Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
Open accessAbstract
Accumulation of depolarized mitochondria within beta-cells has been associated with oxidative damage and development of diabetes. To determine the source and fate of depolarized mitochondria, individual mitochondria were photolabeled and tracked through fusion and fission. Mitochondria were found to go through frequent cycles of fusion and fission in a 'kiss and run' pattern. Fission events often generated uneven daughter units: one daughter exhibited increased membrane potential (delta psi(m)) and a high probability of subsequent fusion, while the other had decreased membrane potential and a reduced probability for a fusion event. Together, this pattern generated a subpopulation of non-fusing mitochondria that were found to have reduced delta psi(m) and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1(K38A) or FIS1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins, reduced respiration and impaired insulin secretion. Pulse chase and arrest of autophagy at the pre-proteolysis stage reveal that before autophagy mitochondria lose delta psi(m) and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.
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Dysfunctional mitochondrial dynamics, particularly excessive mitochondrial fission, have been associated with oxidative stress, mitochondrial DNA damage, and cellular senescence in various cell types.
“Dysfunctional mitochondrial dynamics, as observed here, particularly excessive mitochondrial fission, have been associated with oxidative stress, mitochondrial DNA damage, and cellular senescence in various cell types (Twig et al., 2008; Miwa et al., 2022).”
From Aging promotes an increase in mitochondrial fragmentation in astrocytes (2024) · cites this paper as Twig et al., 2008
In “Inhibition of fission reduces mitochondrial autophagy” (page not provided), the paper reports increased oxidized mitochondrial proteins when fission is inhibited, but not increased ROS. “Mitochondrial dynamics and insulin secretion” (page not provided) discusses senescence in cells where fission has been hampered. These passages do not support excessive fission as the associated change, and the copy does not report mitochondrial DNA damage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFusion between healthy and damaged organelles allows dilution of damaged material into the healthy network, avoids accumulation of dysfunctional mitochondria, and maintains overall function.
“Besides, the fusion between healthy and damaged organelles allows to dilute the damaged material into the healthy network, avoids the accumulation of dysfunctional mitochondria, and maintains their overall function [58].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [58]
Impairment of fission leads to disruption of selective mitochondrial autophagic degradation, followed by dysfunctional organelle accumulation.
“Impairment of fission leads to the disruption of selective mitochondrial autophagic degradation, followed by dysfunctional organelles accumulation [58, 196–200].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [58]
Mitochondrial fusion in mammalian cells is regulated by Mfn1, Mfn2, and Opa1.
“Mitochondrial fusion in mammalian cells is regulated by the proteins mitofusin 1 and mitofusin 2 (Mfn1 and Mfn2) and optic atrophy 1 (Opa1).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Twig et al, 2008
Fission segregates components of the mitochondrial network that are irreversibly damaged or unnecessary for subsequent removal.
“Fission segregates components of the network that are irreversibly damaged or unnecessary for subsequent removal (Twig et al., 2008).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Twig et al., 2008
A functional fission machinery is important to discard damaged mitochondria by autophagy or mitophagy.
“These facts highlight the importance of a functional fission machinery to discard damaged mitochondria by autophagy or mitophagy (Gomes and Scorrano, 2008; Twig et al., 2008).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Twig et al., 2008
The fragmentation of mitochondria is a prerequisite for autophagy, and smaller mitochondria might be autophagocytosed more easily than larger ones and require less energy.
“The fragmentation of mitochondria is a prerequisite for autophagy (Twig et al., 2008), which might be physiologically favorable: smaller mitochondria might be autophagocytosed more easily than larger ones and require less energy.”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Twig et al., 2008
In response to oxidant-induced damage, mitochondrial fission generates daughter mitochondria with different Δψm, whereby mitochondria with a lower Δψm can be targeted for degradation by autophagy, whereas parent mitochondria remain intact.
“Intriguingly, in response to oxidant-induced damage, mitochondrial fission generates daughter mitochondria with different Δψm, whereby mitochondria with a lower Δψm can be targeted for degradation by autophagy, whereas parent mitochondria remain intact (Gomes and Scorrano, 2008; Twig et al., 2008).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Twig et al., 2008
In neuronal cells, Fis1 was shown to activate autophagy and the selective degradation of depolarized mitochondria.
“The link between fission proteins and mitochondrial turnover has also been illustrated in neuronal cells, in which Fis1 was shown to activate autophagy and the selective degradation of depolarized mitochondria (Twig et al., 2008).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Twig et al., 2008
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<i>Drosophila</i> Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin
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AUTACs: Cargo-Specific Degraders Using Selective Autophagy
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Self-citationMiD49 and MiD51, new components of the mitochondrial fission machinery
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Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD
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- Authors
- Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., Alroy, J., Wu, M., Py, B. F., Yuan, J., Deeney, J. T., Corkey, B. E., & Shirihai, O. S.
- Affiliations
- Tufts University (US)
- Boston University (US)
- Billerica Public Library (US)
- Harvard University (US)
- Corresponding author
- Shirihai, Orian S
- ORCID
- Venue
- The EMBO Journal
- Published
- 2008-01-17
- Volume
- 27
- Issue
- 2
- Pages
- 433-446
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2234339
- OpenAlex
- W2139636031
- Cited by
- 3,082
- References
- 39
- Citations by year
- 2026: 107 · 2025: 144 · 2024: 207 · 2023: 167 · 2022: 186 · 2021: 217 · 2020: 204 · 2019: 176 · 2018: 194 · 2017: 193 · 2016: 188 · 2015: 185 · 2014: 165 · 2013: 171 · 2012: 202
- FWCI
- 91.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Science Foundation (0215829)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL071629)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074778)
- National Center for Research Resources (P41RR001395)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- mitochondrial fission, mitochondrial fusion, kiss-and-run, mitophagy, OPA1, Drp1, Fis1, pancreatic beta cells, insulin secretion, mitochondrial membrane potential, oxidative stress, diabetes mellitus, mitochondrial segregation
- MeSH terms
- Autophagy-Related Protein 5, Insulin Secretion, Animals, Autophagy, Cell Line, Genotype, Insulin, Male, Mice, Inbred C57BL, Microtubule-Associated Proteins, Mitochondria, Models, Biological, Mutation, Reactive Oxygen Species, Microscopy, Confocal, GTP Phosphohydrolases, Mitochondrial Proteins, Green Fluorescent Proteins, Insulin-Secreting Cells, Mice, Membrane Potential, Mitochondrial
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