Mitochondrial maintenance failure in aging and role of sexual dimorphism

Abstract

Gene expression changes during aging are partly conserved across species, and suggest that oxidative stress, inflammation and proteotoxicity result from mitochondrial malfunction and abnormal mitochondrial-nuclear signaling. Mitochondrial maintenance failure may result from trade-offs between mitochondrial turnover versus growth and reproduction, sexual antagonistic pleiotropy and genetic conflicts resulting from uni-parental mitochondrial transmission, as well as mitochondrial and nuclear mutations and loss of epigenetic regulation. Aging phenotypes and interventions are often sex-specific, indicating that both male and female sexual differentiation promote mitochondrial failure and aging. Studies in mammals and invertebrates implicate autophagy, apoptosis, AKT, PARP, p53 and FOXO in mediating sex-specific differences in stress resistance and aging. The data support a model where the genes Sxl in Drosophila, sdc-2 in C. elegans, and Xist in mammals regulate mitochondrial maintenance across generations and in aging. Several interventions that increase life span cause a mitochondrial unfolded protein response (UPRmt), and UPRmt is also observed during normal aging, indicating hormesis. The UPRmt may increase life span by stimulating mitochondrial turnover through autophagy, and/or by inhibiting the production of hormones and toxic metabolites. The data suggest that metazoan life span interventions may act through a common hormesis mechanism involving liver UPRmt, mitochondrial maintenance and sexual differentiation.

Drosophila melanogaster mitochondrial Hsp22: a role in resistance to oxidative stress, aging and the mitochondrial unfolding protein response

“…Accordingly, UPR MT activation in muscles was shown to have repercussion in peripheral tissues and to promote healthy longevity (Owusu-Ansah et al 2008). While the ImpL2 branch of mitochondrial stress defense would promote mitophagy, the concomitant dFOXO activation may also up-regulate the mitochondrial superoxide dismutase (MnSOD), which can in return induce UPR MT (Curtis et al 2007;Demontis and Perrimon 2010;Honda and Honda 1999;Shen and Tower 2013;Tower 2014;Zarse et al 2012). Interestingly, in addition to being a direct transcriptional target of dFOXO activity, Hsp22 is also induced by MnSOD over-expression (Curtis et al 2007;Harvey et al 2008;Tower et al 2014).…”

“…1). One peculiarity of this sHSP is that it can influence its own level of expression , and it was therefore suggested that Hsp22 could take part in the amplification of the UPR MT signal (Shen and Tower 2013;Tower 2014). The level of induction of Hsp60 expression depends on the cause of mitochondrial stress underlying the existence of more then one branch of UPR MT (Bennett and Kaeberlein 2014;Bennett et al 2014;Hill and Van Remmen 2014;Jensen and Jasper 2014;Runkel et al 2013Runkel et al , 2014.…”

“…In fact some aspects of the UPR MT are limited by the nature of the stress, the age and the sex of the animal (Tower 2014). Accordingly, flies UPR MT driven by TRAP1 is different in males and females due partly to differences in bioenergetics between both sexes Baqri et al 2014).…”

“…Among mitochondrial chaperones, Hsp60/Hsp10 and mitochondrial Hsp70 (mtHsp70) have been associated with UPR MT in different organisms. In Drosophila melanogaster, two other mitochondrial chaperones are involved in this important stress response, namely Hsp22 and tumor necrosis factor receptor associated protein 1 (TRAP1) (Baqri et al 2014;Shen and Tower 2013;Tower 2014;Tower et al 2014). While TRAP1 is a member of the HSP90 family of chaperone, Hsp22 is a small heat shock protein (sHSP) that is preferentially up-regulated during aging.…”

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

“…Autophagy is likely to be an important process for control of aging (Rubinsztein et al ., 2011; Tower, 2015). As a quality control mechanism that ensures adequate function of proteins and organelles over time, autophagy would enable cells to maintain viability over long periods.…”