Increased hexokinase interactions with mitochondria protect against cell damage

Abstract

Deaths due to cancer and ischemic heart disease are the most common; dysfunction of mitochondrial energy (ATP) metabolism is key in these pathologies. Therefore, therapeutic strategies, which remain elusive, have focused on energetic metabolism. Cells use glucose and oxygen in glycolysis and oxidative phosphorylation to generate ATP. The cytosolic protein hexokinase (HK) plays a crucial role in glycolysis by catalyzing the breakdown of glucose to produce most of the ATP generated from mitochondria. For efficient glycolysis, HK must access the mitochondrial ATP, which flows out via the voltage dependent anion channel (VDAC), a 30‐kDa protein in the outer mitochondrial membrane (OMM). Cancer cells grow and proliferate by increasing access to ATP via increased HK‐VDAC associations. This strategy has potential implications for protection against cardiac ischemic injury. Ischemia promotes dissociation of HK from VDAC leading to cardiac damage, but cardio‐protective interventions can increase HK‐VDAC association, preserving function. The overall objective is to determine the biophysical and biochemical features that lead to HK‐VDAC association or dissociation. HK, a 100‐KDa dimeric protein, has 918 amino acids in two domains: an N‐terminus and C‐terminus joined by a linker a‐helix. HK interactions with mitochondria are not well known but, HK, with its non‐polar sequence of 15 amino acids on the N‐terminus, may insert in the OMM close to VDAC. Glucose and glucose‐6‐phospate have distinct binding sites on HK. Glucose binds at K173, D209, and E260 in the N‐terminus and at K621, D657, and E708 in the C‐terminus. The Brown Deer High School SMART Team designed a model of HK using 3‐D printing technology to investigate structure‐function relationships. Understanding HK‐VDAC binding mechanisms could provide better targeted approaches to manage pathologies, including cancer, cardiac and neurodegenerative diseases.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.