CLU1: a regulator of mitochondrial distribution and translation of nuclear-encoded mitochondrial proteins

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Mitochondria are essential organelles, implicated in ATP production, crucial metabolic processes, calcium buffering, and cell death. Mitochondria distribution in cells is crucial for their function, especially in highly polarized cells as neurons, where mitochondria travel long distances to reach regions of high ATP demand in axons and dendrites. The vast majority of mitochondrial proteins are synthesized in the cytosol and imported in the organelle. This raises the important question whether synthesis of nuclear-encoded mitochondrial proteins occurs close to the organelle. We have identified mammalian CLU1 as a candidate molecule regulating both translation of nuclear encoded mitochondrial proteins and mitochondrial distribution. CLU1 is highly conserved during evolution, from Arabidopsis thaliana to humans. In plant, yeast, and Drosophila melanogaster, CLU1 knock-out leads to clustering of mitochondria close to the nucleus. We have evidence that mammalian CLU1 can similarly affect mitochondrial distribution in cells. Moreover, we find that CLU1 is a ribosomal-associated protein, which directly binds RNA. In addition, CLU1 interacts with the astrin-SKAP complex, which is implicated in kinetochore separation during mitosis. An attractive hypothesis is that CLU1 might regulate the translation of nuclear-encoded mitochondrial proteins, or the transport of a subset of ribonucleoparticles close to mitochondria, thereby affecting mitochondrial distribution. Here we propose to: 1) investigate a possible the role of CLU1 in regulation of translation of nuclear-encoded mitochondrial proteins, by identifying target mRNAs which are bound by CLU1 and performing polysome profiling to assess the efficiency of their translation under different conditions; 2) identify the role of CLU1 interaction with the astrin-SKAP complex; 3) assess the physiological consequences of CLU1 knock-out in vivo in different tissues of the mouse.