A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity

Nat Cell Biol. 2015 Jun;17(6):782-92. doi: 10.1038/ncb3170. Epub 2015 May 11.

Abstract

The coordinated regulation of mitochondrial and nuclear activities is essential for cellular respiration and its disruption leads to mitochondrial dysfunction, a hallmark of ageing. Mitochondria communicate with nuclei through retrograde signalling pathways that modulate nuclear gene expression to maintain mitochondrial homeostasis. The monooxygenase CLK-1 (human homologue COQ7) was previously reported to be mitochondrial, with a role in respiration and longevity. We have uncovered a distinct nuclear form of CLK-1 that independently regulates lifespan. Nuclear CLK-1 mediates a retrograde signalling pathway that is conserved from Caenorhabditis elegans to humans and is responsive to mitochondrial reactive oxygen species, thus acting as a barometer of oxidative metabolism. We show that, through modulation of gene expression, the pathway regulates both mitochondrial reactive oxygen species metabolism and the mitochondrial unfolded protein response. Our results demonstrate that a respiratory enzyme acts in the nucleus to control mitochondrial stress responses and longevity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Animals, Genetically Modified
  • COS Cells
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Respiration
  • Cell Survival
  • Chlorocebus aethiops
  • Chromatin / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Longevity
  • Mitochondria / metabolism*
  • Oxidative Stress
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Stress, Physiological
  • Unfolded Protein Response / genetics

Substances

  • CLK-1 protein, C elegans
  • Caenorhabditis elegans Proteins
  • Chromatin
  • Reactive Oxygen Species
  • Clk dual-specificity kinases
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases