Alternative germ cell death pathway in Drosophila involves HtrA2/Omi, lysosomes, and a caspase-9 counterpart

Dev Cell. 2013 Apr 15;25(1):29-42. doi: 10.1016/j.devcel.2013.02.002. Epub 2013 Mar 21.

Abstract

In both flies and mammals, almost one-third of the newly emerging male germ cells are spontaneously eliminated before entering meiosis. Here, we show that in Drosophila, germ cell death (GCD) involves the initiator caspase Dronc independently of the apoptosome and the main executioner caspases. Electron microscopy of dying germ cells revealed mixed morphologies of apoptosis and necrosis. We further show that the lysosomes and their catabolic enzymes, but not macroautophagy, are involved in the execution of GCD. We then identified, in a screen, the Parkinson's disease-associated mitochondrial protease, HtrA2/Omi, as an important mediator of GCD, acting mainly through its catalytic activity rather than by antagonizing inhibitor of apoptosis proteins. Concomitantly, other mitochondrial-associated factors were also implicated in GCD, including Pink1 (but not Parkin), the Bcl-2-related proteins, and endonuclease G, which establish the mitochondria as central mediators of GCD. These findings uncover an alternative developmental cell death pathway in metazoans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 9 / genetics
  • Caspase 9 / metabolism*
  • Caspases / genetics
  • Caspases / metabolism*
  • Cell Death
  • Cell Division
  • DNA Fragmentation
  • Drosophila / enzymology
  • Drosophila / genetics
  • Drosophila / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Enzyme Activation
  • Germ Cells / metabolism
  • Germ Cells / ultrastructure*
  • High-Temperature Requirement A Serine Peptidase 2
  • In Situ Nick-End Labeling
  • Lysosomes / genetics
  • Lysosomes / metabolism*
  • Male
  • Microscopy, Electron, Transmission
  • Mitochondria / enzymology
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Species Specificity
  • Spermatogenesis
  • Spermatozoa / metabolism
  • Spermatozoa / ultrastructure*
  • Testis / cytology
  • Testis / metabolism

Substances

  • Drosophila Proteins
  • Reactive Oxygen Species
  • PINK1 protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • Serine Endopeptidases
  • High-Temperature Requirement A Serine Peptidase 2
  • HtrA2 protein, Drosophila
  • Caspase 9
  • Caspases
  • dronc protein, Drosophila