A Novel Glutamine (Q) Sensory Role for Primary Cilia: Implications for Health and Disease

Primary cilia are single, microtubule-based, organelles protruding as antennae at the surface of most cells. Their dysfunction is associated with several genetic disorders, called the ciliopathies.

We recently identified a new, previously undescribed, role for primary cilia as sensors of cellular nutrient availability.

In this novel mTORC1-independent pathway, cilia directly communicate with mitochondria to drive metabolic reprogramming under nutrient stress, when glutamine (Q) becomes an obligated carbon source.Here, we will tackle two fundamental questions: i. why mammalian cells “taste” the extracellular milieu via a sensory monocilium, and how is the resulting information conveyed to mitochondria? ii. what are the consequences when the cross-communication is impaired?

While our newly identified cilia pathway is relevant in multiple cell types, here we focus on renal epithelia, because the kidney is severely affected in the ciliopathies and because we contributed defining the crucial role of metabolic balancing in this organ.

The goals are: 1) to identify the precise mechanism(s) underlying the ciliary response to nutrients; 2) to test the hypothesis that primary cilia directly cross-communicate with mitochondria via protein exchange; 3) to define the relevance of this pathway for the pathogenesis and treatment of ciliopathies.We will use newly developed methods and combine high-throughput with hypothesis-driven approaches in a broad program designed to balance high-risk/high-gain with low-risk/high-gain tasks.

The project has two inherent souls: one devoted to the understanding of a novel, very basic biological process; the second to the translation of novel basic concepts to decipher disease pathophysiology.QtCilia (Q tasting Cilia) benefits from a unique across-disciplines background and expertise of the PI, who positions herself strategically to make paradigm-changing discoveries, for which exceptional resources via innovative funding schemes are sought.