HK1

The HK1 gene spans approximately 131 kb and consists of 25 exons. Alternative splicing of its 5’ exons produces different transcripts in different cell types: exons 1-5 and exon 8 (exons T1-6) are testis-specific exons; exon 6, located approximately 15 kb downstream of the testis-specific exons, is the erythroid-specific exon (exon R); and exon 7, located approximately 2.85 kb downstream of exon R, is the first 5’ exon for the ubiquitously expressed HK1 isoform. Moreover, exon 7 encodes the porin-binding domain (PBD) conserved in mammalian HK1 genes. Meanwhile, the remaining 17 exons are shared among all HK1 isoforms.

In addition to exon R, a stretch of the proximal promoter that contains a GATA element, an SP1 site, CCAAT, and an Ets-binding motif is necessary for expression of HK-R in erythroid cells.[6]

This gene encodes a 100 kDa homodimer with a regulatory N-terminal domain (1-475), catalytic C-terminal domain (residues 476-917), and an alpha-helix connecting its two subunits.[6][8][9][10] Both terminal domains are composed of a large subdomain and a small subdomain. The flexible region of the C-terminal large subdomain (residues 766–810) can adopt various positions and is proposed to interact with the base of ATP. Moreover, glucose and G6P bind in close proximity at the N- and C-terminal domains and stabilize a common conformational state of the C-terminal domain.[8][9] According to one model, G6P acts as an allosteric inhibitor which binds the N-terminal domain to stabilize its closed conformation, which then stabilizes a conformation of the C-terminal flexible subdomain that blocks ATP. A second model posits that G6P acts as an active inhibitor that stabilizes the closed conformation and competes with ATP for the C-terminal binding site.[8] Results from several studies suggest that the C-terminal is capable of both catalytic and regulatory action.[11] Meanwhile, the hydrophobic N-terminal lacks enzymatic activity by itself but contains the G6P regulatory site and the PBD, which is responsible for the protein’s stability and binding to the outer mitochondrial membrane (OMM).[6][12][10][13]

HK1 may be causally linked to mood and psychotic disorders, including unipolar depression (UPD), bipolar disorder (BPD), and schizophrenia via both its roles in energy metabolism and cell survival. For instance, the accumulation of lactate in the brains of BPD and SCHZ patients potentially results from the decoupling of HK1 from the OMM, and by extension, glycolysis from mitochondrial oxidative, phosphorylation. In the case of SCHZ, decreasing HK1 attachment to the OMM in the parietal cortex resulted in decreased glutamate reuptake capacity and, thus, glutamate spillover from the synapses. The released glutamate activates extrasynaptic glutamate receptors, leading to altered structure and function of glutamate circuits, synaptic plasticity, frontal cortical dysfunction, and ultimately, the cognitive deficits characteristic of SCHZ.[15] Similarly, Hk1 mitochondrial detachment has been associated with hypothyroidism, which involves abnormal brain development and increased risk for depression, while its attachment leads to neural growth.[14] In Parkinson’s disease, HK1 detachment from VDAC via Parkin-mediated ubiquitylation and degradation disrupts the MPTP on depolarized mitochondria, consequently blocking mitochondrial localization of Parkin and halting glycolysis.[7] Further research is required to determine the relative HK1 detachment needed in various cell types for different psychiatric disorders. This research can also contribute to developing therapies to target causes of the detachment, from gene mutations to interference by factors such as beta-amyloid peptide and insulin.[14]

A heterozygous missense mutation in the HK1 gene (a change at position 847 from glutamate to lysine) has been linked to retinitis pigmentosa.[20][17] Since this substitution mutation is located far from known functional sites and does not impair the enzyme’s glycolytic activity, it is likely that the mutation acts through another biological mechanism unique to the retina.[20] Notably, studies in mouse retina reveal interactions between Hk1, the mitochondrial metallochaperone Cox11, and the chaperone protein Ranbp2, which serve to maintain normal metabolism and function in the retina. Thus, the mutation may disrupt these interactions and lead to retinal degradation.[17] Alternatively, this mutation may act through the enzyme’s anti-apoptotic function, as disrupting the regulation of the hexokinase-mitochondria association by insulin receptors could trigger photoreceptor apoptosis and retinal degeneration.[20][17] In this case, treatments that preserve the hexokinase–mitochondria association may serve as a potential therapeutic approach.[17]