Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins
Open accessAbstract
Mitochondrial injury, characterized by outer membrane permeabilization and consequent release of apoptogenic factors, is a key to apoptosis of mammalian cells. Bax and Bak, two multidomain Bcl-2 family proteins, provide a requisite gateway to mitochondrial injury. However it is unclear how Bax and Bak cooperate to provoke mitochondrial injury and whether their roles are redundant. Here, we have identified a unique role of Bak in mitochondrial fragmentation, a seemingly morphological event that contributes to mitochondrial injury during apoptosis. We show that mitochondrial fragmentation is attenuated in Bak-deficient mouse embryonic fibroblasts, baby mouse kidney cells, and, importantly, also in primary neurons isolated from brain cortex of Bak-deficient mice. In sharp contrast, Bax deficiency does not prevent mitochondrial fragmentation during apoptosis. Bcl-2 and Bcl-XL inhibit mitochondrial fragmentation, and their inhibitory effects depend on the presence of Bak. Reconstitution of Bak into Bax/Bak double-knockout cells restores mitochondrial fragmentation, whereas reconstitution of Bax is much less effective. Bak interacts with Mfn1 and Mfn2, two mitochondrial fusion proteins. During apoptosis, Bak dissociates from Mfn2 and enhances the association with Mfn1. Mutation of Bak in the BH3 domain prevents its dissociation from Mfn2 and diminishes its mitochondrial fragmentation activity. This study has uncovered a previously unrecognized function of Bak in the regulation of mitochondrial morphological dynamics during apoptosis. By this function, Bak may collaborate with Bax to permeabilize the outer membrane of mitochondria, unleashing the apoptotic cascade.
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Mitochondrial fusion is inhibited following MOMP, primarily due to repression of Mfn2 activity by Bax.
“It has been shown that mitochondrial fusion is inhibited following MOMP (Brooks et al., 2007), primarily due to repression of Mfn2 activity by Bax (Karbowski et al., 2002; Karbowski et al., 2006).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Brooks et al., 2007
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- Authors
- Brooks, C., Wei, Q., Feng, L., Dong, G., Tao, Y., Mei, L., Xie, Z.-J., & Dong, Z.
- Affiliations
- Augusta University (US)
- *Department of Cellular Biology and Anatomy,
- University of Toledo (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-07-10
- Volume
- 104
- Issue
- 28
- Pages
- 11649-11654
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1913853
- OpenAlex
- W2002321863
- Cited by
- 351
- References
- 47
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 17 · 2023: 10 · 2022: 15 · 2021: 16 · 2020: 20 · 2019: 19 · 2018: 11 · 2017: 18 · 2016: 23 · 2015: 15 · 2014: 22 · 2013: 26 · 2012: 22
- FWCI
- 10.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- University of Pittsburgh
- National Institutes of Health
- School of Medicine, Stanford University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Bak, Bax, apoptosis, mitochondrial fragmentation, mitochondrial morphology, mitofusins, Mfn1, mitofusin 2, Bcl-2, Bcl-xL, outer membrane permeabilization, BH3 domain, Bcl-2 family proteins, neurons, mitochondrial injury
- MeSH terms
- Animals, Animals, Newborn, Cells, Cultured, HeLa Cells, Humans, Intracellular Membranes, Mitochondria, Permeability, Apoptosis, GTP Phosphohydrolases, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mice
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