Distinct fission signatures predict mitochondrial degradation or biogenesis.
Open accessPublished version of a preprint
Abstract
Mitochondrial fission is a highly regulated process that, when disrupted, can alter metabolism, proliferation and apoptosis 1-3. Dysregulation has been linked to neurodegeneration 3,4, cardiovascular disease 3 and cancer 5. Key components of the fission machinery include the endoplasmic reticulum 6 and actin 7, which initiate constriction before dynamin-related protein 1 (DRP1)8 binds to the outer mitochondrial membrane via adaptor proteins 9-11, to drive scission 12. In the mitochondrial life cycle, fission enables both biogenesis of new mitochondria and clearance of dysfunctional mitochondria through mitophagy 1,13. Current models of fission regulation cannot explain how those dual fates are decided. However, uncovering fate determinants is challenging, as fission is unpredictable, and mitochondrial morphology is heterogeneous, with ultrastructural features that are below the diffraction limit. Here, we used live-cell structured illumination microscopy to capture mitochondrial dynamics. By analysing hundreds of fissions in African green monkey Cos-7 cells and mouse cardiomyocytes, we discovered two functionally and mechanistically distinct types of fission. Division at the periphery enables damaged material to be shed into smaller mitochondria destined for mitophagy, whereas division at the midzone leads to the proliferation of mitochondria. Both types are mediated by DRP1, but endoplasmic reticulum- and actin-mediated pre-constriction and the adaptor MFF govern only midzone fission. Peripheral fission is preceded by lysosomal contact and is regulated by the mitochondrial outer membrane protein FIS1. These distinct molecular mechanisms explain how cells independently regulate fission, leading to distinct mitochondrial fates.
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The dysregulation of mitochondrial fusion and fission pathways in senescent astrocytes likely contributes to mitochondrial dysfunction, oxidative stress, and the overall senescence-associated phenotype observed in these cells.
“Therefore, the dysregulation of mitochondrial fusion and fission pathways in senescent astrocytes likely contributes to mitochondrial dysfunction, oxidative stress, and the overall senescence-associated phenotype observed in these cells (Ma et al., 2020; Kleele et al., 2021; Miwa et al., 2022).”
From Aging promotes an increase in mitochondrial fragmentation in astrocytes (2024) · cites this paper as Kleele et al., 2021
The ‘Dysfunction precedes peripheral fission’ section (page unavailable) links one type of fission with elevated ROS and reduced mitochondrial membrane potential, and the Discussion says dysregulated fission could disrupt cell homeostasis. But the paper studies Cos-7 cells and mouse cardiomyocytes, not senescent astrocytes; it does not establish that disrupted fusion and fission cause oxidative stress or the senescence-associated phenotype in those cells. Indeed, its measurements place ROS accumulation before peripheral fission. (LLM, conf=0.84)
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“Mitochondrial fission separates the damaged part from the healthy mitochondrial network or occurs during cell mitosis, producing two new mitochondria to meet cell division needs (33, 37).”
BackgroundAging promotes an increase in mitochondrial fragmentation in astrocytes
Araujo, A. P. B., Vargas, G., Hayashide, L. D. S., Matias, I., Andrade, C. B. V., de Carvalho, J. J., Gomes, F. C. A., & Diniz, L. P. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1496163 · Cited by 43 · see citing works
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“Notably, newly emerged daughter mitochondria originating from peripheral fi ssion typically lack nucleoids and replicative mitochondrial DNA (mtDNA); instead, they tend to encapsulate damaged constituents and are marked for eventual mitophagic degradation (Kleele et al, 2021; Kraus et al, 2021).”
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Ohno, H., Nishimura, T., Kainoh, K., Ohashi, Y., Onodera, N., Kano, M., Sari, L. N., Masuda, M., Tamura, Y., Nishino, T., et al. (2026) · The FEBS Journal · doi:10.1111/febs.70286 · Cited by 2 · see citing works
- Authors
- Kleele, T., Rey, T., Winter, J., Zaganelli, S., Mahecic, D., Perreten Lambert, H., Ruberto, F. P., Nemir, M., Wai, T., Pedrazzini, T., & Manley, S.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lausanne (CH)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Kleele, Tatjana
- Manley, Suliana
- ORCID
- Venue
- Nature
- Published
- 2021-05-05
- Volume
- 593
- Issue
- 7859
- Pages
- 435-439
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3157724466
- Cited by
- 794
- References
- 13
- Citations by year
- 2026: 167 · 2025: 175 · 2024: 173 · 2023: 142 · 2022: 99 · 2021: 36 · 2020: 1 · 2012: 1
- FWCI
- 35.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nd)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Zenodo (CERN European Organization for Nuclear Research) (cc-by)
- Funders
- National Science Foundation
- École Polytechnique Fédérale de Lausanne
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (182429, 173738, 182322)
- National Institutes of Health
- H2020 European Research Council (819823)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- mitochondrial fission, mitophagy, mitochondrial biogenesis, Drp1, Fis1, Mff, endoplasmic reticulum, actin, mitochondrial morphology, mitochondrial dynamics, cardiomyocytes, COS-7 cells, structured illumination microscopy
- MeSH terms
- Actins, Animals, Cell Survival, Cells, Cultured, Chlorocebus aethiops, DNA, Mitochondrial, Endoplasmic Reticulum, Humans, Lysosomes, Membrane Proteins, Mitochondria, COS Cells, Mitochondrial Proteins, Dynamins, Mice, Mitochondrial Dynamics, Mitophagy
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