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Pathogenic Morphological Signatures of Perturbations in Mitochondrial-Related Genes Revealed by Pooled Imaging Assay
Open accessPreprint — published as 10.1038/s44303-025-00097-9 · Paper page
Abstract
Mutations in mitochondrial-related genes underlie numerous neurodegenerative diseases, yet the significance of most variants remains uncertain concerning disease phenotypes. Several thousand genes have been shown to regulate mitochondria in eukaryotic cells, but which of these genes are necessary for proper mitochondrial dynamics? We investigated the degree of morphological disruptions in mitochondrial gene-silenced cells to understand the magnitude of genetic contribution to properly functioning mitochondria and to identify pathogenic variants. We analyzed 5,835 gRNAs in a high dimensional phenotypic dataset produced by the image-based pooled analysis platform Raft-Seq. Using the MFN2-mutant cell phenotype, we identified several genes, including TMEM11, TIMM8A, and three NADH Ubiquinone proteins, as crucial for normal mitochondrial morphology in human U2OS cells. Additionally, we found several missense and UTR variants within the genes SLC25A19 and ATAD3A as drivers of mitochondrial aggregation. By examining multiple features instead of a single readout, this analysis was powered to detect genes which had morphological ‘signatures’ aligned with MFN2-mutant phenotypes. Reanalysis with anomaly detection revealed other critical genes, including APOOL, MCEE, NIT, PHB, and SLC16A7, which perturb mitochondrial network morphology in a manner divergent from MFN2. These studies offer insights into the molecular basis for mitochondrial dysfunction, setting the stage for new genomic diagnostics and therapeutic discovery.
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Metadata
- Authors
- Kremitzki, C., Waligorski, J., Bachman, G., Mohammed Ali, L., Bramley, J., Vakaki, M., Chandrasekaren, V., Patel, P., Mather, D., Hime, P., Mitra, R., Milbrandt, J., & Buchser, W.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Buchser, William
- ORCID
- Venue
- npj Imaging
- Publisher
- openRxiv
- Published
- 2023-10-02
- Volume
- 3
- Issue
- 1
- Pages
- 35-35
- ISSN
- 2948-197X (ISSN-L)
- PMC
- PMC12316947
- OpenAlex
- W4412825679
- Cited by
- 2
- References
- 1
- Citations by year
- 2026: 2
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- npj Imaging (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- mitochondrial dynamics, mitochondrial morphology, MFN2 mutations, neurodegenerative diseases, complex I, ATAD3A, mitochondrial aggregation, U2OS cells, pathogenic variants
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