Downregulation of the human Lon protease impairs mitochondrial structure and function and causes cell death.
Lon now emerges as a major regulator of multiple mitochondrial functions in human beings. Lon catalyzes the degradation of oxidatively modified matrix proteins, chaperones the assembly of inner membrane complexes, and participates in the regulation of mitochondrial gene expression and genome integrity. An early result of Lon downregulation in WI-38 VA-13 human lung fibroblasts is massive caspase 3 activation and extensive (although not universal) apoptotic death. At a later stage, the surviving cells fail to divide, display highly abnormal mitochondrial function and morphology, and rely almost exclusively on anaerobic metabolism. In a selected subpopulation of cells, the mitochondrial mass decreases probably as a result of mitochondrial inability to divide. At this final point the Lon-deficient cells are not engaged anymore in apoptosis, and are lost by necrosis or "mitoptosis." Our results indicate that mitochondrial Lon is required for normal survival and proliferation; a clear impetus for Lon's evolutionary conservation.
Bota
Daniela A
DA
Ethel Percy Andrus Gerontology Center, and Division of Molecular and Computational Biology, 3715 McClintock Avenue, University of Southern California, Los Angeles, CA 90089-0191, USA.
Ngo
Jenny K
JK
Davies
Kelvin J A
KJ
D017209:Apoptosis / Q000502:physiology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002478:Cells, Cultured; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008168:Lung / Q000166:cytology; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D018832:Molecular Chaperones / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D049070:Protease La / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D018832:Molecular Chaperones; D016376:Oligonucleotides, Antisense; D049070:Protease La; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D001973:Bromodeoxyuridine