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Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Item Type:Article
Title:Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript
Creators Name:Alemi, M., Prigione, A., Wong, A., Schoenfeld, R., DiMauro, S., Hirano, M., Taroni, F. and Cortopassi, G.
Abstract:Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre syndrome (KSS) and chronic progressive external opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed six cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.
Keywords:Autophagy, Biological Markers, Chronic Progressive External Ophthalmoplegia, Cultured Cells, Gene Expression Profiling, Genetic Transcription, Kearns-Sayre Syndrome, Messenger RNA, Mitochondrial DNA, Oligonucleotide Array Sequence Analysis, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Reverse Transcriptase Polymerase Chain Reaction, Sequence Deletion, Ubiquitin
Source:Free Radical Biology and Medicine
Page Range:32-43
Date:1 January 2007
Official Publication:https://doi.org/10.1016/j.freeradbiomed.2006.09.014
PubMed:View item in PubMed

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