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

Nina Klimova, Aaron Long, Susanna Scafidi, Tibor Kristian

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

NAD
Ischemia
Post Translational Protein Processing
Cerebrovascular Circulation
Oxidative Phosphorylation
Acetylation
Metabolic Networks and Pathways
Organelles
Brain Injuries
Energy Metabolism
Reperfusion
Mitochondria
Adenosine Triphosphate
Enzymes
Inhibition (Psychology)
Therapeutics
Neuroprotection

Keywords

  • Acetyl‑CoA
  • Brain
  • Ischemia
  • Mitochondria
  • NAD

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

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abstract = "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.",
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AU - Long, Aaron

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AU - Kristian, Tibor

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