Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript.

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.

Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts.

Mutations in gene products expressed in the mitochondrion cause a nuclear transcriptional response that leads to neurological disease. To examine the extent to which the transcriptional profile was shared among 5 mitochondrial diseases (LHON, FRDA, MELAS, KSS, and NARP), we microarrayed mutant and control groups in N-tera2, SH-SY5Y, lymphoblasts, fibroblasts, myoblasts, muscle, and osteosarcoma cybrids. Many more transcripts were observed to be significantly altered and shared among these 5 mitochondrial diseases and cell types than expected on the basis of random chance, and these genes are significantly clustered with respect to biochemical pathways. Mitochondrial disease activated multiple transcripts of the unfolded protein response (UPR), and of the cell cycle pathway, and low doses of the mitochondrial inhibitor rotenone induced UPR transcripts in the absence of cell death. By contrast, functional clusters inhibited by mitochondrial disease included: vesicular secretion, protein synthesis, and oligodendrogenesis. As it is known that UPR activation specifically inhibits vesicular secretion and protein synthesis, these data support the view that mitochondrial disease and dysfunction triggers the UPR, which in turn causes secretory defects which inhibit cellular migratory, synaptic, and oligodendrocytic functions, providing a testable hypothesis for how mitochondrial dysfunction causes disease. Since ischemic hypoxia, chemical hypoxia, and mitochondrial genetic disease (which could be considered 'genetic hypoxia') produce an overlapping induction of UPR and cell cycle genes which appears to have negative consequences, the modulation of these responses might be of benefit to patients with mitochondrial disease.