FBP ALDOA complex is located on

FBP2-ALDOA complex is located on both sides of Z-line in striated muscles (Rakus et al., 2003a; Gizak et al., 2003) and its stability is regulated by calcium ions (Mamczur et al., 2005; Rakus et al., 2013) (Fig. 3). An increasing titre of [Ca2+] which occurs during muscle contraction stimulates dissociation of FBP2 from FBP2-ALDOA-Z-line (precisely: α-actinin) complex and free, cytosolic FBP2 becomes immediately inhibited by AMP and Ca2+. This protects ll 37 receptor against energy dissipation which would occur during simultaneous activity of glyconeogenesis and glycolysis. A similar mechanism of glyconeogenesis inhibition at a time of glycolysis rate acceleration has been shown to result from insulin action (Gizak et al., 2013). Insulin stimulates glycolysis and glycogen synthesis from blood stream-derived glucose but inhibits glyconeogenesis. Insulin also phosphorylates and thus inhibits glycogen synthase kinase 3 (GSK3) and it has been shown that this effects in disruption of the FBP2–Z-line interactions and reduces muscle glycogen content in vivo (Gizak et al., 2013). In accordance with this mechanism, inhibition of AKT kinase, which is known be activated by insulin, preserves the Z-line based FBP2 localisation (Gizak et al., 2013). The above study suggests that GSK3-mediated phosphorylation of FBP2, probably at S320, may be one of a trigers stimulating glyconeogenic complex formation on the Z-line (Fig. 3). Although the structure of FBP2-ALDOA complex is poorly understood, the results presented by Gizak et al. (2008) suggest that a crucial role in the interaction may play the N-terminal residues and the unique, cross-like quaternary structure of the R-state of FBP2 (Barciszewski et al., 2016). The N-terminally truncated forms of FBP2 interact with ALDOA much weaker than the wild-type isozyme: the strength of the interactions is close to that of the liver isoform and is not presumed to play a significant role in a cell biology (Gizak et al., 2008). The N-terminal region of FBP2 is crucial for the cross-like arrangement of its subunits in the active R-state and in such state, a new surfaces are exposed that are most likely targets for the interactions with various cellular and enzymatic partners (Barciszewski et al., 2016). However, it cannot be excluded that FBP2 interacts with ALDOA as the dimer which is the active, but not susceptible for AMP inhibition, form of FBP2 (Wiśniewski et al., 2017). Nevertheless, these findings point to FBP2 as an important link between calcium-induced contractive and metabolic (glycolytic) activity of striated muscles.
FBPase as a mitochondria-protecting and anti-oncogenic factor As it was mentioned above, activation of glycolysis by insulin results in inhibition of glyconeogenesis by disruption of FBP2-ALDOA complex. Intriguingly, studies performer by Gizak et al. have demonstrated that this correlates with accumulation of FBP2 on/in mitochondria (Gizak et al., 2012a, 2013). Interaction of FBP2, but not FBP1, with mitochondria reduces the rate of calcium-induced mitochondrial swelling and protects ATP synthesis (Gizak et al., 2012a). While a minor rise in intracellular [Ca2+] is crucial for stimulation of glycolysis and oxidative phosphorylation, continuing high [Ca2+] is associated with a number of cardiovascular pathologies, including cardiac hypertrophy. In the development of the hypertrophy, the sustained elevation of intracellular [Ca2+] leads to inhibition of GSK3 and accumulation of Ca2+ in mitochondria which in turn, might induce their swelling and depolarisation (Antos et al., 2002; Fiedler and Wollert, 2004). Thus, the calcium- and GSK3-inhibition-induced association of FBP2 with mitochondria might be a mechanism adapting cardiomyocytes to calcium overload during prolonged, high-intensity work, without progression to heart failure and, eventually, death. Mitochondrial binding partners of FBP2 and the mechanism of the enzyme protective action have not been definitely characterised as yet, however, it has been shown that the enzyme may interact with both mitochondrial membrane and matrix-related proteins (Gizak et al., 2012a). Among them are ATP synthase, adenine nucleotide translocator (ANT), and voltage dependent anion channel (VDAC2) and all members of the histone family. Both ANT and VDAC are presumed to play a regulatory role in opening of mitochondrial permeability transition pores (mPTP), and it is well accepted that permanent mPTP opening induces matrix swelling, release of cytochrome c and leads to apoptosis (Petronilli et al., 2001). It has been shown that GSK3 modulates mitochondrial membrane permeability (Chanoit et al., 2008). On the other hand, although the active GSK3 inhibits accumulation of FBP2 on mitochondria, the GSK3-dependent phosphorylation of FBP2 is not directly related to the regulation of mitochondrial association of the enzyme. It is thus conceivable that GSK3 regulates FBP2–mitochondria interaction by phosphorylating one of the mitochondrial proteins (e.g. VDAC, which is known to be a target of the kinase (Das et al., 2008) rather than FBP2. All the putative FBP2-interacting mitochondrial partner proteins also possess Ca2+ binding sites which play a role in regulation of mitochondrial membranes permeability or energy homeostasis. It is thus plausible that the factors regulating FBP2 binding to the organelles act by influencing the structure of mitochondrial binding partners of FBP2 (Fig. 4).