Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Mansour Alemi, Alessandro Prigione, Alice Wong, Robert Schoenfeld, Salvatore DiMauro, Michio Hirano, Franco Taroni, Gino A Cortopassi

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)32-43
Number of pages12
JournalFree Radical Biology and Medicine
Volume42
Issue number1
DOIs
StatePublished - Jan 1 2007

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Kearns-Sayre Syndrome
Mitochondrial DNA
Proteasome Endopeptidase Complex
Autophagy
Ubiquitin
Amino Acids
Salvaging
Adenylate Kinase
Heart Block
Retinitis Pigmentosa
Muscle Weakness
Deafness
Pathology
Substantia Nigra
Ataxia
Membrane Potentials
Energy Metabolism
Dementia
Muscle
Adenosine Triphosphate

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

Cite this

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript. / Alemi, Mansour; Prigione, Alessandro; Wong, Alice; Schoenfeld, Robert; DiMauro, Salvatore; Hirano, Michio; Taroni, Franco; Cortopassi, Gino A.

In: Free Radical Biology and Medicine, Vol. 42, No. 1, 01.01.2007, p. 32-43.

Research output: Contribution to journalArticle

Alemi, Mansour ; Prigione, Alessandro ; Wong, Alice ; Schoenfeld, Robert ; DiMauro, Salvatore ; Hirano, Michio ; Taroni, Franco ; Cortopassi, Gino A. / Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript. In: Free Radical Biology and Medicine. 2007 ; Vol. 42, No. 1. pp. 32-43.
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