ALDH7A1 inhibits the intracellular transport pathways during hypoxia and starvation to promote cellular energy homeostasis

Nat Commun. 2019 Sep 6;10(1):4068. doi: 10.1038/s41467-019-11932-0.

Abstract

The aldehyde dehydrogenase (ALDH) family of metabolic enzymes converts aldehydes to carboxylates. Here, we find that the reductive consequence of ALDH7A1 activity, which generates NADH (nicotinamide adenine dinucleotide, reduced form) from NAD, underlies how ALDH7A1 coordinates a broad inhibition of the intracellular transport pathways. Studying vesicle formation by the Coat Protein I (COPI) complex, we elucidate that NADH generated by ALDH7A1 targets Brefeldin-A ADP-Ribosylated Substrate (BARS) to inhibit COPI vesicle fission. Moreover, defining a physiologic role for the broad transport inhibition exerted by ALDH7A1, we find that it acts to reduce energy consumption during hypoxia and starvation to promote cellular energy homeostasis. These findings advance the understanding of intracellular transport by revealing how the coordination of multiple pathways can be achieved, and also defining circumstances when such coordination is needed, as well as uncovering an unexpected way that NADH acts in cellular energetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism*
  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase / metabolism*
  • Biological Transport
  • COP-Coated Vesicles / metabolism
  • Cell Hypoxia
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Energy Metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Homeostasis*
  • Humans
  • Intracellular Space / metabolism*
  • NAD / metabolism
  • Signal Transduction
  • Starvation

Substances

  • DNA-Binding Proteins
  • NAD
  • Alcohol Oxidoreductases
  • C-terminal binding protein
  • ALDH7A1 protein, human
  • Aldehyde Dehydrogenase