Mitochondrial peptidase IMMP2L mutation causes early onset of age‐associated disorders and impairs adult stem cell self‐renewal
Open accessAbstract
Summary: Mitochondrial reactive oxygen species (ROS) are proposed to play a central role in aging and age‐associated disorders, although direct in vivo evidence is lacking. We recently generated a mouse mutant with mutated inner mitochondrial membrane peptidase 2‐like (Immp2l) gene, which impairs the signal peptide sequence processing of mitochondrial proteins cytochrome c1 and glycerol phosphate dehydrogenase 2. The mitochondria from mutant mice generate elevated levels of superoxide ion and cause impaired fertility in both sexes. Here, we design experiments to examine the effects of excessive mitochondrial ROS generation on health span. We show that Immp2l mutation increases oxidative stress in multiple organs such as the brain and the kidney, although expression of superoxide dismutases in these tissues of the mutants is also increased. The mutants show multiple aging‐associated phenotypes, including wasting, sarcopenia, loss of subcutaneous fat, kyphosis, and ataxia, with female mutants showing earlier onset and more severe age‐associated disorders than male mutants. The loss of body weight and fat was unrelated to food intake. Adipose‐derived stromal cells (ADSC) from mutant mice showed impaired proliferation capability, formed significantly less and smaller colonies in colony formation assays, although they retained adipogenic differentiation capability in vitro. This functional impairment was accompanied by increased levels of oxidative stress. Our data showed that mitochondrial ROS is the driving force of accelerated aging and suggested that ROS damage to adult stem cells could be one of the mechanisms for age‐associated disorders.
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Mitochondrial reactive oxygen species is a driving force of accelerated aging caused by reactive oxygen species damage in adult stem cells.
“Mitochondrial ROS has also been suggested to be a driving force of accelerated aging caused by ROS damage in adult stem cells [139].”
From Ultraviolet Radiation‐Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging (2016) · cites this paper as [139]
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- Authors
- George, S. K., Jiao, Y., Bishop, C. E., & Lu, B.
- Affiliations
- Wake Forest University Health Sciences (US)
- Corresponding author
- Lu, Baisong
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2011-04-07
- Volume
- 10
- Issue
- 4
- Pages
- 584-594
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3111879
- OpenAlex
- W1595040614
- Cited by
- 66
- References
- 67
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 7 · 2019: 3 · 2018: 8 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 6 · 2013: 7 · 2012: 7
- FWCI
- 2.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wake Forest University
- National Institutes of Health
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01HD043421, R01HD058058)
- 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 › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- IMMP2L, mitochondrial reactive oxygen species, superoxide, aging, adipose-derived stromal cells, oxidative stress, signal peptide processing, cytochrome c1, superoxide dismutase, sex differences, sarcopenia, healthspan
- MeSH terms
- Animals, Ataxia, Female, Kyphosis, Male, Mice, Mutant Strains, Mitochondria, Mutation, Endopeptidases, Sex Factors, Reactive Oxygen Species, Oxidative Stress, Wasting Syndrome, Aging, Premature, Mitochondrial Proteins, Mitochondrial Membranes, Mice, Adult Stem Cells, Sarcopenia
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