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MBC in Press, published online ahead of print January 12, 2005
Mol. Biol. Cell 10.1091/mbc.E04-08-0697

A more recent version of this article appeared on March 1, 2005
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Submitted on August 12, 2004
Revised on December 2, 2004
Accepted on December 21, 2004

The Mitochondrial Inner Membrane Protein Mitofilin Controls Cristae Morphology

George B. John,* Yonglei Shang,{dagger} Li Li,* Christian Renken,{ddagger} Carmen A. Mannella,{ddagger} Jeanne M.L. Selker,{sect} Linda Rangell,{dagger} Michael J. Bennett,* and Jiping Zha*{dagger}||

*Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; {ddagger}Resource for Visualization of Biological Complexity, Wadsworth Center, Empire State Plaza, Albany, NY 12201; {sect}Institute of Molecular Biology, Electron Microscope Facility, University of Oregon, Eugene, OR 97403; {dagger}Genentech, South San Francisco, CA 94080

Monitoring Editor: Randy Schekman

Mitochondria are complex organelles with a highly dynamic distribution and internal organization. Here we demonstrate that mitofilin, a previously identified mitochondrial protein of unknown function, controls mitochondrial cristae morphology. Mitofilin is enriched in the narrow space between the inner boundary and the outer membranes, where it forms a homotypic interaction and assembles into a large multimeric protein complex. Down-regulation of mitofilin in HeLa cells using specific siRNA lead to decreased cellular proliferation and increased apoptosis, suggesting abnormal mitochondrial function. While gross mitochondrial fission and fusion appeared normal, ultrastructural studies revealed disorganized mitochondrial inner membrane. Inner membranes failed to form tubular or vesicular cristae and appeared as closely packed stacks of membrane sheets that fused intermittently resulting in a complex maze of membranous network. Electron microscopic tomography estimated a substantial increase in inner:outer membrane ratio, while no cristae junctions were detected. In addition, mitochondria subsequently exhibited increased reactive oxygen species production and membrane potential. Although metabolic flux increased due to mitofilin deficiency, mitochondrial oxidative phosphorylation was not increased accordingly. We propose that mitofilin is a critical organizer of the mitochondrial cristae morphology, thus indispensable for normal mitochondrial function.

||Corresponding author. E-mail: jzha{at}gene.com






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