The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans

Cell. 2014 May 8;157(4):897-909. doi: 10.1016/j.cell.2014.02.055.


The increased longevity of the C. elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here we show that the mtROS signal is relayed by the conserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein. Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival. In vertebrates, mtROS induce apoptosis through the intrinsic pathway to protect from severely damaged cells. Our observations in nematodes demonstrate that sensing of mtROS by the apoptotic pathway can, independently of apoptosis, elicit protective mechanisms that keep the organism alive under stressful conditions. This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aging
  • Animals
  • Apoptosis*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Electron Transport / genetics
  • Electron Transport Complex III / genetics
  • Electron Transport Complex III / metabolism
  • Longevity*
  • Mitochondria / metabolism*
  • Oxygen / metabolism
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Superoxide Dismutase / metabolism
  • Transcriptome


  • Caenorhabditis elegans Proteins
  • Ced-13 protein, C elegans
  • Nuo-6 protein, C elegans
  • Reactive Oxygen Species
  • Adenosine Triphosphate
  • Isp-1 protein, Caenorhabditis elegans
  • Sod-3 protein, C elegans
  • Superoxide Dismutase
  • Electron Transport Complex III
  • Oxygen