Abstract
TAp73 loss impairs mitochondrial respiration and ROS homeostasis and promotes senescence.
Major finding: TAp73 loss impairs mitochondrial respiration and ROS homeostasis and promotes senescence.
Mechanism: Reduced expression of the p73 target gene COX4I1 compromises mitochondrial complex IV activity.
Impact: These findings expand on the functions of the TP53 tumor suppressor family of proteins.
Increased oxidative damage, mediated by mitochondrial dysfunction and accumulation of reactive oxygen species (ROS), has been implicated as a potential mechanism underlying aging. A key protein in this process is the tumor suppressor TP53, which modulates mitochondrial oxidative respiration. Rufini and colleagues investigated the role of the closely related family member, TP73, in aging using mice deficient for the transcriptionally active (TAp73) isoform. These mice exhibited several age-related phenotypes, including decreased survival, reduced body weights and percentage of body fat, and epidermal thinning. In addition, elevated levels of oxidized proteins were detected in knockout tissues, suggesting that TAp73 loss promotes an aging phenotype. In support of this idea, TAp73 deficiency sensitized mouse embryonic fibroblasts (MEF) to oxidative damage and enhanced intracellular ROS production, which correlated with induction of replicative senescence in vitro. This increased susceptibility to oxidative damage was mediated by decreased oxygen consumption and diminished ATP levels in TAp73-depleted MEFs and human colon carcinoma cells, as well as in murine tissues, and a selective reduction in the function of the mitochondrial electron transport chain complex IV cytochrome C oxidase (COX), indicative of impaired mitochondrial respiration. TAp73-mediated regulation of mitochondrial bioenergetics was dependent on the induction of cytochrome C oxidase subunit 4 isoform 1 (COX4I1), which encodes for the regulatory subunit of the COX enzyme and was confirmed to be a direct transcriptional target of TAp73. Furthermore, COX4I1 depletion phenocopied the effects of TAp73 loss, including decreased oxygen flux, enhanced sensitivity to oxidative damage, and induction of senescence, whereas Cox4i1 overexpression was sufficient to restore mitochondrial function in TAp73-deficient MEFs. These results indicate that all members of the TP53 family are involved in linking the DNA damage response to antiaging metabolic functions.
