Muscle Mitohormesis Promotes Longevity via Systemic Repression of Insulin Signaling

Abstract

Summary Mitochondrial dysfunction is usually associated with aging. To systematically characterize the compensatory stress signaling cascades triggered in response to muscle mitochondrial perturbation, we analyzed a Drosophila model of muscle mitochondrial injury. We find that mild muscle mitochondrial distress preserves mitochondrial function, impedes the age-dependent deterioration of muscle function and architecture, and prolongs lifespan. Strikingly, this effect is mediated by at least two pro-longevity compensatory signaling modules: one involving a muscle-restricted redox-dependent induction of genes that regulate the mitochondrial unfolded protein response (UPRmt); and another involving the transcriptional induction of the Drosophila ortholog of insulin-like growth factor binding protein 7, which systemically antagonizes insulin signaling, and facilitates mitophagy. Given that several secreted IGF-binding proteins (IGFBPs) exist in mammals, our work raises the possibility that muscle mitochondrial injury in humans may similarly result in the secretion of IGFBPs, with important ramifications for diseases associated with aberrant insulin signaling.

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

“…In a paradoxical way, in yeast (Delaney et al., 2013), worms (Dillin et al., 2002), flies (Owusu‐Ansah, Song & Perrimon, 2013), and mice (Liu et al., 2005), suppression of mitochondrial ETC function increases lifespan (Dell'agnello et al., 2007; Durieux, Wolff & Dillin, 2011). While counterintuitive, these findings are supported by reports demonstrating that upregulation of mitochondrial stress response contributes to enhanced longevity in the long‐lived mitochondrial mutants (Durieux et al., 2011; Kirchman, Kim, Lai & Jazwinski, 1999).…”

“…RNAi knockdown of either UBL5 or DVE1 (mediators of mtUPR) reversed lifespan extension in both mutants. Similar to that, increased longevity by muscle‐specific disruption of ETC Complex I in Drosophila was dependent on mtUPR (Owusu‐Ansah et al., 2013), and Surf1 knockout mice deficient for ETC Complex IV had increased expression of mtUPR genes (Dell'agnello et al., 2007; Pulliam et al., 2014). It is important that, a number of other pro‐longevity models, such as NAD+/Sirtuin1 or rapamycin in C. elegans , also require mtUPR (Houtkooper et al., 2013; Owusu‐Ansah et al., 2013).…”

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

“…I suggest that this inadequacy of ATP supply is communicated to the cytoplasm by an increase in mitochondrial ROS production. For example, mouse cardiac cells under metabolic load and Drosophila muscle cells with genetically impaired complex I function increase ROS generation (Sundaresan et al ., 2009; Owusu‐Ansah et al ., 2013). Other studies indicate increased ROS generation from mitochondria defective in oxidative phosphorylation (Turrens, 2003; Kregel & Zhang, 2007; Murphy, 2009, 2013; Tal et al ., 2009; West et al ., 2011; Raimundo et al ., 2012).…”

“…I suggest that induction of mitohormesis by high ROS production explains at least in part the well‐established observation that pharmacologically or genetically crippling ATP production is capable of increasing lifespan (Lee et al ., 2003; Schulz et al ., 2007; Copeland et al ., 2009; Owusu‐Ansah et al ., 2013; Sun et al ., 2014). For example, Owusu‐Ansah et al .…”

“…For example, Owusu‐Ansah et al . (2013) reported that the increased lifespan caused by knockdown of the complex I subunit ND75 is accompanied by, and requires, a ROS increase, followed by JNK activation, transcriptional induction of several Foxo target genes, including 4E‐BP , InR, and ImpL2 , and increased mitophagy (Owusu‐Ansah et al ., 2013). In addition, Schulz et al .…”