Allosteric Regulation of NCLX by Mitochondrial Membrane Potential Links the Metabolic State and Ca2+ Signaling in Mitochondria

Cell Rep. 2018 Dec 18;25(12):3465-3475.e4. doi: 10.1016/j.celrep.2018.11.084.

Abstract

Calcium is a key regulator of mitochondrial function under both normal and pathological conditions. The mechanisms linking metabolic activity to mitochondrial Ca2+ signaling remain elusive, however. Here, by monitoring mitochondrial Ca2+ transients while manipulating mitochondrial membrane potential (ΔΨm), we found that mild fluctuations in ΔΨm, which do not affect Ca2+ influx, are sufficient to strongly regulate NCLX, the major efflux pathway of Ca2+ from the mitochondria. Phosphorylation of NCLX or expression of phosphomimicking mutant (S258D) rescued NCLX activity from ΔΨm-driven allosteric inhibition. By screening ΔΨm sensitivity of NCLX mutants, we also identified amino acid residues that, through functional interaction with Ser258, control NCLX regulation. Finally, we find that glucose-driven ΔΨm changes in pancreatic β-cells control mitochondrial Ca2+ signaling primarily via NCLX regulation. Our results identify a feedback control between metabolic activity and mitochondrial Ca2+ signaling and the "safety valve" NCLX phosphorylation that can rescue Ca2+ efflux in depolarized mitochondria.

Keywords: NCLX; mitochondrial Ca(2+) signaling; mitochondrial membrane potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Calcium / metabolism
  • Calcium Signaling* / drug effects
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Enzyme Activation / drug effects
  • Glucose / pharmacology
  • Humans
  • Membrane Potential, Mitochondrial* / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / metabolism*
  • Models, Biological
  • Phosphorylation / drug effects
  • Protein Domains
  • Sodium-Calcium Exchanger / chemistry
  • Sodium-Calcium Exchanger / metabolism*
  • Uncoupling Protein 1 / metabolism

Substances

  • Mitochondrial Proteins
  • SLC8B1 protein, human
  • Sodium-Calcium Exchanger
  • Uncoupling Protein 1
  • Cyclic AMP-Dependent Protein Kinases
  • Glucose
  • Calcium