal Muscle Dysfunction of Chronic Obstructive Pulmonary Disease.
Scrutinizing neurodegenerative diseases: decoding the complex genetic architectures through a multi-omics lens.
Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.
Exploiting Mitochondria by Triggering a Faulty Unfolded Protein Response Leads to Effective Cardioprotection.
Mitochondrial calcium uniporter complex: An emerging therapeutic target for cardiovascular diseases (Review).
Gene therapy targets the retina to treat eye disease.
Targeting mitochondrial transfer: a new horizon in cardiovascular disease treatment.
Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits.
Basic Science and Pathogenesis.
Basic Science and Pathogenesis.
Basic Science and Pathogenesis.
In defence of ferroptosis.
The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis.
Histone mark age of human tissues and cell types.
Rational engineering of minimally immunogenic nucleases for gene therapy.

Nat Commun. 2024 Dec 30. 15(1): 10815

Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70.

Marc A Morizono, Kelly L McGuire, Natalie I Birouty, Mark A Herzik.

Maintenance of protein homeostasis is necessary for cell viability and depends on a complex network of chaperones and co-chaperones, including the heat-shock protein 70 (Hsp70) system. In human mitochondria, mitochondrial Hsp70 (mortalin) and the nucleotide exchange factor (GrpEL1) work synergistically to stabilize proteins, assemble protein complexes, and facilitate protein import. However, our understanding of the molecular mechanisms guiding these processes is hampered by limited structural information. To elucidate these mechanistic details, we used cryoEM to determine structures of full-length human mortalin-GrpEL1 complexes in previously unobserved states. Our structures and molecular dynamics simulations allow us to delineate specific roles for mortalin-GrpEL1 interfaces and to identify steps in GrpEL1-mediated nucleotide and substrate release by mortalin. Subsequent analyses reveal conserved mechanisms across bacteria and mammals and facilitate a complete understanding of sequential nucleotide and substrate release for the Hsp70 chaperone system.

DOI: https://doi.org/10.1038/s41467-024-54499-1
Curr Opin Cell Biol. 2024 Dec 29. pii: S0955-0674(24)00139-X. [Epub ahead of print]92 102460

Beyond static snapshots: Mitochondria in action.

Julien Cicero, Uri Manor.

Mitochondria are dynamic organelles essential for cellular homeostasis, undergoing continuous fission and fusion processes that regulate their morphology, distribution, and function. Disruptions in these dynamics are linked to numerous diseases, including neurodegenerative disorders and cancer. Understanding these processes is vital for developing therapeutic strategies aimed at mitigating mitochondrial dysfunction. This review provides an overview of recent perspectives on mitochondrial dynamics, focusing on the need for live video microscopy imaging in order to fully understand mitochondrial phenotypes and pathology. Advanced imaging tools, such as machine learning-based segmentation and label-free microscopy approaches, have the potential to transform our ability to study mitochondrial dynamics in live cells.

DOI: https://doi.org/10.1016/j.ceb.2024.102460
Sci Adv. 2025 Jan 03. 11(1): eads8489

Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.

Xiujie Li-Harms, Jingjun Lu, Yu Fukuda, John Lynch, Aditya Sheth, Gautam Pareek, Marcin M Kaminski, Hailey S Ross, Christopher W Wright, Amber L Smith, Huiyun Wu, Yong-Dong Wang, Marc Valentine, Geoffrey Neale, Peter Vogel, Stanley Pounds, John D Schuetz, Min Ni, Mondira Kundu.

The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on this process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.

DOI: https://doi.org/10.1126/sciadv.ads8489
Nat Commun. 2024 Dec 30. 15(1): 10806

DLK-dependent axonal mitochondrial fission drives degeneration after axotomy.

Jorge Gómez-Deza, Matthew Nebiyou, Mor R Alkaslasi, Francisco M Nadal-Nicolás, Preethi Somasundaram, Anastasia L Slavutsky, Wei Li, Michael E Ward, Trent A Watkins, Claire E Le Pichon.

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protects mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and provide potential focus for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-024-54982-9
Alzheimers Dement. 2024 Dec;20 Suppl 1 e091624

Basic Science and Pathogenesis.

Taylor A Strope, Brittany M Hauger, Heather M Wilkins, Kealan Schroeder.

BACKGROUND: Amyloid Precursor Protein (APP) processing to Aβ is well understood but the function of APP is largely unknown. APP is expressed ubiquitously and localizes to mitochondria. The consequences of mitochondrial APP localization are not known. We leveraged models of altered APP mitochondrial localization to understand the relationship between APP and mitochondrial function.
METHOD: We have generated several isogenic iPSC lines using Crispr/Cas9 including WT APP (no gene targeting), 3M APP homozygous and hemizygous (which harbors mutations at amino acids +41, +44, and +52 (His to Asp)), APP knockdown (missing one allele), APP knockout (missing both alleles), and APP duplication. These iPSC lines were differentiated into both neurons and astrocytes. Mitochondrial localization of APP was quantified using Western blot analysis. Aβ was measured via ELISA. Mitochondrial respiratory function was analyzed using Seahorse Technology or Vmax spectrophotometric assays. Mitophagy was examined by qPCR against mitochondrial DNA content and an adenovirus expressing EGFP-COX8. Mitochondrial biogenesis and turnover were measured using an adenoviral MitoTimer vector.
RESULT: 3M APP and knockdown/knockout APP models had reduced mitochondrial APP localization while APP duplication had increased mitochondrial APP localization. Models with reduced APP localization to mitochondria had reduced Aβ production, while APP duplication had increased Aβ production. Reduced mitophagy levels and altered mitochondrial biogenesis were observed in models with reduced mitochondrial APP localization. APP duplication increased mitophagy and altered mitochondrial biogenesis. Both reduced and increased mitochondrial APP localization reduced mitochondrial respiratory function.
CONCLUSION: APP localization to mitochondria alters mitochondrial function, mitochondrial mass, and mitophagy. Further studies are in progress to elucidate the effects of mitochondrial localization of APP on bioenergetics.

