title: Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript.
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.
authors.affiliation: Department of Molecular Biosciences, 1311 Haring Hall, University of California, Davis, CA 95616, USA.
authors.forename: Mansour
authors.initials: M
authors.lastname: Alemi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prigione
authors.forename: Alice
authors.initials: A
authors.lastname: Wong
authors.forename: Robert
authors.initials: R
authors.lastname: Schoenfeld
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Franco
authors.initials: F
authors.lastname: Taroni
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
mesh_terms: D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007625:Kearns-Sayre Syndrome / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex