The Cell Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity

“…because reactive oxygen species (ROS) are generated as a byproduct of the metabolic activity of the mitochondrial ETC during the production of ATP (Harman, 1956), a decrease in ROS production is the major contributing factor to the long-lived phenotypes of ETC mutants (Feng et al., 2001; Rea and…”

“) is also induced under conditions of protein misfolding, although confined to the ER (Ron and Walter , 2007).”

“We testedwhethermitochondrial reduction resulted in a general upregulation of all protein misfolding pathways by treating hsp-4p::GFP reporter worm strains (Calfon et al., 2002) with cco-1 RNAi.”

“These systems have offered the simplicity of studying tissue-specific expression in organisms in which single-gene mutations can affect longevity, and have been extended to mammalian model systems (Bluher et al., 2003; Conboy et al., 2005; Taguchi et al., 2007).”

“…increased longevity of tissue specific cco-1 hairpin animals did not correlate with the known stress resistance phenotypes associated with other pathways that modulate the aging process (Arantes-Oliveira et al., 2002; Larsen et al., 1995; Lee et al., 1999; Lee et al., 2003; McElwee et al., 2004).”

“These changes occur coordinately across multiple tissues and organs, in concordance with theories that posit a strong role for the participation of the endocrine system in the regulation of age-related phenotypes (Russell and Kahn, 2007; Tatar et al., 2003).”

“…Kenyon, 1999); restoration or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter the capacity for the…”

“These systems have offered the simplicity of studying tissue-specific expression in organisms in which single-gene mutations can affect longevity, and have been extended to mammalian model systems (Bluher et al., 2003; Conboy et al., 2005; Taguchi et al., 2007).”

“RNAi of cco-1 slows development, growth, movement and reduces fecundity (Dillin et al., 2002b).”

“Hormetic reactions may trigger a mitochondrial defensive response both in the same tissue in which mitochondria are defective and even in distant tissues, as shown in C. elegans (Durieux et al., 2011).”

“A non-cell-autonomous mitochondrial regulatory pathway was also reported in C. elegans: a tissuespecific RNA interference-mediated knockdown of cytochrome c oxidase subunit in neurons causes a local cellular stress response in neurons that is also communicated to the gut (Durieux et al., 2011).”

“In fact, in C. elegans, conditions of increased ROS generation such as ETC dysfunction, loss of sod-2, PQ treatment, and reduced glucose metabolism were shown to promote longevity (Schulz et al., 2007; Durieux et al., 2011; Wang and Hekimi, 2015).”