DOI: https://doi.org/10.1002/alz.091624
Alzheimers Dement. 2024 Dec;20 Suppl 1 e084464

Basic Science and Pathogenesis.

Daniel Barnett, Till S Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M Meadows, Haopeng Xiao, Edward T Chouchani, Anna G Orr, Adam L Orr.

BACKGROUND: Mitochondrial reactive oxygen species (mROS), such as superoxide and hydrogen peroxide (H2O2), are implicated in aging-associated neurological disorders, including Alzheimer's Disease and frontotemporal dementia. Mitochondrial complex III of the respiratory chain has the highest capacity for mROS production and generates mROS toward the cytosol, poising it to regulate intracellular signaling and disease mechanisms. However, the exact triggers of complex III-derived ROS (CIII-ROS), its downstream molecular targets, and its functional roles in dementia-related pathogenesis remain unclear.
METHOD: Here, we investigated the drivers and consequences of CIII-ROS production in primary mouse astrocytes and mouse models of dementia-linked proteinopathy using site-selective mROS suppressors and genetic approaches together with live-cell imaging of sub-compartmental H2O2 dynamics, stoichiometric redox proteomics, and transcriptomics.
RESULT: We found that specific disease-related factors transiently increase astrocytic CIII-ROS levels, and this effect is dependent on a mitochondrial sodium-calcium exchanger. CIII-ROS oxidized specific cysteines on astrocytic proteins associated with disease, amplified STAT3 phosphorylation and nuclear translocation, and promoted gene expression changes linked to STAT3 and related neuroimmune pathways. Inhibition of other sites of ROS production, including mitochondrial complex I and NADPH oxidase, had no effects on mROS responses or STAT3 signaling, demonstrating the specificity of CIII-ROS induction and its context-dependent modulation of STAT3 activities. Blockade of CIII-ROS in transgenic mouse models of dementia with a site-selective and brain-penetrant suppressor reduced astrocytic alterations, neuropathology, and premature mortality.
CONCLUSION: Our data suggest that dementia-associated factors induce site-specific mROS production and that CIII-ROS promote precise post-translational redox modifications and amplify STAT3-linked signaling and changes in gene expression. Together, our findings reveal CIII-ROS as an important node of mitochondrial-nuclear communication in pathogenic conditions, whereby mROS transients are converted into long-lasting changes in gene transcription and cell function. CIII-ROS and redox signaling offer new therapeutic opportunities for aging-associated neurological disorders.

DOI: https://doi.org/10.1002/alz.084464
Sci Rep. 2024 Dec 28. 14(1): 31401

Imaging phenotype reveals that disulfirams induce protein insolubility in the mitochondrial matrix.

Ken Ohno, Hisashi Murakami, Naohisa Ogo, Akira Asai.

  The cell painting assay is useful for understanding cellular phenotypic changes and drug effects. To identify other aspects of well-known chemicals, we screened 258 compounds with the cell painting assay and focused on a mitochondrial punctate phenotype seen with disulfiram. To elucidate the reason for this punctate phenotype, we looked for clues by examining staining steps and gene knockdown as well as examining protein solubility and comparing cell lines. From these results, we found that the punctate phenotype was caused by protein insolubility in the mitochondrial matrix. Interestingly, the punctate phenotype of disulfiram was sensitive to the relative expression of LonP1, a protease in the mitochondrial matrix that regulates proteostasis, suggesting that the punctate phenotype manifests when the protein quality control capacity in the mitochondrial matrix is exceeded. Moreover, we discovered that disulfiram and its derivatives, which have all been reported to increase acetaldehyde in the blood after the in vivo intake of alcohol, induced a punctate phenotype as well. The investigated punctate phenotype not only provides a novel clue for elucidating the common mechanism of action among disulfiram derivatives but is also a novel example of chemical perturbation of proteostasis in the mitochondrial matrix.

Keywords:  Cell painting assay; Disulfiram; LonP1; Oligomycin A; Protein insolubility; Proteostasis

DOI:  https://doi.org/10.1038/s41598-024-82939-x
Alzheimers Dement. 2024 Dec;20 Suppl 1 e091488

Basic Science and Pathogenesis.

Wenzhang Wang.

BACKGROUND: Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD.
METHOD: An unbiased screening of intraneuronal Aβ42 protein-interactome was perfumed in AD cell culture. Mitochondrial protease activity and mitochondria functions were investigated in AD models in vitro and in vivo, while cognitive behaviors of AD transgenic mice were analyzed by memory capacity tests.
RESULT: We identified LONP1, an ATP-dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6A signaling contributed at least in part to Aβ42-induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ-induced mitochondrial deficits and cognitive deficits.
CONCLUSION: These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a novel mechanism underlying intracellular Aβ42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.

