Abstract
Recently, we successfully generated and demonstrated relevant mouse models of tissue-specific electron transport chain (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 mitoribosomal factor (large subunit) 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”.
We wished to determine how tissue-specific altered mitochondrial proteostasis with reduced mitoribosomal function controls systemic energy homeostasis. Using these tissue-specific knockout mice, we found that tissue (skeletal muscle, adipose and liver)-specific deficiency of Crif1 is sufficient to activate the UPRmt and stimulate production of mitokines that regulate systemic energy homeostasis. Indeed, studies of rodents with tissue-specific reduction of mitoribosomal function and disturbed matrix proteostasis in skeletal myocytes, white adipocytes and hepatocytes revealed that these models are more insulin sensitive and thus protected against diet-induced obesity and diabetes, suggesting that dysfunctional mitochondria in a given tissue communicate with other tissues. We identified growth differentiation factor 15 (GDF15) as a critical cell–non-autonomous factor that promotes oxidative function and lipolysis in liver and adipose tissues. We hypothesized that elevated production of GDF15 was responsible for the marked decrease of fat mass, resistance to obesity, and improved insulin sensitivity in tissue-specific Crif1 deficient mice.
These findings provide robust evidence that the cell–non-autonomous factor GDF15 is a regulator of systemic energy homeostasis and is thus a potentially promising therapeutic agent for the treatment of obesity-associated insulin resistance.