Inositol hexakisphosphate kinase-2 determines cellular energy dynamics by regulating creatine kinase-B

Area of Science:

• Biochemistry
• Neuroscience
• Cell Biology

Background:

• Inositol hexakisphosphate kinases (IP6Ks) are enzymes that convert inositol hexakisphosphate (IP6) into pyrophosphates like IP7 and IP8.
• IP6K family members, including IP6K1, IP6K2, and IP6K3, have distinct roles in mammalian cells.
• IP6K2 is known to regulate cellular apoptosis and its function in the brain is less understood.

Purpose of the Study:

• To investigate the role of IP6K2 in brain function.
• To identify IP6K2 interacting proteins in the mouse brain.
• To understand the impact of IP6K2 deficiency on brain energy metabolism and oxidative stress.

Main Methods:

• Proteomic analysis to identify IP6K2 interactors in mouse brain.
• Biochemical assays to measure phosphocreatine, ATP, and reactive oxygen species (ROS) levels in IP6K2-knockout (KO) mice.
• Assessment of mitochondrial function and protein oxidative damage.
• Pharmacological intervention with N-acetylcysteine and phosphocreatine.

Main Results:

• IP6K2 robustly associates with creatine kinase-B (CK-B) in the mouse brain.
• IP6K2-KO mice exhibit reduced phosphocreatine and ATP levels, increased ROS, and elevated protein oxidative damage in the cerebellum.
• Mitochondrial dysfunction, including impaired expression of cytochrome-c1, was observed in IP6K2-KO mice.
• Combined treatment with N-acetylcysteine and phosphocreatine partially reversed some observed detrimental effects.

Conclusions:

• IP6K2 plays a significant role in maintaining brain energy homeostasis through its interaction with CK-B.
• The IP6K2-CK-B axis is important for neuroprotection by regulating mitochondrial function and mitigating oxidative stress.
• Targeting the IP6K2-CK-B interaction may offer therapeutic strategies for neurological conditions associated with energy deficits and oxidative damage.