DOI: https://doi.org/10.1002/alz.091488
Cell Death Differ. 2024 Dec 29.

Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53.

Anna Kasprzyk-Pawelec, Mingjun Tan, Raneen Rahhal, Alec McIntosh, Harvey R Fernandez, Rami M Mosaoa, Lei Jiang, Gray W Pearson, Eric Glasgow, Jerry Vockley, Christopher Albanese, Maria Laura Avantaggiati.

Germline inactivating mutations of the SLC25A1 gene contribute to various human disorders, including Velocardiofacial (VCFS), DiGeorge (DGS) syndromes and combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic disease characterized by the accumulation of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 loss leads to these syndromes remain largely unclear. Here, we describe a mouse model of SLC25A1 deficiency that mimics human VCFS/DGS and D/L-2HGA. Surprisingly, inactivation of both Slc25a1 alleles results in alterations in the development of multiple organs, and in a severe proliferation defect by activating two senescence programs, oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), which converge upon the induction of the p53 tumor suppressor. Mechanistically, cells and tissues with dysfunctional SLC25A1 protein undergo metabolic and transcriptional rewiring leading to the accumulation of 2HG via a non-canonical pathway and to the depletion of nicotinamide adenine dinucleotide, NAD+, which trigger senescence. Replenishing the pool of NAD+ or promoting the clearance of 2HG rescues the proliferation defect of cells with dysfunctional SLC25A1 in a cooperative fashion. Further, removal of p53 activity via RNA interference restores proliferation, indicating that p53 acts as a critical barrier to the expansion of cells lacking functional SLC25A1. These findings reveal unexpected pathogenic roles of senescence and of p53 in D/L-2HGA and identify potential therapeutic strategies to correct salient molecular alterations driving this disease.

DOI: https://doi.org/10.1038/s41418-024-01428-w
PLoS One. 2024 ;19(12): e0306243

Loss of Mfn1 but not Mfn2 enhances adipogenesis.

Jake P Mann, Luis Carlos Tábara, Satish Patel, Pushpa Pushpa, Anna Alvarez-Guaita, Liang Dong, Afreen Haider, Koini Lim, Panna Tandon, Fabio Scurria, James E N Minchin, Stephen O'Rahilly S, Daniel J Fazakerley, Julien Prudent, Robert K Semple, David B Savage.

OBJECTIVE: A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells.
METHODS: We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA.
RESULTS: Mfn1-/- MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile including Pparg upregulation. Mfn2-/- MEFs also had a disrupted mitochondrial morphology, but in contrast to Mfn1-/- MEFs they showed reduced expression of adipocyte markers. Mfn1 and Mfn2 siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings.
CONCLUSIONS: Loss of Mfn1 but not Mfn2 in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.

DOI: https://doi.org/10.1371/journal.pone.0306243
Nat Struct Mol Biol. 2025 Jan 02.

Molecular basis of human nuclear and mitochondrial tRNA 3' processing.

Arjun Bhatta, Bernhard Kuhle, Ryan D Yu, Lucas Spanaus, Katja Ditter, Katherine E Bohnsack, Hauke S Hillen.

Eukaryotic transfer RNA (tRNA) precursors undergo sequential processing steps to become mature tRNAs. In humans, ELAC2 carries out 3' end processing of both nucleus-encoded (nu-tRNAs) and mitochondria-encoded (mt-tRNAs) tRNAs. ELAC2 is self-sufficient for processing of nu-tRNAs but requires TRMT10C and SDR5C1 to process most mt-tRNAs. Here we show that TRMT10C and SDR5C1 specifically facilitate processing of structurally degenerate mt-tRNAs lacking the canonical elbow. Structures of ELAC2 in complex with TRMT10C, SDR5C1 and two divergent mt-tRNA substrates reveal two distinct mechanisms of pre-tRNA recognition. While canonical nu-tRNAs and mt-tRNAs are recognized by direct ELAC2-RNA interactions, processing of noncanonical mt-tRNAs depends on protein-protein interactions between ELAC2 and TRMT10C. These results provide the molecular basis for tRNA 3' processing in both the nucleus and the mitochondria and explain the organelle-specific requirement for additional factors. Moreover, they suggest that TRMT10C-SDR5C1 evolved as a mitochondrial tRNA maturation platform to compensate for the structural erosion of mt-tRNAs in bilaterian animals.

DOI: https://doi.org/10.1038/s41594-024-01445-w
Front Aging Neurosci. 2024 ;16 1517965

Mitochondrial dysfunction and Alzheimer's disease: pathogenesis of mitochondrial transfer.

Yun Wei, Xinlei Du, Hongling Guo, Jingjing Han, Meixia Liu.

