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Spatial colocalization and functional link of purinosomes with mitochondria

Science  12 Feb 2016:
Vol. 351, Issue 6274, pp. 733-737
DOI: 10.1126/science.aac6054

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Spatial control of cellular enzymes

Purine is a building block of DNA and also a component of ATP that is used as an energy source in the cell. Enzymes involved in purine biosynthesis organize into dynamic bodies called purinosomes. French et al. found that purinosomes colocalize with mitochondria, organelles that generate ATP (see the Perspective by Ma and Jones). Dysregulation of mitochondria caused an increase in the number of purinosomes. This suggests a synergy, with the purinosomes supplying the purine required for ATP production and in turn using ATP in the biosynthetic pathway. A master regulator of cellular metabolism, mTOR, appears to mediate the association of purinosomes and mitochondria. This could make purine and ATP synthesis responsive to changes in the metabolic needs of the cell.

Science, this issue p. 733; see also p. 670

Abstract

Purine biosynthetic enzymes organize into dynamic cellular bodies called purinosomes. Little is known about the spatiotemporal control of these structures. Using super-resolution microscopy, we demonstrated that purinosomes colocalized with mitochondria, and these results were supported by isolation of purinosome enzymes with mitochondria. Moreover, the number of purinosome-containing cells responded to dysregulation of mitochondrial function and metabolism. To explore the role of intracellular signaling, we performed a kinome screen using a label-free assay and found that mechanistic target of rapamycin (mTOR) influenced purinosome assembly. mTOR inhibition reduced purinosome-mitochondria colocalization and suppressed purinosome formation stimulated by mitochondria dysregulation. Collectively, our data suggest an mTOR-mediated link between purinosomes and mitochondria, and a general means by which mTOR regulates nucleotide metabolism by spatiotemporal control over protein association.

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