Nitric oxide is a very small lipophilic and rapidly diffusible signaling molecule produced constitutively at low levels by bone cell and acutely in a response to diverse stimuli such as proinflammatory cytokines, mechanical strain, and sex hormone. Nitric oxide exhibits concentration dependent effects on the net bone apposition-resorption rates and is believed to play a central role in mechanosensory bone remodelling control. Although it has been long recognized that osteoblast produce nitric oxide in response to mechanical stimuli, the identity of the enzyme catalysing this reaction remains the subject of heated debate.

In 2003 atNOS1 protein was described by Guo et. al. in the plant as a putative nitric oxide synthases. Our interest in the gene was sparked by the realization that it belongs to a novel evolutionary conserved GTP-binding protein family, with members in organisms ranging from bacterium to human.

In search for a possible source of nitric oxide in osteoblasts, we identified a mammalian ortholog of atNOS1 protein and showed that it functions in the sub-cellular context of mitochondria (FEBS Lett, 2006). In spite of intensive effort in our and several other laboratories nitric oxide synthase activity of atNOS1 in-vitro could not be confirmed. Based on biochemical and bioinformatic data we proposed that atNOS1 (now termed atNOA1 for Arabidopsis Thaliana Nitric Oxide Associated1) contributes to cellular NO production indirectly, by the control of mitochondrial ribosome assembly and/or process of translation (TRENDS in Plant Science, 2006).

We recently determined function of NOA1 through generation of the knock-out mice and analysis of the purified to homogeneity protein. These studies revealed that NOA1 is an essential mitochondrial protein, indispensable for normal development of the embryo proper as well as embryonal part of placental, the trophoblast. Noa1-/- mice are severely growth retarded and die at gestation stage ~E10.5. We could show that Noa1 inactivation ablates mitochondrial protein synthesis and causes global defect of phosphorylative oxidation. Consequently, NOA1 deficient cells exhibit diminished viability and reduced ATP level upon nutrient starvation. Additionally, Noa1-/- cells are impaired in caspase dependent apoptosis. The mito-protein synthesis defect was traced back to the defective assembly of the large mitoribosomal subunit. Thus NOA1 is a critical factor required for the mitochondrial function. (MBoC, 2011)

We are seeking answers to the following main questions:
- What is the developmental role of the mito-ribosomal genes?
- Which signaling pathways control mitochondrial function during embryogenesis?
- What role does the regulation of cellular energetic state play in embryo morphogenesis?

References:

Kolanczyk M, Pech M, Zemojtel T, Yamamoto H, Mikula I, Calvaruso MA, van den Brand M, Richter R, Fischer B, Ritz A, Kossler N, Thurisch B, Spoerle R, Smeitink J, Kornak U, Chan D, Vingron M, Martasek P, Lightowlers RN, Nijtmans L, Schuelke M, Nierhaus KH, Mundlos, 2011, NOA1 is an essential GTPase required for mitochondrial protein synthesis S.Mol Biol Cell. 2011 Jan 1;22(1):1-11. Epub 2010 Nov 30.PMID: 21118999 [PubMed - in process]).

Zemojtel, T. and Kolanczyk, M., Kossler, N., Stricker, S., Lurz, R., Mikula, I., Duchniewicz, M., Schuelke, M., Ghafourifar, P., Martasek, P., Vingron, M., and Mundlos, S., 2006, Mammalian mitochondrial nitric oxide synthase: characterization of a novel candidate, FEBS Lett 580, 455-462.

Zemojtel T, Fröhlich A, Palmieri MC, Kolanczyk M, Mikula I, Wyrwicz LS, Wanker EE, Mundlos S, Vingron M, Martasek P, Durner J,2006, Plant nitric oxide synthase: a never-ending story? Trends Plant Sci. 2006 Nov;11(11):524-5.