  In recent years, mitochondrial transfer has emerged as a universal phenomenon intertwined with various systemic physiological and pathological processes. Alzheimer's disease (AD) is a multifactorial disease, with mitochondrial dysfunction at its core. Although numerous studies have found evidence of mitochondrial transfer in AD models, the precise mechanisms remain unclear. Recent studies have revealed the dynamic transfer of mitochondria in Alzheimer's disease, not only between nerve cells and glial cells, but also between nerve cells and glial cells. In this review, we explore the pathways and mechanisms of mitochondrial transfer in Alzheimer's disease and how these transfer activities contribute to disease progression.

Keywords:  AD treatment; Alzheimer’s disease; mitochondrial dysfunction; mitochondrial transfer; neuroprotection

DOI:  https://doi.org/10.3389/fnagi.2024.1517965
Alzheimers Dement. 2024 Dec;20 Suppl 1 e086516

Basic Science and Pathogenesis.

Subodh Kumar.

BACKGROUND: Mitochondria plays a crucial role at synapses in providing synaptic energy, healthy synaptic function, and cognitive functions. Amyloid-beta and phosphorylated tau protein oligomers cause severe mitochondrial defects in Alzheimer's disease (AD), which leads to the lack of synaptic energy and impaired synapse functions in AD. MicroRNAs (miRNAs) present within the mitochondria are involved in multiple mitochondrial activities and mitochondrial function. Mitochondrial dysfunction is well established in AD; but status of mitochondria localized miRNAs are unknown in AD. This current study is focused on the identification of mitochondria localized miRNAs in AD and to unveil their possible roles in disease pathogenesis.
METHOD: Mitochondria and cytosolic fraction were extracted from postmortem AD brains (n = 5) and cognitively normal postmortem brains (n = 5). Mitochondria purity was characterized by transmission electron microscopy (TEM) and immunoblot analysis of mitochondrial marker proteins. Mitochondria activity was determined by mitochondrial function assay. Further, total RNA was extracted from mitochondria and cytosolic fraction and subjected to miRNAs HiSeq analysis. The significantly deregulated mitochondrial miRNAs were further validated on large number of AD postmortem brain and subjected to in-silico bioinformatic analysis.
RESULT: TEM analysis, immunoblotting and mitochondrial function assay confirmed the extraction of intact and active mitochondria from AD and control postmortem brains. MiRNAs HiSeq analysis showed the mitochondria localized distribution of some novel miRNAs in AD and control samples. We found some miRNAs localization and differential expression in mitochondrial fraction relative to cytosolic fraction. Our validation analysis unveiled previously unknown, most potential mitochondria localized miRNAs in AD. Further, in silico bioinformatic analysis revealed the critical roles of mitochondrial localized miRNAs in several mitochondrial function and synaptic pathways in AD.
CONCLUSION: Our study discovered some novel mitochondria localized miRNAs, which could be a potential therapeutic target to retrieve mitochondrial and synaptic dysfunction in AD.

DOI: https://doi.org/10.1002/alz.086516
Aging Dis. 2024 Dec 21.

Mitochondrial Quality Control: A New Perspective in Skeletal Muscle Dysfunction of Chronic Obstructive Pulmonary Disease.

Yanxia Song, Xiaoyu Han, Yingqi Wang, Kangxia Li, Huanping Li, Yizhu Tian, Xiaoqing Ma, Weibing Wu, Jihong Wang.

Skeletal muscle dysfunction (SMD), one of the extrapulmonary complications in patients with chronic obstructive pulmonary disease (COPD), considerably influences patient prognosis. Mitochondria regulates their dynamic networks through a mitochondria quality control (MQC) mechanism, involving mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. The MQC is crucial for mitochondrial homeostasis and health, and disruption of it can lead to mitochondrial damage, which is a key factor in the structural and functional impairment of skeletal muscle in COPD. The mitochondria in the skeletal muscles of these patients undergo changes, mainly including decrease in mitochondrial density and biogenesis levels, imbalanced mitochondrial fission and fusion, and altered mitophagy status. However, the potential mechanisms linking MQC to the damaged structure and function of skeletal muscles in COPD have not been fully clarified. Therefore, this review highlights the effects and potential pathways of the MQC system on the dysfunction of skeletal muscle (muscle atrophy, impaired myogenesis and regeneration, and aerobic endurance) in patients with COPD, and summarizes potential interventions targeted MQC, intending to provide a theoretical basis for further research on COPD, improve SMD, and enhance the quality of life.

DOI: https://doi.org/10.14336/AD.2024.1129
Hum Genomics. 2024 Dec 31. 18(1): 141

Scrutinizing neurodegenerative diseases: decoding the complex genetic architectures through a multi-omics lens.

Relu Cocoș, Bogdan Ovidiu Popescu.

