Cell - 8 September 2016

integrate multiple signals about the environment with the current
physiological nutrient and stress threshold of the organism.
Similarly, while neuronal mitochondrial dysfunction may affect
serotonin synthesis or release, serotonin must then affect mito-
chondrial function in distal tissues. Serotonin acts locally upon
its release and is not predicted to directly elicit long-range

effects. Therefore, it is possible that release of serotonin from

affected neurons signals to peripheral tissues through a yet to

be indentified secondary cell to release a longer range acting

neurocrine. Serotonin has been shown to regulate feeding

behavior indirectly through release of kynurenic acid, a break-

down metabolite of tryptophan, which also plays a protective

Figure 6. Alternative Models of Neuronal Mitochondrial Stress Also Require Serotonin to Induce Peripheral UPRmt
(A) Photomicrographs depictinghsp-6p::GFP reporter induction inunc-119p::tom20::KillerRedor rab-3p::tom20::KillerRed animals
(B) Photomicrographs depictinghsp-6p::GFP reporter induction ingly-19p::tom20::KillerRed,ges-1p::tom20::KillerRed,or myo-3p::tom20::KillerRed animals.
(C) Photomicrographs depictinghsp-6p::GFP reporter induction inrab-3p::Cas9+u6p::spg-7-sg, unc-119p::Cas9+u6p::spg-7-sg, rab-3p::Cas9+u6p::cco-1-sg,
or unc-119p::Cas9+u6p::cco-1-sganimals.
(D) Photomicrographs depictinghsp-6p::GFP reporter induction intph-1(mg280);rab-3p::Cas9+u6p::spg-7-sganimals.
(E) Quantification ofhsp-6p::GFP reporter induction intph-1(mg280);rab-3p::Cas9+u6p::spg-7-sganimals. (Mean±SEM for n = 30–60 animals/experiment,
2 replicate experiments, p < 0.05 by ANOVA test fortph-1mutant)
(F) Photomicrographs depictinghsp-6p::GFP reporter induction intph-1p::Cas9+u6p::cco-1-sganimals.

1560 Cell 166 , 1553–1563, September 8, 2016