The mitochondrial inner membrane protein mitofilin controls cristae morphology.
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.
John
George B
GB
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Shang
Yonglei
Y
Li
Li
L
Renken
Christian
C
Mannella
Carmen A
CA
Selker
Jeanne M L
JM
Rangell
Linda
L
Bennett
Michael J
MJ
Zha
Jiping
J
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002499:Centrifugation, Density Gradient; D004591:Electrophoresis, Polyacrylamide Gel; D005990:Glycerol / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D007425:Intracellular Membranes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000502:physiology; D009124:Muscle Proteins / Q000737:chemistry* / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection; D020798:Two-Hybrid System Techniques
C088548:IMMT protein, human; D046911:Macromolecular Substances; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D005990:Glycerol