  Neurodegenerative diseases present complex genetic architectures, reflecting a continuum from monogenic to oligogenic and polygenic models. Recent advances in multi-omics data, coupled with systems genetics, have significantly refined our understanding of how these data impact neurodegenerative disease mechanisms. To contextualize these genetic discoveries, we provide a comprehensive critical overview of genetic architecture concepts, from Mendelian inheritance to the latest insights from oligogenic and omnigenic models. We explore the roles of common and rare genetic variants, gene-gene and gene-environment interactions, and epigenetic influences in shaping disease phenotypes. Additionally, we emphasize the importance of multi-omics layers including genomic, transcriptomic, proteomic, epigenetic, and metabolomic data in elucidating the molecular mechanisms underlying neurodegeneration. Special attention is given to missing heritability and the contribution of rare variants, particularly in the context of pleiotropy and network pleiotropy. We examine the application of single-cell omics technologies, transcriptome-wide association studies, and epigenome-wide association studies as key approaches for dissecting disease mechanisms at tissue- and cell-type levels. Our review introduces the OmicPeak Disease Trajectory Model, a conceptual framework for understanding the genetic architecture of neurodegenerative disease progression, which integrates multi-omics data across biological layers and time points. This review highlights the critical importance of adopting a systems genetics approach to unravel the complex genetic architecture of neurodegenerative diseases. Finally, this emerging holistic understanding of multi-omics data and the exploration of the intricate genetic landscape aim to provide a foundation for establishing more refined genetic architectures of these diseases, enhancing diagnostic precision, predicting disease progression, elucidating pathogenic mechanisms, and refining therapeutic strategies for neurodegenerative conditions.

Keywords:  Genetic architecture; Heritability; Multi-omics; Networks; Neurodegenerative

DOI:  https://doi.org/10.1186/s40246-024-00704-7
Nat Commun. 2024 Dec 30. 15(1): 10796

Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.

Célia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez Comaduran, Morgane Verbrugghe, Jia Ming Stella Xu, Sandra Minotti, James Lynch, Jeetayu Biswas, Tad Wu, Heather D Durham, Gene W Yeo, Maria Vera.

Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhances HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites is impaired by depleting fused in sarcoma-an amyotrophic lateral sclerosis-related protein-in cultured spinal cord mouse motor neurons or by expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.

DOI: https://doi.org/10.1038/s41467-024-55055-7
Int J Med Sci. 2025 ;22(1): 188-196

Exploiting Mitochondria by Triggering a Faulty Unfolded Protein Response Leads to Effective Cardioprotection.

Yang Shen, Xin Gao, Ying Xiang, Hao Zhou, Hang Zhu, Qiang Wu, Jinfeng Liu.

  This study investigates the role of Fundc1 in cardiac protection under high-altitude hypoxic conditions and elucidates its underlying molecular mechanisms. Using cardiomyocyte-specific Fundc1 knockout (Fundc1CKO ) mice, we demonstrated that Fundc1 deficiency exacerbates cardiac dysfunction under simulated high-altitude hypoxia, manifesting as impaired systolic and diastolic function. Mechanistically, we identified that Fundc1 regulates cardiac function through the mitochondrial unfolded protein response (mito-UPR) pathway. Fundc1 deficiency led to significant downregulation of multiple mito-UPR-related factors, including ATF5, Chop, and PITRM1. Further investigation revealed that Fundc1 deficiency results in increased cardiomyocyte apoptosis, calcium dysregulation, reduced cell viability, and impaired mitochondrial function, characterized by decreased ATP production, reduced membrane potential, and increased ROS production. Notably, activation of mito-UPR with oligomycin significantly ameliorated these cardiac abnormalities in Fundc1-deficient mice. We identified ATF5 as a key downstream effector of Fundc1, as ATF5 overexpression effectively reversed cardiac dysfunction and restored mito-UPR-related gene expression in Fundc1-deficient hearts. Additionally, we discovered that Fundc1-mediated cardioprotection involves regulation of mitophagy, where its activation improved cardiac function and mitochondrial homeostasis in Fundc1-deficient mice. Our findings reveal a novel Fundc1-ATF5-mito-UPR axis in cardioprotection against high-altitude hypoxia and highlight the crucial role of mitophagy in this protective mechanism, providing new insights into potential therapeutic strategies for high-altitude heart disease.

Keywords:  ATF5; FUNDC1; mito-UPR; mitochondria.

DOI:  https://doi.org/10.7150/ijms.100523
Int J Mol Med. 2025 Mar;pii: 40. [Epub ahead of print]55(3):

Mitochondrial calcium uniporter complex: An emerging therapeutic target for cardiovascular diseases (Review).

Yaling Li, Hongmin Hu, Chun Chu, Jun Yang.

  Cardiovascular disease (CVD) is currently a major factor affecting human physical and mental health. In recent years, the relationship between intracellular Ca2+ and CVD has been extensively studied. Ca2+ movement across the mitochondrial inner membrane plays a vital role as an intracellular messenger, regulating energy metabolism and calcium homeostasis. It is also involved in pathological processes such as cardiomyocyte apoptosis, hypertrophy and fibrosis in CVD. The selective mitochondrial calcium uniporter complex (MCU complex) located in the inner membrane is essential for mitochondrial Ca2+ uptake. Therefore, the MCU complex is a potential therapeutic target for CVD. In this review, recent research progress on the pathophysiological mechanisms and therapeutic potential of the MCU complex in various CVDs was summarized, including myocardial ischemia‑reperfusion injury, pulmonary arterial hypertension, other peripheral vascular diseases, myocardial remodeling and arrhythmias. This review contributes to a deeper understanding of these mechanisms at the molecular level and highlights potential intervention targets for CVD treatment in clinical practice.

Keywords:  cardiovascular diseases; emerging; mitochondrial calcium uniporter complex; therapeutic target

DOI:  https://doi.org/10.3892/ijmm.2024.5481
Nat Med. 2025 Jan 02.

Gene therapy targets the retina to treat eye disease.

