While non-mammalian embryos often rely on spatial pre-patterning, mammalian development has long been thought to begin with equivalent blastomeres. However, emerging evidence challenges this. Here, using multiplexed and label-free single-cell proteomics, we identify over 300 asymmetrically abundant proteins—many involved in protein degradation and transport—dividing mouse 2-cell-stage blastomeres into two distinct clusters, which we term alpha and beta. These proteomic asymmetries are detectable as early as the zygote stage, intensify by the 4-cell stage, and correlate with the sperm entry site, implicating fertilization as a symmetry-breaking event. Splitting 2-cell-stage embryos into halves reveals that beta blastomeres possess greater developmental potential than alpha blastomeres. Similar clustering and protein enrichment patterns found in human 2-cell embryos suggest this early asymmetry might be conserved. These findings uncover a previously unrecognized proteomic pre-patterning triggered by fertilization in mammalian embryos, with important implications for understanding totipotency and early lineage bias.
", "doi": "10.1016/j.cell.2025.11.006", "issn": "0092-8674", "publisher": "Cell Press", "publication": "Cell", "publication_date": "2025-12-03" }, { "id": "authors:jhh97-h1c30", "collection": "authors", "collection_id": "jhh97-h1c30", "cite_using_url": "https://authors.library.caltech.edu/records/jhh97-h1c30", "type": "article", "title": "The gut microbiome promotes mitochondrial respiration in the brain of a Parkinson's disease mouse model", "author": [ { "family_name": "Morais", "given_name": "Livia H.", "orcid": "0000-0002-5738-2658", "clpid": "Morais-Livia-H" }, { "family_name": "Stiles", "given_name": "Linsey" }, { "family_name": "Freeman", "given_name": "Milla", "clpid": "Freeman-Milla" }, { "family_name": "Oguienko", "given_name": "Anastasiya D.", "orcid": "0000-0002-8473-6378", "clpid": "Oguienko-Anastasiya-D" }, { "family_name": "Hoang", "given_name": "Jonathan D.", "orcid": "0000-0002-3762-9596", "clpid": "Hoang-Jonathan-D" }, { "family_name": "Ji", "given_name": "Jenny", "orcid": "0000-0002-7901-5605", "clpid": "Ji-Jenny" }, { "family_name": "Jones", "given_name": "Jeff", "orcid": "0000-0002-7142-2222", "clpid": "Jones-Jeff" }, { "family_name": "Quan", "given_name": "Baiyi", "orcid": "0000-0001-6313-4274", "clpid": "Quan-Baiyi" }, { "family_name": "Devine", "given_name": "Jack", "clpid": "Devine-Jack" }, { "family_name": "Bois", "given_name": "Justin S.", "orcid": "0000-0001-7137-8746", "clpid": "Bois-J-S" }, { "family_name": "Chou", "given_name": "Tsui-Fen", "orcid": "0000-0003-2410-2186", "clpid": "Chou-Tsui-Fen" }, { "family_name": "Trinh", "given_name": "Joanne" }, { "family_name": "Picard", "given_name": "Martin" }, { "family_name": "Gradinaru", "given_name": "Viviana", "orcid": "0000-0001-5868-348X", "clpid": "Gradinaru-V" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "orcid": "0000-0003-2713-1513", "clpid": "Mazmanian-S-K" } ], "abstract": "The pathophysiology of Parkinson’s disease (PD) involves gene-environment interactions that impair various cellular processes including mitochondrial dysfunction. Mitochondria-associated mutations increase PD risk, respiration is altered in the PD brain, and mitochondria-damaging toxicants cause PD-like motor and gastrointestinal symptoms in animal models. The gut microbiome is altered in PD, representing an environmental risk, however a relationship between mitochondrial function and the microbiome in PD has not been previously established. Herein, we discover that dysregulation of mitochondria-associated genes and hyperactive striatal mitochondria are induced by the microbiome in α-synuclein-overexpressing (Thy1-ASO) mice. Thy1-ASO mice elaborate increased reactive oxygen species in the striatum whereas germ-free counterparts express increased oxygen scavenging proteins. Indeed, treatment with an antioxidant drug improves motor performance in Thy1-ASO mice and blocking oxidant scavenging in germ-free mice enhances motor deficits in an α-synuclein dependent manner. Thus, the gut microbiome promotes motor symptoms in a mouse model of PD via increased mitochondrial respiration and oxidative stress in the brain.
