Drp-1-dependent Division of the Mitochondrial Network Blocks Intraorganellar Ca2+ Waves and Protects Against Ca2+-mediated Apoptosis

Mol Cell. 2004 Oct 8;16(1):59-68. doi: 10.1016/j.molcel.2004.09.026.

Abstract

By transiently or stably overexpressing the mitochondrial fission factor dynamin-related protein-1 (Drp-1), we evaluated the role of mitochondrial division in organelle Ca2+ homeostasis and apoptotic signaling. Quantitative 3D digital microscopy revealed a split mitochondrial network in Drp-1-overexpressing cells without changes in cell viability. High-speed mitochondrial [Ca2+] ([Ca2+]m) imaging revealed propagating intramitochondrial Ca2+ waves in intact cells, which were blocked in the Drp-1-fragmented network, leaving a fraction of individual mitochondria without substantial [Ca2+]m elevation. Consequently, in Drp-1-expressing cells the apoptotic efficacy of ceramide, which causes a Ca2+-dependent perturbation of mitochondrial structure and function, was drastically reduced. Conversely, the sensitivity to staurosporine-induced apoptosis, previously shown to be directly triggered by Drp-1-dependent recruitment of proapoptotic proteins to mitochondria, was enhanced. These results demonstrate that the regulated process of mitochondrial fusion and fission controls the spatiotemporal properties of mitochondrial Ca2+ responses and, thus, physiological and pathological consequences of cellular Ca2+ signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Calcium / metabolism*
  • Endoplasmic Reticulum / metabolism
  • HeLa Cells
  • Humans
  • Mitochondria / metabolism*
  • Nerve Tissue Proteins / metabolism*

Substances

  • CRMP1 protein, human
  • Nerve Tissue Proteins
  • Calcium