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

Significance Inositol hexakisphosphate kinase 2 (IP6K2) regulates various cellular processes. Here we establish a role for IP6K2 in the brain. IP6K2 deletion leads to impaired mitochondrial function and repression of the cytochrome c1 subunit of the mitochondrial electron transport chain, complex III. IP6K2 deletion also elicits decreased creatine kinase-B, ATP, and phosphocreatine levels as well as enhanced oxidative stress. Restoring ATP levels abrogates mitochondrial deficits and mitigates neuronal death. These observations reveal a unique role for IP6K2 in mitochondrial homeostasis associated with neuroprotection.