Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis

• Published in: Molecular cell 2004-10, Vol.16 (1), p.59-68
• Main Authors: Szabadkai, György, Simoni, Anna Maria, Chami, Mounia, Wieckowski, Mariusz R, Youle, Richard J, Rizzuto, Rosario
• Format: Article
• Language: English
• Subjects: Apoptosis - physiology; Calcium - metabolism; Endoplasmic Reticulum - metabolism; HeLa Cells; Humans; Mitochondria - metabolism; Nerve Tissue Proteins - metabolism
• ISSN: 1097-2765
• DOI: 10.1016/j.molcel.2004.09.026

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.