The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans
Open accessAbstract
The increased longevity of the C. elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here we show that the mtROS signal is relayed by the conserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein. Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival. In vertebrates, mtROS induce apoptosis through the intrinsic pathway to protect from severely damaged cells. Our observations in nematodes demonstrate that sensing of mtROS by the apoptotic pathway can, independently of apoptosis, elicit protective mechanisms that keep the organism alive under stressful conditions. This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging.
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The canonical caspase-dependent C. elegans PCD pathway was recently found to be required for increased life span caused by ETC mutants and retrograde ROS signaling.
“Intriguingly, the canonical caspase-dependent C. elegans PCD pathway was recently found to be required for increased life span caused by ETC mutants and retrograde ROS signaling (Yee et al., 2014), in the absence of overt PCD.”
From Programmed cell death in aging (2015) · cites this paper as Yee et al., 2014
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- Authors
- Yee, C., Yang, W., & Hekimi, S.
- Affiliations
- McGill University (CA)
- Corresponding author
- Hekimi, Siegfried
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 157
- Issue
- 4
- Pages
- 897-909
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4454526
- OpenAlex
- W1980429333
- Cited by
- 356
- References
- 42
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 21 · 2023: 20 · 2022: 31 · 2021: 33 · 2020: 20 · 2019: 36 · 2018: 36 · 2017: 41 · 2016: 48 · 2015: 37 · 2014: 17
- FWCI
- 16.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P40OD010440)
- Canadian Institutes of Health Research (97869_1, 123295_1, 114891_1, MOP-97869)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- 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
- Keywords
- mitochondrial reactive oxygen species, mitochondrial apoptosis, longevity, Caenorhabditis elegans, isp-1, electron transport chain, BH3-only proteins, mitochondrial dysfunction, stress tolerance, aging, mitochondrial signaling
- MeSH terms
- Adenosine Triphosphate, Aging, Animals, Electron Transport, Longevity, Mitochondria, Oxygen, Superoxide Dismutase, Electron Transport Complex III, Signal Transduction, Caenorhabditis elegans, Apoptosis, Reactive Oxygen Species, Caenorhabditis elegans Proteins, Transcriptome
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