Muscle FBPase binds to cardiomyocyte mitochondria under glycogen synthase kinase‐3 inhibition or elevation of cellular Ca²⁺ level

Abstract

Edited by Judit OvádiKeywords: FBPase Mitochondria GSK3 Calcium Cardiomyocyte Hypertrophy a b s t r a c t A growing body of research suggests that fructose 1,6-bisphosphatase (FBPase) might be involved in regulation of cell mortality/survival. However, the precise role of FBPase in the process remains unknown. Here, we show for the first time that in HL-1 cardiomyocytes, inhibition of glycogen synthase kinase-3 results in translocation of FBPase to mitochondria. In vitro experiments demonstrate that FBPase reduces the rate of calcium-induced mitochondrial swelling, affects ATP synthesis and interacts with mitochondrial proteins involved in regulation of volume and energy homeostasis. We suggest that FBPase might be engaged in a regulation of cell survival by influencing mitochondrial function. Structured summary of protein interactions:FBPase physically interacts with VDAC2, Vdac3, ATP synthase subunit beta, Slc25a5, ATP synthase subunit alpha, Histone cluster 1, H1d, Histone H2A, Histone H4 and Histone H3 by affinity chromatography technology (View interaction) FBPase physically interacts with ATP synthase subunit b, ATP synthase subunit a, ADP/ATP translocase 1, ADP/ATP translocase 2 and VDAC2 by cross-linking study (View interaction)

GSK-3 as potential target for therapeutic intervention in cancer

“…Thursday Inhibtition of GSK-3beta activity was also shown to be critical for association of two metabolic enzymes: hexokinase II [120 PMID: 21430642] and muscle isoform of fructose-1,6-bisphosphatase (FBP2) [121 PMID: 22154964] with mitochondria which results in the protection of the organella against stress stimuli and the promotion of ATP synthesis.…”

Mitochondrial calcium: Transport and modulation of cellular processes in homeostasis and cancer (Review)

“…During such Ca 2+ elevations, mitochondria accumulate calcium rapidly, which induces the opening of permeability transition pores (PTP), matrix swelling, OMM rupture and cell death (39). High concentrations of calcium (300 mM) decrease ATP production >2-fold in cardiomyocytic mitochondria; however, incubation of these mitochondria with Ca 2+ and muscle fructose 1,6-bisphosphatase (FBP) allows recovery of ATP levels, thus suggesting that FBP blocks the inhibitory effects of high [Ca 2+ ] (39). Muscle FBP has two predominant oligomeric states that determine its subcellular localization.…”

Quadruple space-group ambiguity owing to rotational and translational noncrystallographic symmetry in human liver fructose-1,6-bisphosphatase

“…a rotation angle of close to 90 (Barciszewski et al, 2016). Since the human muscle and liver FBPase isoforms share only 76.9% sequence identity (89.3% homology) over 337 residues and the muscle isoform has additional functions in the cell, including higher sensitivity of hmFBPase to AMP and its regulation by Ca 2+ (Gizak et al, 2012;Pirog et al, 2014), some differences in their R/T transition behaviour might be expected. In solution, porcine FBPase subunits have been shown to exchange on a time scale of a few hours (Nelson et al, 2001), indicating flexibility at the interfaces.…”