Recent in vivo studies in C. elegans and Drosophila revealed that UPRmt activation by inhibition of mitochondrial electron transport chain (ETC) functions increases lifespan (Houtkooper RH et al., Nature 2013; Durieux J et al., Cell 2011) This effect of ETC inhibition on longevity is modulated by cell-autonomous and cell-non-autonomous factors, known as mitokines, which may promote metabolic homeostasis. However, extrapolation of these studies into mammalian systems is extremely difficult because generalized impairment of ETC function in mice uniformly results in progressive deterioration of organ functions and premature death. To investigate whether the role of cell-non-autonomous mitokine networks is conserved in mammalian systems, we designed a spatio-temporal approach for gene expression and secretome analysis in mice with tissue-specific UPRmt activation. Recently, we successfully generated and demonstrated relevant mouse models of tissue-specific UPRmt activation and ETC deficiency that are reminiscent of complex human disorders, e.g., neurodegeneration (Kim et al., Cell Metab, 2012), Parkinson’s disease, insulin resistance (Ryu et al., PLOS Genetics, 2013), and type 1 diabetes (Kim et al., Diabetologia, 2015). These models are based on tissue-specific knockout (KO) of Crif1, which encodes a factor required for biogenesis of ETC subunits. Loss of Crif1 resulted in abnormal proteostasis in the mitochondrial matrix and triggered the mitochondrial unfolded protein response (UPRmt). Preliminary observations on phenotypes of tissue-specific Crif1-deficient mice revealed that Crif1-deficient cells and tissues express unique UPRmt activation e.g., adaptive transcriptomic changes and secretome responses (mitokines). which can be considered to be part of the phenomenon of “mitohormesis” (Yun J and Finkel T, Cell Metab, 2014). Based on these observations, we postulated that tissue-specific UPRmt and mitokine responses are critical cell-non-autonomous modifiers in disease progression, and that individual mitokines may act as disease markers and potential therapeutic targets in complex human disorders.