Abstract
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.
Highlights
Lon is the best evolutionarily conserved ATP-stimulated protease [1], with homologues identified in a number of bacterial species such as Escherichia coli [2], Bacillus brevis [3], and Myxococcus xantus [4,5]; the yeast Saccharomyces cerevisiae [6]; and the mitochondria of mammals [7,8,9]
We have previously reported that Lon downregulation, by antisense oligomorpholine treatment of WI-38 VA-13 human lung fibroblasts, leads to impaired mitochondrial proteolysis and accumulation of both native and oxidized aconitase [24]
We treated WI-38 VI-13 human lung fibroblasts with morpholino oligonucleotides directed against the lon protease sequence, or with a control oligonucleotide, and we obtained a significant downregulation of Lon in the antisense oligonucleotide-treated cells
Summary
Lon is the best evolutionarily conserved ATP-stimulated protease [1], with homologues identified in a number of bacterial species such as Escherichia coli [2], Bacillus brevis [3], and Myxococcus xantus [4,5]; the yeast Saccharomyces cerevisiae [6]; and the mitochondria of mammals [7,8,9] This high level of conservation suggests that Lon might play a very important role in the maintenance of mitochondrial homeostasis, and in the bioenergetics and survival of cells. We were no longer able to detect Lon protein by Western blot analysis, and the mitochondrial ATP-stimulated proteolytic activity was 87% lower in the lon antisense oligonucleotide-treated cells in the control oligonucleotide-treated cells
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