Mitochondrial DNA deletions and chloramphenicol treatment stimulate the autophagic transcript ATG12.
Deletion mutations of mitochondrial DNA (mtDNA) accumulate somatically on a cell-by-cell basis with age, resulting in decreased cell function in muscle and substantia nigra. In osteosarcoma cells deletions incapacitate mitochondria and induce the autophagic transcript ATG12, which is involved in an early step of the mammalian autophagy pathway. We discuss here which consequences of mtDNA deletions could induce ATG12, and provide two new pieces of data. Our previous studies demonstrated that mtDNA deletions decreased mitochondrial ATP production and proteasomal function, induced the AMPK transcript (likely as a consequence of bioenergetic depletion), and decreased the intracellular concentration of 20 amino acids (possibly as a consequence of decreased proteasomal activity). Deletions eliminate essential tRNAs for mitochondrial protein synthesis, as well as essential components of mitochondrial multisubunit enzymes; therefore, the increased level of ATG12 could result from decreased bioenergetic function, increased oxidative damage, or decreased mitochondrial protein synthesis. However, the bioenergetic inhibitor rotenone does not induce ATG12. We show here that chloramphenicol, which inhibits mitochondrial protein synthesis, induces ATG12, and that mtDNA deletions result in an increased burden of oxidatively damaged protein. Thus, mtDNA deletions could induce ATG12 through a mechanism such as the following: deletions > mitochondrial protein synthesis inhibition or ROS > proteasome inhibition > amino acid depletion > ATG12.
Prigione
Alessandro
A
Department of Neuroscience and Biomedical Technologies, University of Milan-Bicocca, Monza, Italy.
Cortopassi
Gino
G
D001343:Autophagy / Q000502:physiology*; D000071192:Autophagy-Related Protein 12; D002701:Chloramphenicol / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008954:Models, Biological; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins; D014158:Transcription, Genetic
C466624:ATG12 protein, human; D000071192:Autophagy-Related Protein 12; D004272:DNA, Mitochondrial; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D002701:Chloramphenicol