Carrie Arnold.

DOI: https://doi.org/10.1038/s41591-024-03454-0
J Transl Med. 2024 Dec 31. 22(1): 1160

Targeting mitochondrial transfer: a new horizon in cardiovascular disease treatment.

Baile Zuo, Xiaoyan Li, Dawei Xu, Liping Zhao, Yang Yang, Yi Luan, Bi Zhang.

  Cardiovascular diseases (CVDs) are the leading cause of mortality among individuals with noncommunicable diseases worldwide. Obesity is associated with an increased risk of developing cardiovascular disease (CVD). Mitochondria are integral to the cardiovascular system, and it has been reported that mitochondrial transfer is associated with the pathogenesis of multiple CVDs and obesity. This review offers a comprehensive examination of the relevance of mitochondrial transfer to cardiovascular health and disease, emphasizing the critical functions of mitochondria in energy metabolism and signal transduction within the cardiovascular system. This highlights how disruptions in mitochondrial transfer contribute to various CVDs, such as myocardial infarction, cardiomyopathies, and hypertension. Additionally, we provide an overview of the molecular mechanisms governing mitochondrial transfer and its potential implications for CVD treatment. This finding underscores the therapeutic potential of mitochondrial transfer and addresses the various mechanisms and challenges in its implementation. By delving into mitochondrial transfer and its targeted modulation, this review aims to advance our understanding of cardiovascular disease treatment, presenting new insights and potential therapeutic strategies in this evolving field.

Keywords:  Cardiomyopathies; Cardiovascular diseases; Mitochondrial transfer; Myocardial infarction; Therapeutic strategies

DOI:  https://doi.org/10.1186/s12967-024-05979-x
Nat Genet. 2025 Jan 02.

Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits.

Nora Scherer, Daniel Fässler, Oleg Borisov, Yurong Cheng, Pascal Schlosser, Matthias Wuttke, Stefan Haug, Yong Li, Fabian Telkämper, Suraj Patil, Heike Meiselbach, Casper Wong, Urs Berger, Peggy Sekula, Anselm Hoppmann, Ulla T Schultheiss, Sahar Mozaffari, Yannan Xi, Robert Graham, Miriam Schmidts, Michael Köttgen, Peter J Oefner, Felix Knauf, Kai-Uwe Eckardt, Sarah C Grünert, Karol Estrada, Ines Thiele, Johannes Hertel, Anna Köttgen.

Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene-metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism. Allelic series of functional variants in transporters responsible for transcellular sulfate reabsorption (SLC13A1, SLC26A1) exhibited graded effects on plasma sulfate and human height and pinpointed alleles associated with increased odds of diverse musculoskeletal traits and diseases in the population. This integrative approach can identify new players in incompletely characterized human metabolic reactions and reveal metabolic readouts informative of human traits and diseases.

DOI: https://doi.org/10.1038/s41588-024-01965-7
Alzheimers Dement. 2024 Dec;20 Suppl 1 e084267

Basic Science and Pathogenesis.

Thi Kim Oanh Nguyen, Md Fayad Hasan, Eugenia Trushina.

BACKGROUND: Despite recent FDA approvement of disease-modifying treatments that reduce Aβ, the identification of novel therapeutic strategies that could delay the Alzheimer's disease (AD) development are needed. We identified and developed novel small molecule compounds that mildly inhibit mitochondrial complex I (MCI). Chronic treatment with a tool compound CP2 in 4 mouse models of familial AD was efficacious protecting against synaptic dysfunction and memory impairment, improving brain energetics and cognitive performance, reducing levels of human pTau and Ab. The objective of this study was to validate efficacy of this approach in a human brain-like environment to support its translation into clinical trials. Human induced pluripotent stem cells (hiPSC) retain the host's endogenous AD-associated genetic alterations and recapitulate multiple hallmarks of late-onset Alzheimer's disease (LOAD).
METHOD: Using pure human induced neurons (iNs) from ApoE4/4-carrying LOAD patients, we evaluated mitochondrial bioenergetics and morphology using a Seahorse XFe96 flux analyzer and electron microscopy. Axonal trafficking was assessed using MitoTracker Red and live confocal imaging. Immunohistochemistry, quantitative-PCR, and western blot were carried out to assess changes in the expression of genes and proteins, and cell viability assays were used to perform H2O2 challenge.
RESULTS: Cultures of hiPSC-derived neurons were established using a lentiviral delivery for tetracycline-inducible expression of NGN2-GFP fusion gene driven by tetracycline-responsive promoter. The validation of NGN2-iNs confirmed the development of mature molecular, cellular, and synaptic properties. LOAD iNs have a significant reduction in the motile mitochondria in axons, increased accumulation of pTau, and altered bioenergetics compared to the control neurons. At CP2 concentrations relevant to in vivo treatment in APP/PS1 and 3xTgAD mice, significant reduction of pTau was associated with improved cellular bioenergetics, restored mitochondrial motility, and increased resistance to H2O2 induced oxidative stress.
CONCLUSION: LOAD neurons carrying ApoE4/4 alleles recapitulate LOAD phenotype allowing validation of a novel mitochondria-targeted therapeutics. These data support previous observations in AD mice demonstrating that mild inhibition of MCI induce mild energetic stress with subsequent activation of multifaceted adaptive stress response and neuroprotective mechanisms improving cellular energetics and mitochondrial morphofunction in LOAD human neurons. Further efforts will be focused on the determination of mechanisms of neuroprotection.

