Acid, Succinate and Glyoxal Metabolism in Ischemia

ABSTRACT
In the US there are >700,000 new heart attacks (acute myocardial infarctions) a year, and >300,000 patients
undergo scheduled ischemia during cardiac surgery. Beyond tissue reperfusion (angioplasty, thrombolysis)
there are no FDA-approved interventions to limit acute cardiac injury due to ischemia and reperfusion (IR). This
renewal proposal supports our ongoing research program in cardiac metabolism, and is focused on novel
cardioprotective metabolic signaling events downstream of glycolysis. It is built on the following premise: (i)
Acidic pH during IR is cardioprotective, and many therapies that boost glycolysis work in-part by enhancing
metabolic acidosis. (ii) Succinate accumulation is a key event in ischemia, and its oxidation at reperfusion
drives reactive oxygen species generation. We propose acid can regulate succinate dynamics (accumulation,
oxidation, transport). (iii) The glycolytic byproduct methylglyoxal (MGO) causes glycative stress in diabetes, but
type-I diabetic hearts are acutely protected against IR injury, and MGO inhibits the mitochondrial permeability
transition (PT) pore, a key event in IR injury. Some cardioprotective interventions also elevate MGO. (iv) The
mitochondrial enzyme ALKBH7 is necessary for necrosis. Inhibition or ablation of ALKBH7 is cardioprotective,
and this protection requires the MGO metabolizing enzyme GLO-1. Based on these published and preliminary
findings, our central hypothesis is that the cardioprotective effects of elevated glycolysis are mediated
by pH, succinate, and MGO. This hypothesis will be tested by addressing 3 related aims… Aim 1 will
investigate succinate dynamics in IR injury and the impact of pH. Aim 2 will investigate the role of MGO as an
acute cardioprotective signal, including identifying its targets in mitochondria. Aim 3 will study ALKBH7, identify
its substrates, and develop ALKBH7 inhibitors as cardioprotective drugs. The aims will use established
experimental systems (adult cardiomyocytes, perfused hearts, LC-MS based metabolomics, in-vivo IR injury,
and a high-fat diet model of diabetes) and engineered mice including Alkbh7-/-, Glo1-/- and hGlo1TG. Innovation
is embedded in the idea that MGO can serve an acute protective signaling role separate from its well-known
chronic pathologic effects (i.e. hormesis). This work will advance basic knowledge on ischemic cardiac
metabolism, will develop small molecule therapeutics, and will offer mechanistic insights to other pathologies
beyond IR.

Grant Number: 5R01HL071158-22
NIH Institute/Center: NIH
Principal Investigator: Paul Brookes