As a member of the histidine triad nucleotide-binding (Hint) protein family, which is a subfamily of the histidine triad (HIT) family, HINT2 contains a conserved histidine and HIT sequence motif (His-X-His-X-His-X-X), and the latter two histidines contribute to a catalytic triad.[6][8]
The 163-amino acid protein encoded by this gene forms a 17-kDa homodimer.[6][7][8] Compared to other members of the Hint family, HINT2 has a 61% sequence homology to HINT1 and 28% sequence homology to HINT3.[6] When compared with HINT1, the 35–amino acid extension at the HINT2 N-terminal corresponds to a predicted mitochondria import signal.[8]
Hint2, one of the three members of the Hint family of proteins, is localized to mitochondria of various cell types. In human adrenocarcinoma cells, Hint2 modulates Ca2+ handling by mitochondria. In all living organisms, intracellular calcium controls a wide variety of physiological processes. Extracellular stimuli generate temporally organized Ca2+ signals, which most of the time occur as repetitive spikes. The frequency of these oscillations controls the nature and the extent of the cellular response. Ca2+ oscillations originate from the repetitive opening of the inositol 1,4,5-trisphosphate (InsP3) receptors that are Ca2+ channels embedded in the membrane of the endoplasmic reticulum (ER). Opening of these channels is initiated by the stimulus-induced rise in InsP3; because their activity is biphasically regulated by the level of cytoplasmic Ca2+, oscillations can occur. Mitochondria also affect cytoplasmic Ca2+ signals. They can both buffer cytosolic Ca2+ changes (7 and 8) and release Ca2+. At rest, intramitochondrial ([Ca2+]m) and cytosolic Ca2+ concentration ([Ca2+]i) are similar, of the order of 100 nM (9).
The Hint family has been implicated in tumor suppression.[6] Int2, a member of the superfamily of histidine triad proteins, has been localized exclusively in mitochondria, near the contact sites of the inner membrane. This enzyme is highly expressed in the liver, where it has been shown to stimulate mitochondrial lipid metabolism, respiration, and glucose homeostasis. Hint2 modulates cytoplasmic and mitochondrial Ca2+ dynamics by stimulating the activity of the mitochondrial respiratory chain. It appears that the absence of Hint2 leads to a premature opening of the mitochondrial permeability transition pore (mPTP) in mitochondrial suspensions. As such, HINT2 plays a prominent role in mitochondrial cell death signaling (e.g. apoptosis) and in ischemia-reperfusion injury (for instance during heart attacks) through calcium homeostasis.
