Oxidized SOD1 accelerates aging by compromising the formation of mitochondrial-derived vesicles

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dc.contributor.authorGuo, Ying
dc.contributor.examiningcommitteeWang, Junfeng (Pharmacology and Therapeutics)
dc.contributor.examiningcommitteeGhavami, Saeid (Human Anatomy and Cell Science)
dc.contributor.examiningcommitteeMarzban, Hassan (Human Anatomy and Cell Science)
dc.contributor.examiningcommitteeZhang, Guohui (Human Anatomy and Cell Science)
dc.contributor.examiningcommitteeTaghibiglou, Changiz (University of Saskatchewan)
dc.contributor.supervisorKong, Jiming
dc.date.accessioned2023-12-01T20:41:51Z
dc.date.available2023-12-01T20:41:51Z
dc.date.issued2023-11-30
dc.date.submitted2023-11-30T07:11:18Zen_US
dc.degree.disciplineHuman Anatomy and Cell Scienceen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)
dc.description.abstractAging is a complex process marked by a gradual decline in the function of multiple organelles, contributing to various age-related disorders. The specific causes and underlying mechanisms of aging remain largely unknown. Superoxide dismutase 1 (SOD1) is an antioxidant but is susceptible to oxidative modification. Once oxidized, SOD1 undergoes aberrant misfolding and acquires toxic properties associated with age-related disorders. The present study aims to investigate the role of oxidized SOD1 in aging. We found that the mouse motor neuron-like NSC34 cells expressing the human SOD1 (hSOD1) gene with a G93A mutation (hSOD1G93A) underwent early entrance into senescence, and the hSOD1G93A transgenic mice exhibited aging phenotypes at an early age. In addition, we discovered that the wild-type hSOD1, when oxidized, could also induce cellular senescence in neural stem cells (NSCs). A high level of oxidized SOD1 was present in both senescent NSC34 cells and mouse NSCs expressing the hSOD1 gene. Notably, the extracellular vesicles (EVs) derived from senescent NSCs containing a high level of oxidized SOD1 accelerated the senescence of young NSCs and induced the death of neurons in the culture. Blocking oxidized SOD1 in EVs by an interference peptide restored the proliferation of NSCs and mitigated the toxicity of EVs to neurons. Additionally, we found mitochondria malfunctioned in both senescent NSC34 cells and mouse motor neurons of hSODG93A transgenic mice in middle age. Interestingly, mitochondria exhibited increased production of mitochondrial-derived vesicles (MDVs) during the early stages of aging; however, the responsiveness of mitochondria to mild oxidative stress gradually declined. In conclusion, our data show that oxidized SOD1 increases in senescent cells and transgenic mice with advancing age. Targeted removal of oxidized SOD1 significantly decreases biomarkers of senescence. Therefore, oxidized SOD1 is a causal factor of aging. Selective removal of oxidized SOD1 represents a promising strategy to rejuvenate senescent NSCs and decelerate aging. Meanwhile, the modulation of MDVs plays a role in early aging. Thus, the mitochondrial responsiveness to produce MDVs could serve as an indicator of premature aging.
dc.description.noteFebruary 2024
dc.identifier.urihttp://hdl.handle.net/1993/37840
dc.language.isoeng
dc.rightsopen accessen_US
dc.subjectAging
dc.subjectCellular senescence
dc.subjectSuperoxide dismutase 1
dc.subjectOxidative modification
dc.subjectMitochondrial dysfunction
dc.subjectMitochondrial-derived vesicles
dc.titleOxidized SOD1 accelerates aging by compromising the formation of mitochondrial-derived vesicles
dc.typedoctoral thesisen_US
local.subject.manitobano
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