Mitochondria in which PGAM resides are the largest cellular

Mitochondria, in which PGAM5 resides, are the largest cellular Aminoallyl-dCTP - Cy3 store, housing OXPHOS proteins for ATP generation and β-oxidation enzymes for fuel delivery. When bodies are exposed to stresses that disrupt energy homeostasis, it is expected that several metabolic challenges are imposed on mitochondria. Among such metabolic stresses, mitochondria play important roles in cold resistance. Cold stress sympathetically activates brown adipose tissue (BAT), a center of heat production (Morrison et al., 2014). Heat generation in BAT requires the IMM-resident uncoupler UCP1, which dissipates chemical energy to heat, and this process is termed nonshivering adaptive thermogenesis (Krauss et al., 2005). Activated BAT burns lipids through β-oxidation to sustain heat production, which results in an increase in energy expenditure (Townsend and Tseng, 2014). In addition to UCP1, the ablation of components that are required for β-oxidation, such as carnitine palmitoyl-transferase 1β (CPT1β) and acyl-CoA synthetase long-chain family member 1 (ACSL1), all of which are vulnerable to cold stress (Ellis et al., 2010; Enerback et al., 1997; Ji et al., 2008), emphasizes the importance of mitochondria for cold resistance. Several humoral factors also participate in the activation of BAT (Villarroya and Vidal-Puig, 2013). Among these factors, FGF21, the 21st member of the fibroblast growth factor (FGF) family (Nishimura et al., 2000), is induced by cold stress (Chartoumpekis et al., 2011; Hondares et al., 2011) and ultimately protects mice from cold (Fisher et al., 2012). Interestingly, several recent reports have suggested that FGF21 is also induced in response to mitochondrial dysfunction (Dogan et al., 2014; Kim et al., 2013a,b), raising the possibility that FGF21 can regulate whole-body energy expenditure when enormous metabolic challenges are imposed on mitochondria. Here, we revealed that Pgam5 knockout (KO) mice are resistant to cold stress combined with fasting. Consistent with the knowledge that cold sensitivity is correlated with obese phenotype (Lin and Li, 2004), Pgam5 KO mice also showed a resistance against high-fat-diet-induced obesity. Our study uncovered that mitochondria-resident stress responsive molecule PGAM5 may act as a metabolic regulator in vivo.
Materials and Methods
Results
Discussion In this report, we uncovered two metabolic-stress-related phenotypes of Pgam5 KO mice. In our analysis of the cold-resistance phenotypes of Pgam5 KO mice under fasting condition, we focused especially on BAT, a center of adaptive thermogenesis. Under cold exposure, it is known that BAT is a major tissue that takes up TGs from the blood stream (Bartelt et al., 2011). In BAT, TGs that were transported from the blood stream and those that were stored in lipid droplets were degraded to release FFAs via lipolysis in response to cold (Townsend and Tseng, 2014). The released FFAs not only become fuel for β-oxidation but also promote adaptive thermogenesis through activating UCP1-mediated thermogenesis (Fedorenko et al., 2012). Thus, the enhanced lipid utilization in BAT is critical for cold resistance. Of note, several signs of enhanced lipid metabolism were observed in Pgam5 KO mice after fasting and cold stress: serum TGs decreased in Pgam5 KO mice (Fig. 2a), lipid droplets were significantly smaller in Pgam5-deficient BAT (Fig. 2f), and the expression level of lipid elongation factor, Elovl3 was enhanced in Pgam5-deficient BAT (Fig. 2h). These observations suggest that the ablation of Pgam5 results in the enhancement of lipid uptake and utilization in BAT, which ultimately confers the cold resistance to mice (Fig. 6). Because the decrease of lipid content in Pgam5-deficient BAT was striking (Fig. 2e and f), uncovering the precise mechanisms by which mitochondria-resident PGAM5 regulates the activity of BAT is expected in the future study. Interestingly, recent report suggests that adrenergic stimulation promotes rapid mitochondrial fission in brown adipocytes, which ultimately results in promoting energy expenditure (Wikstrom et al., 2014). Moreover, it has been reported that the ablation PGAM5 promotes rapid mitochondrial fragmentation in some cells under several stress conditions (Wang et al., 2012; Moriwaki et al., 2016). Thus, it would be possible that PGAM5 in BAT might be also involved in the regulation of mitochondrial dynamics. Alternatively, considering that the lipid metabolism in BAT is known to be activated by sympathetic nervous system, it would be possible that the enhanced lipid metabolism observed in Pgam5-deficient BAT is induced by the increased sympathetic neuronal input. For further understanding of the roles of PGAM5 in lipid metabolism in BAT, it is required to determine in which tissues PGAM5 exert its roles, i.e. in BAT itself, central nervous system, or even other tissues.