Plenary Lecture Topic
Cell Autonomous and Non-autonomous Regulation of Mitochondrial Proteostasis in Mammal
Interorgan Coordination of Organ-specific Mitoribosomal Stress Response
Mitoribosome is essential in cell viability, growth, differentiation and function.(Greber and Ban, 2016; Ott et al., 2016). Loss or mutations of any of the 78 proteins in mitoribosomal components might affect the mitoribosomal RNA processing and produce human mitochondrial disorders (Sylvester et al., 2004). In fact, the expression of genes encoding for mitoribosomal proteins (MRPs), mitoribosome assembly factors and mitochondrial translation factors is modified in numerous diseases (De Silva et al., 2015) (Kim et al., 2017a). Mutations of the single component of MRPs frequently do not fully inactivate mitoribosomal function resulting diminished oxidative phosphorylation capacity. Although all of the MRPs genes are candidate for primary mitochondrial disease, but only a small numbers of MRPs mutations (MRPL9, MRPL27, MRPL45) manifest diabetes (Sylvester et al., 2004). These findings indicate that the mutations of MRPs may also manifest in a tissue-specific manner that give rise to a spectrum of disorders including diabetes. Surprisingly, it has been demonstrated that linkage of MRPs with organismal lifespan (Houtkooper et al., 2013). These observations suggest that functional expression level of MRPs may affect tissue homeostasis and organismal health.
Reduced mitochondrial electron transport chain activity promotes longevity and improves energy homeostasis via cell-autonomous and –non-autonomous factors in multiple model systems. This mitohormetic effect is thought to involve the mitochondrial unfolded protein response (UPRmt), an adaptive stress-response pathway activated by mitochondrial proteotoxic stress. Using mice with skeletal muscle–specific deficiency of Crif1 (muscle-specific knockout [MKO]), an integral protein of the large mitoribosomal subunit (39S), we identified growth differentiation factor 15 (GDF15) as a UPRmt-associated cell–non-autonomous myomitokine that regulates systemic energy homeostasis. MKO mice were protected against obesity and sensitized to insulin, an effect associated with elevated GDF15 secretion after UPRmt activation.
To identify the differential effects of mitokines, GDF15 and FGF21 on the metabolic phenotype of adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO). Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice. Our data from AdGKO mice fed an HFD for 8 weeks revealed that long-term induction of GDF15 in AdKO mice attenuated progression of obesity in this context through increased EE. Our findings in AdFKO mice suggested that prolonged induction of FGF21 in AdKO mice did not affect EE, but remarkably ameliorated HFD-induced obesity and insulin resistance. The present study demonstrated that the muscle and adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways.