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Vol. 16, Issue 3, 1543-1554, March 2005

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The Mitochondrial Inner Membrane Protein Mitofilin Controls Cristae Morphology

George B. John ^*, Yonglei Shang , Li Li ^*, Christian Renken , Carmen A. Mannella , Jeanne M.L. Selker , Linda Rangell , Michael J. Bennett ^*, and Jiping Zha ^* 

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

Submitted August 12, 2004; Revised December 2, 2004; Accepted December 21, 2004
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 by using specific small interfering RNA lead to decreased cellular proliferation and increased apoptosis, suggesting abnormal mitochondrial function. Although gross mitochondrial fission and fusion seemed normal, ultrastructural studies revealed disorganized mitochondrial inner membrane. Inner membranes failed to form tubular or vesicular cristae and showed 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, whereas 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 and thus indispensable for normal mitochondrial function.

Abbreviations used: CC, coiled coil; CFSE, carboxyfluorescein diacetate, succinimidyl ester; DHFR, dihydrofolate reductase; DiOC₆, 3,3'-dihexyloxacarbocyanine iodide; _m, mitochondrial membrane potential; ROS, reactive oxygen species; siRNA, small inhibitory RNA; Su9, subunit 9 of ATP synthase.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Jiping Zha (jzha{at}gene.com).

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