Mdm38 Protein Depletion Causes Loss of Mitochondrial K+/H+ Exchange Activity, Osmotic Swelling and Mitophagy

Cell Death Differ. 2007 Sep;14(9):1647-56. doi: 10.1038/sj.cdd.4402167. Epub 2007 Jun 1.

Abstract

Loss of the MDM38 gene product in yeast mitochondria results in a variety of phenotypic effects including reduced content of respiratory chain complexes, altered mitochondrial morphology and loss of mitochondrial K(+)/H(+) exchange activity resulting in osmotic swelling. By use of doxycycline-regulated shut-off of MDM38 gene expression, we show here that loss of K(+)/H(+) exchange activity and mitochondrial swelling are early events, associated with a reduction in membrane potential and fragmentation of the mitochondrial reticulum. Changes in the pattern of mitochondrially encoded proteins are likely to be secondary to the loss of K(+)/H(+) exchange activity. The use of a novel fluorescent biosensor directed to the mitochondrial matrix revealed that the loss of K(+)/H(+) exchange activity was immediately followed by morphological changes of mitochondria and vacuoles, the close association of these organelles and finally uptake of mitochondrial material by vacuoles. Nigericin, a K(+)/H(+) ionophore, fully prevented these effects of Mdm38p depletion. We conclude that osmotic swelling of mitochondria triggers selective mitochondrial autophagy or mitophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy*
  • Gene Expression
  • Hydrogen / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Proteins
  • Mitochondrial Swelling*
  • Mutation
  • Potassium / metabolism*
  • Potassium-Hydrogen Antiporters / metabolism*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae / physiology*
  • Saccharomyces cerevisiae / ultrastructure
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • MDM38 protein, S cerevisiae
  • Membrane Proteins
  • Mitochondrial Proteins
  • Potassium-Hydrogen Antiporters
  • Saccharomyces cerevisiae Proteins
  • Hydrogen
  • Potassium