Role of Inositol Hexakisphosphate Kinase‐2 (IP6K2) in regulating mitochondrial brain functions

Abstract

Inositol hexakisphosphate kinase (IP6K) isoform ‐ IP6K2, selectively controls cellular apoptosis. To explore the possible role of IP6K2 in degenerative brain damage, we elucidated its protein interactome in mouse brain to identify its functional partners. IP6K2‐immunoprecipitates from wild‐type mouse brain lysates were subjected to co‐immunoprecipitation followed by liquid chromatography mass spectrometric analysis. This revealed robust association of IP6K2 with creatine kinase‐B (CK‐B), an enzyme responsible for synthesis of phosphocreatine and ATP. Notably, both IP6K2 and CK‐B were highly expressed in the mouse cerebellum. IP6K2‐knockout mice (IP6K2‐KO) produced less phosphocreatine and ATP and generated higher levels of ROS and consequent protein oxidative damage in their cerebellum compared to wild‐type counterparts. As mitochondrial respiratory chains regulate energy metabolism/ATP production through glycolysis and TCA cycle coupled to oxidative phosphorylation and electron transfer, functional abrogation of any event that controls these processes can lead to abnormal electron transfer, increased ROS and consequent mitochondrial oxidative stress/damage and cell death as observed in the IP6K2‐KO mice. IP6K2‐KO mice also showed significant impairment of locomotive and cognitive functions. We thus propose to identify the precise metabolic events that are controlled by IP6K2‐CK‐B interaction and examine the possible causal role of oxidative stress and determine whether antioxidant treatment can restore normal brain functions. We plan to explore mitochondria‐targeted antioxidants like CoQ10/Mito Q along with derivatives of higher inositol phosphates (IP7‐product of IP6K2) in the IP6K2‐KO mice to reinforce the therapeutic potential of such anti‐oxidative treatment for the clinical management of diseases associated with mitochondrial dysfunction of the brain. Overall, our proposed study would help to establish the precise role of IP6K2‐CK‐B interaction in controlling cellular degeneration in the brain.