Interplay between NAD⁺ and acetyl‑CoA metabolism in ischemia-induced mitochondrial pathophysiology

Brain injury caused by ischemic insult due to significant reduction or interruption in cerebral blood flow leads to disruption of practically all cellular metabolic pathways. This triggers a complex stress response followed by overstimulation of downstream enzymatic pathways due to massive activation of post-translational modifications (PTM). Mitochondria are one of the most sensitive organelle to ischemic conditions. They become dysfunctional due to extensive fragmentation, inhibition of acetyl‑CoA production, and increased activity of NAD⁺ consuming enzymes. These pathologic conditions ultimately lead to inhibition of oxidative phosphorylation and mitochondrial ATP production. Both acetyl‑CoA and NAD⁺ are essential intermediates in cellular bioenergetics metabolism and also serve as substrates for post-translational modifications such as acetylation and ADP‑ribosylation. In this review we discuss ischemia/reperfusion-induced changes in NAD⁺ and acetyl‑CoA metabolism, how these affect relevant PTMs, and therapeutic approaches that restore the physiological levels of these metabolites leading to promising neuroprotection.