Mitochondria are multifunctional organelles whose dysfunction leads to neuromuscular degeneration and ageing. The multi-functionality poses a great challenge for understanding the mechanisms by which mitochondrial dysfunction causes specific pathologies. Among the leading mitochondrial mediators of cell death are energy depletion, free radical production, defect in iron-sulfur cluster biosynthesis, the release of pro-apoptotic and non-cell-autonomous signaling molecules, and altered stress signaling 1–5. Here, we identified a novel pathway of mitochondria-mediated cell death. This pathway was named mitochondrial Precursor Over-accumulation Stress (mPOS), characterized by aberrant accumulation of mitochondrial precursors in the cytosol. mPOS can be triggered by clinically relevant mitochondrial damage which is not limited to the core machineries of protein import. We also identified a large network of genes that suppress mPOS, by modulating ribosomal biogenesis, mRNA decapping, transcript-specific translation, protein chaperoning and turnover. In response to mPOS, several ribosome-associated proteins were up-regulated including Gis2 and Nog2, which promote cap-independent translation and inhibit the nuclear export of the 60S ribosomal subunit respectively 6, 7. Gis2 and Nog2 up-regulation promotes cell survival, which may be part of a feedback loop that attenuates mPOS. Our data indicate that mitochondrial dysfunction contributes directly to cytosolic proteostatic stress, and provide an explanation for the enigmatic association between these two hallmarks of degenerative diseases and ageing. The results are relevant to understanding diseases (e.g., spinocerebellar ataxia, amyotrophic lateral sclerosis and myotonic dystrophy) that involve mutations within the anti-degenerative network.

Mitochondrial DNA (mtDNA) encodes essential components of the cellular energy-producing apparatus, and lesions in mtDNA and mitochondrial dysfunction contribute to numerous human diseases. Understanding mtDNA organization and inheritance is therefore an important goal. Recent studies have revealed that mitochondria use diverse metabolic enzymes to organize and protect mtDNA, drive the segregation of the organellar genome, and couple the inheritance of mtDNA with cellular metabolism. In addition, components of a membrane-associated mtDNA segregation apparatus that might link mtDNA transmission to mitochondrial movements are beginning to be identified. These findings provide new insights into the mechanisms of mtDNA maintenance and inheritance.

Mitochondrial DNA (mtDNA) is essential for cells to maintain respiratory competency and is inherited as a protein-DNA complex called the nucleoid. We have identified 22 mtDNA-associated proteins in yeast, among which is mitochondrial aconitase (Aco1p). We show that this Krebs-cycle enzyme is essential for mtDNA maintenance independent of its catalytic activity. Regulation of ACO1 expression by the HAP and retrograde metabolic signaling pathways directly affects mtDNA maintenance. When constitutively expressed, Aco1p can replace the mtDNA packaging function of the high-mobility-group protein Abf2p. Thus, Aco1p may integrate metabolic signals and mtDNA maintenance.

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The R4GI gene of Kluyveromyces lactis encodes a low-affinity glucose/fructose transporter. Its transcription is induced by glucose, fructose, and several other sugars. The RAG4, RAGS, and RAG8 genes are trans-acting genes controlling the expression of the RAG) gene. We report here the characterization of one of these genes, RAG5. The nucleotide sequence of the cloned RAGS gene indicated that it encodes a protein that is homologous to hexokinases of Saccharomyces cerevisiae. ragS mutants showed no detectable hexokinase or glucokinase activity, suggesting that the sugar kinase activity encoded by this gene is the only hexokinase in K. lactis. Both high-and low-affinity transport systems of glucose were affected in ragS mutants. The defect of the low-affinity component was found to be due to a block of transcription of the RAG) gene by the hexokinase mutation. In vivo complementation of the rag5 mutation by the K2 gene of S. cerevisiae and complementation of hxikl hxk2 mutations of S. cerevisiae by the RAGS gene showed that RAGS and HXK2 were equivalent for sugar-phosphorylating activity but that RA4GS could not restore glucose repression in the S. cerevisiae hexokinase mutants.