DOI: https://doi.org/10.1002/alz.084267
Alzheimers Dement. 2024 Dec;20 Suppl 1 e090369

Basic Science and Pathogenesis.

Marzieh Eini Keleshteri, Chris D Cadonic, Taravat Ghafourian, Ella Thomson, Wanda M Snow, Danielle McAllister, Jelena Djordjevic, Subir K Roy Chowdhury, Paul Fernyhough, Jason D Fiege, Stephanie D Portet, Benedict C Albensi.

BACKGROUND: Mitochondrial bioenergetics are essential for cellular function, specifically the intricacies of the electron transport chain (ETC), with Complex IV playing a crucial role in unraveling the mechanisms governing energy production. Mathematical models offer a valuable approach to simulate these complex processes, providing insights into normal mitochondrial function and aberrations associated with various diseases, including neurodegenerative disorders. Our research focuses on introducing and refining a mathematical model, emphasizing Complex IV in the ETC, with objectives including incorporating mitochondrial activity modulation using inhibiting and uncoupling reagents, akin to oxygen consumption experiments. Rigorous validation, calibrating against Oroboros Oxygraph-2k data from C57BL/6 mouse mitochondria, ensures accurate reproduction of dynamic bioenergetic activities. The developed graphical user interface (GUI) complements objectives, providing an in silico platform for seamless hypothesis testing (in MATLAB).
METHOD: Employing an innovative kinetic methodology, our research integrates inhibiting reagents (oligomycin, rotenone, antimycin A, FCCP) into the developed computational model to simulate bioenergetic responses across varied physiological conditions. Optimization of the Mean Square Error (MSE) objective function using multiple optimizing algorithms, including the genetic algorithm, and calibration against Oroboros Oxygraph-2k data using freshly isolated mitochondria from C57BL/6 mice ensures rigorous validation of the model's precision under both unperturbed and perturbed scenarios. These outcomes unequivocally affirm the model's efficacy in accurately simulating the intricate contributions of Complex IV to bioenergetics.
RESULT: The outcomes highlight the model's efficacy in reproducing bioenergetic activities, mirroring experimental outcomes. The GUI facilitates user-friendly in silico simulations, offering a valuable complement to traditional experiments. Beyond bioenergetics, the model proves beneficial in studying mitochondrial dysfunction, presenting insights into neurodegenerative diseases. The model's potential for early detection and therapeutic intervention contributes to advancements in understanding and treating neurological disorders.
CONCLUSION: Our refined mathematical model successfully simulates mitochondrial bioenergetics, emphasizing Complex IV dynamics. Validated against experimental data, the model accurately reproduces bioenergetic activities and demonstrates the potential for studying mitochondrial dysfunction and neurodegenerative diseases. The integration of inhibiting and uncoupling reagents, along with the user-friendly GUI, enhances accessibility and usability. Our research contributes to advancing the medical understanding, emphasizing the role of computational models in unraveling mitochondrial complexities in neurological disorders.

DOI: https://doi.org/10.1002/alz.090369
Alzheimers Dement. 2024 Dec;20 Suppl 1 e085373

Basic Science and Pathogenesis.

Thi Kim Oanh Nguyen, Sergey A Trushin, Mark Ostroot, Eugenia Trushina.

BACKGROUND: While disease-modifying treatments that reduce Aβ have been recently approved by the FDA, the identification of novel therapeutic targets and strategies that target underlying mechanisms to delay the AD development are still needed. Abnormal brain energy homeostasis and mitochondria dysfunction are observed early in AD. Therefore, the development of treatments to restore these defects could be beneficial. We identified small molecule (code name CP2) as a mild and specific mitochondrial complex I (MCI) inhibitor. Application of CP2 improved brain energy homeostasis, restored synaptic and cognitive function in APP/PS1 and 3xTgAD mice. However, mechanistic relationship between MCI inhibition, glucose uptake/utilization and mitochondrial function remains to be determined.
METHOD: Cellular energy metabolism was assessed in the neuroblastoma SH-SY5Y cells that express either mutant human APP protein (APPswe) or empty vector (control) treated with vehicle or CP2. A Seahorse Extracellular Flux Analyzer was used to measure glycolysis, oxygen consumption rate, and fatty acids β-oxidation (FAO). Flow cytometry allowed determining the translocation of glucose transporters to the cell surface. Changes in protein expression in response to treatment were assessed using Western Blot analysis. Changes in mitochondrial morphology were monitored using electron microscopy. The non-radioactive Glucose Uptake-Glo™ assay was utilized for measuring glucose uptake in cells. Metabolic flux analysis was done using 13C D-Glucose stable isotope-labeling.
RESULTS: APPswe cells have a significant decrease in glycolysis and spare respiratory capacity, an indicator of the mitochondrial ability to produce energy under stress conditions. These observations were consistent with decreased glucose uptake, which was compensated by an increased FAO to provide axillary fuel for ATP production. Mechanistically, at the concentrations relevant to in vivo treatment in APP/PS1 and 3xTgAD mice, acute CP2 treatment increased glucose uptake and utilization through the translocation of glucose transporters to the plasma membrane while prolong CP2 treatment activated metabolic sensors and mitochondrial morphofunctional pathways (e.g., fission, fusion, biogenesis, and turnover) consistent with the improved cellular bioenergetics in the AMPK-dependent pathway.
CONCLUSION: Data suggested that mild MCI inhibition activates multiple neuroprotective mechanisms improving cellular energy homeostasis and mitochondrial function in vivo and in vitro, representing promising strategy that target early AD mechanisms.

