Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer.

Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis.

Mitochondrial lysyl-tRNA synthetase independent import of tRNA lysine into yeast mitochondria.

Aminoacyl tRNA synthetases play a central role in protein synthesis by charging tRNAs with amino acids. Yeast mitochondrial lysyl tRNA synthetase (Msk1), in addition to the aminoacylation of mitochondrial tRNA, also functions as a chaperone to facilitate the import of cytosolic lysyl tRNA. In this report, we show that human mitochondrial Kars (lysyl tRNA synthetase) can complement the growth defect associated with the loss of yeast Msk1 and can additionally facilitate the in vitro import of tRNA into mitochondria.

Mitochondrial genome sequence analysis: a custom bioinformatics pipeline substantially improves Affymetrix MitoChip v2.0 call rate and accuracy.

Background: Mitochondrial genome sequence analysis is critical to the diagnostic evaluation of mitochondrial disease. Existing methodologies differ widely in throughput, complexity, cost efficiency, and sensitivity of heteroplasmy detection. Affymetrix MitoChip v2.

What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes.

Allotopic expression is potentially a gene therapy for mtDNA-related diseases. Some OXPHOS proteins like ATP6 (subunit a of complex V) and COX3 (subunit III of complex IV) that are typically mtDNA-encoded, are naturally nucleus-encoded in the alga Chlamydomonas reinhardtii. The mitochondrial proteins whose genes have been relocated to the nucleus exhibit long mitochondrial targeting sequences ranging from 100 to 140 residues and a diminished overall mean hydrophobicity when compared with their mtDNA-encoded counterparts.

Overexpressed mitochondrial leucyl-tRNA synthetase suppresses the A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene.

The A3243G mutation in the human mitochondrial tRNA(Leu(UUR)) gene causes a number of human diseases. This mutation reduces the level and fraction of aminoacylated tRNA(Leu(UUR)) and eliminates nucleotide modification at the wobble position of the anticodon. These deficiencies are associated with mitochondrial translation defects that result in decreased levels of mitochondrial translation products and respiratory chain enzyme activities.

Lysyl-tRNA synthetase is a target for mutant SOD1 toxicity in mitochondria.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting the motor neurons. The majority of familial forms of ALS are caused by mutations in the Cu,Zn-superoxide dismutase (SOD1). In mutant SOD1 spinal cord motor neurons, mitochondria develop abnormal morphology, bioenergetic defects, and degeneration.

Expression and distribution of acetylcholinesterase among the cellular components of the neuromuscular junction formed in human myotube in vitro.

The results of our recent investigations on the expression and distribution of acetylcholinesterase (EC. 3.1.

Genetic correction of mitochondrial diseases: using the natural migration of mitochondrial genes to the nucleus in chlorophyte algae as a model system.

Mitochondrial diseases display great diversity in clinical symptoms and biochemical characteristics. Although mtDNA mutations have been identified in many patients, there are currently no effective treatments. A number of human diseases result from mutations in mtDNA-encoded proteins, a group of proteins that are hydrophobic and have multiple membrane-spanning regions.

Recognition of human mitochondrial tRNALeu(UUR) by its cognate leucyl-tRNA synthetase.

Accuracy of protein synthesis depends on specific recognition and aminoacylation of tRNAs by their cognate aminoacyl-tRNA synthetases. Rules governing these processes have been established for numerous prokaryotic and eukaryotic cytoplasmic systems, but only limited information is available for human mitochondrial systems. It has been shown that the in vitro transcribed human mitochondrial tRNA(Leu(UUR)) does not fold into the expected cloverleaf, but is however aminoacylated by the human mitochondrial leucyl-tRNA synthetase.

The typically mitochondrial DNA-encoded ATP6 subunit of the F1F0-ATPase is encoded by a nuclear gene in Chlamydomonas reinhardtii.

The atp6 gene, encoding the ATP6 subunit of F(1)F(0)-ATP synthase, has thus far been found only as an mtDNA-encoded gene. However, atp6 is absent from mtDNAs of some species, including that of Chlamydomonas reinhardtii. Analysis of C.

Heparin blocks functional innervation of cultured human muscle by rat motor nerve.

In vitro innervated human muscle is the only experimental model to study synaptogenesis of the neuromuscular junction in humans. Cultured human muscle never contracts spontaneously but will if innervated and therefore is a suitable model to study the effects of specific neural factors on the formation of functional neuromuscular contacts. Here, we tested the hypothesis that nerve derived factor agrin is essential for the formation of functional synapses between human myotubes and motoneurons growing from the explant of embryonic rat spinal cord.