Table 1.

Similarities and distinctions of metformin and carbon monoxide

	Metformin	Carbon monoxide
Similarity	- Exhibiting effects of cytoprotection by production of ROS in mitochondria (Kim et al., 2013a; Liu et al., 2008; Zuckerbraun et al., 2007)
	- Activation of the PERK pathway by induction of mitochondrial stress (Joe et al., 2018; Kim et al., 2013a; 2017; Quentin et al., 2012)
	- Induction of metabolic homeostasis molecules (e.g., FGF21 and SESN2) and anti-tumor and anti-oxidant molecules (e.g., REDD1 and Nrf2, respectively) (Ben Sahra et al., 2011; Deng et al., 2016; Kim et al., 2007; 2013a; 2018b)
Distinction	- Increase of ROS by partial inhibition of mitochondrial complex I (Kim, Jeong et al., 2013a)	- Production of ROS via temporarily blocking cytochrome c oxidase, complex IV (Otterbein et al., 2016; Zuckerbraun et al., 2007)
	- Induction of SESN2 and REDD1 by the p53-dependent pathway in mouse embryonic fibroblasts and prostate cancer cell lines, respectively (Ben Sahra et al., 2011; Deng et al., 2016)	- Induction of SESN2 and REDD1 by PERK-dependent pathway in liver and several cancer cell lines, respectively (Kim et al., 2017; 2018b)
	- Activation of Nrf2 in an AMPK-dependent manner in rat brain and C. elegans (Ashabi et al., 2015; Onken and Driscoll, 2010)	- Activation of Nrf2 via PERK activation in human endothelial cells (Kim et al., 2007)