DOI: https://doi.org/10.1002/alz.085373
Signal Transduct Target Ther. 2025 Jan 03. 10(1): 2

In defence of ferroptosis.

Francesca Alves, Darius Lane, Triet Phu Minh Nguyen, Ashley I Bush, Scott Ayton.

Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained by cellular defences. Ferroptosis is increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation of ferroptosis is conceived to occur not by an endogenous executioner, but by the withdrawal of cellular guardians that otherwise constantly oppose ferroptosis induction. Here, we profile key ferroptotic defence strategies including iron regulation, phospholipid modulation and enzymes and metabolite systems: glutathione reductase (GR), Ferroptosis suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Dihydrofolate reductase (DHFR), retinal reductases and retinal dehydrogenases (RDH) and thioredoxin reductases (TR). A common thread uniting all key enzymes and metabolites that combat lipid peroxidation during ferroptosis is a dependence on a key cellular reductant, nicotinamide adenine dinucleotide phosphate (NADPH). We will outline how cells control central carbon metabolism to produce NADPH and necessary precursors to defend against ferroptosis. Subsequently we will discuss evidence for ferroptosis and NADPH dysregulation in different disease contexts including glucose-6-phosphate dehydrogenase deficiency, cancer and neurodegeneration. Finally, we discuss several anti-ferroptosis therapeutic strategies spanning the use of radical trapping agents, iron modulation and glutathione dependent redox support and highlight the current landscape of clinical trials focusing on ferroptosis.

DOI: https://doi.org/10.1038/s41392-024-02088-5
Nat Commun. 2025 Jan 02. 16(1): 232

The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis.

Peilu She, Bangjun Gao, Dongliang Li, Chen Wu, Xuejiao Zhu, Yuan He, Fei Mo, Yao Qi, Daqing Jin, Yewei Chen, Xin Zhao, Jinzhong Lin, Hairong Hu, Jia Li, Bing Zhang, Peng Xie, Chengqi Lin, Vincent M Christoffels, Yueheng Wu, Ping Zhu, Tao P Zhong.

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function.

DOI: https://doi.org/10.1038/s41467-024-55557-4
Sci Adv. 2025 Jan 03. 11(1): eadk9373

Histone mark age of human tissues and cell types.

Lucas Paulo de Lima Camillo, Muhammad Haider Asif, Steve Horvath, Erica Larschan, Ritambhara Singh.

Aging is a complex and multifaceted process involving many epigenetic alterations. One key area of interest in aging research is the role of histone modifications, which can dynamically regulate gene expression. Here, we conducted a pan-tissue analysis of the dynamics of seven key histone modifications during human aging. Our histone-specific age prediction models showed surprisingly accurate performance, proving resilient to experimental and artificial noise. Simulation experiments for comparison with DNA methylation age predictors revealed competitive performance. Moreover, gene set enrichment analysis uncovered several critical developmental pathways for age prediction. Different from DNA methylation age predictors, genes known to be involved in aging biology are among the most important ones for the models. Last, we developed a pan-tissue pan-histone age predictor, suggesting that age-related epigenetic information is degenerated across the epigenome. This research highlights the power of histone marks as input for creating robust age predictors and opens avenues for understanding the role of epigenetic changes during aging.

DOI: https://doi.org/10.1126/sciadv.adk9373
Nat Commun. 2025 Jan 02. 16(1): 105

Rational engineering of minimally immunogenic nucleases for gene therapy.

Rumya Raghavan, Mirco J Friedrich, Indigo King, Samuel Chau-Duy-Tam Vo, Daniel Strebinger, Blake Lash, Michael Kilian, Michael Platten, Rhiannon K Macrae, Yifan Song, Lucas Nivon, Feng Zhang.

Genome editing using CRISPR-Cas systems is a promising avenue for the treatment of genetic diseases. However, cellular and humoral immunogenicity of genome editing tools, which originate from bacteria, complicates their clinical use. Here we report reduced immunogenicity (Red)(i)-variants of two clinically relevant nucleases, SaCas9 and AsCas12a. Through MHC-associated peptide proteomics (MAPPs) analysis, we identify putative immunogenic epitopes on each nuclease. Using computational modeling, we rationally design these proteins to evade the immune response. SaCas9 and AsCas12a Redi variants are substantially less recognized by adaptive immune components, including reduced binding affinity to MHC molecules and attenuated generation of cytotoxic T cell responses, yet maintain wild-type levels of activity and specificity. In vivo editing of PCSK9 with SaCas9.Redi.1 is comparable in efficiency to wild-type SaCas9, but significantly reduces undesired immune responses. This demonstrates the utility of this approach in engineering proteins to evade immune detection.

DOI: https://doi.org/10.1038/s41467-024-55522-1