", "doi": "10.1038/s41531-025-01142-5", "pmcid": "PMC12537952", "issn": "2373-8057", "publisher": "Nature Publishing Group", "publication": "npj Parkinson's Disease", "publication_date": "2025-10-20", "volume": "11", "pages": "301" }, { "id": "authors:nbrpd-dvh59", "collection": "authors", "collection_id": "nbrpd-dvh59", "cite_using_url": "https://authors.library.caltech.edu/records/nbrpd-dvh59", "type": "article", "title": "Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress", "author": [ { "family_name": "Rosencrans", "given_name": "William M.", "orcid": "0000-0003-1461-8891", "clpid": "Rosencrans-William-M" }, { "family_name": "Lee", "given_name": "Ryan W.", "orcid": "0009-0006-6926-185X", "clpid": "Lee-Ryan-W" }, { "family_name": "McGraw", "given_name": "Logan", "orcid": "0000-0002-7886-5819", "clpid": "McGraw-Logan" }, { "family_name": "Horsburgh", "given_name": "Ian", "orcid": "0009-0003-2111-2415", "clpid": "Horsburgh-Ian" }, { "family_name": "Wang", "given_name": "Ting-Yu", "orcid": "0000-0002-9014-6825", "clpid": "Wang-Ting-Yu" }, { "family_name": "Quan", "given_name": "Baiyi", "orcid": "0000-0001-6313-4274", "clpid": "Quan-Baiyi" }, { "family_name": "Huynh", "given_name": "Diana", "clpid": "Huynh-Diana" }, { "family_name": "Johnston", "given_name": "Jennifer A.", "orcid": "0000-0002-4867-9230", "clpid": "Johnston-Jennifer-A" }, { "family_name": "Chan", "given_name": "David C.", "orcid": "0000-0002-0191-2154", "clpid": "Chan-D-C" }, { "family_name": "Chou", "given_name": "Tsui-Fen", "orcid": "0000-0003-2410-2186", "clpid": "Chou-Tsui-Fen" } ], "abstract": "The PINK1/Parkin pathway targets damaged mitochondria for degradation via mitophagy. Genetic evidence implicates impaired mitophagy in Parkinson’s disease, making its pharmacological enhancement a promising therapeutic strategy. Here, we characterize two mitophagy activators: a novel Parkin activator, FB231, and the reported PINK1 activator MTK458. Both compounds lower the threshold for mitochondrial toxins to induce PINK1/Parkin-mediated mitophagy. However, global proteomics revealed that FB231 and MTK458 independently induce mild mitochondrial stress, resulting in impaired mitochondrial function and activation of the integrated stress response, effects that result from PINK1/Parkin-independent off-target activities. We find that these compounds impair mitochondria by distinct mechanisms and synergistically decrease mitochondrial function and cell viability in combination with classical mitochondrial toxins. Our findings support a model whereby weak or “silent” mitochondrial toxins potentiate other mitochondrial stressors, enhancing PINK1/Parkin-mediated mitophagy. These insights highlight important considerations for therapeutic strategies targeting mitophagy activation in Parkinson’s disease.
", "doi": "10.1126/sciadv.ady0240", "pmcid": "PMC12383277", "issn": "2375-2548", "publisher": "American Association for the Advancement of Science", "publication": "Science Advances", "publication_date": "2025-08-27", "series_number": "35", "volume": "11", "issue": "35", "pages": "ady0240" }, { "id": "authors:x44fc-kq819", "collection": "authors", "collection_id": "x44fc-kq819", "cite_using_url": "https://authors.library.caltech.edu/records/x44fc-kq819", "type": "article", "title": "Increasing Proteome Coverage Through a Reduction in Analyte Complexity in Single-Cell Equivalent Samples", "author": [ { "family_name": "Pang", "given_name": "Marion", "orcid": "0000-0002-0158-2976", "clpid": "Pang-Marion" }, { "family_name": "Jones", "given_name": "Jeff J.", "orcid": "0000-0002-7142-2222", "clpid": "Jones-Jeff-J" }, { "family_name": "Wang", "given_name": "Ting-Yu", "orcid": "0000-0002-9014-6825", "clpid": "Wang-Ting-Yu" }, { "family_name": "Quan", "given_name": "Baiyi", "orcid": "0000-0001-6313-4274", "clpid": "Quan-Baiyi" }, { "family_name": "Kubat", "given_name": "Nicole J.", "clpid": "Kubat-Nicole-J" }, { "family_name": "Qiu", "given_name": "Yanping", "orcid": "0000-0003-2948-2173", "clpid": "Qiu-Yanping" }, { "family_name": "Roukes", "given_name": "Michael L.", "orcid": "0000-0002-2916-6026", "clpid": "Roukes-M-L" }, { "family_name": "Chou", "given_name": "Tsui-Fen", "orcid": "0000-0003-2410-2186", "clpid": "Chou-Tsui-Fen" } ], "abstract": "The advancement of sophisticated instrumentation in mass spectrometry has catalyzed an in-depth exploration of complex proteomes. This exploration necessitates a nuanced balance in experimental design, particularly between quantitative precision and the enumeration of analytes detected. In bottom-up proteomics, a key challenge is that oversampling of abundant proteins can adversely affect the identification of a diverse array of unique proteins. This issue is especially pronounced in samples with limited analytes, such as small tissue biopsies or single-cell samples. Methods such as depletion and fractionation are suboptimal to reduce oversampling in single cell samples, and other improvements on LC and mass spectrometry technologies and methods have been developed to address the trade-off between precision and enumeration. We demonstrate that by using a monosubstrate protease for proteomic analysis of single-cell equivalent digest samples, an improvement in quantitative accuracy can be achieved, while maintaining high proteome coverage established by trypsin. This improvement is particularly vital for the field of single-cell proteomics, where single-cell samples with limited number of protein copies, especially in the context of low-abundance proteins, can benefit from considering analyte complexity. Considerations about analyte complexity, alongside chromatographic complexity, integration with data acquisition methods, and other factors such as those involving enzyme kinetics, will be crucial in the design of future single-cell workflows.
\n