STARS Grantee: Rosario Rizzuto

Stars UnipdProject: MICAMETAFLEX


Rosario Rizzuto


Department: Biomedical Sciences

Total Contribution: Euro 140.000

Call: STARS-2017-WiC

Project Duration in months: 24

Start Date: 01/03/2018
End Date: 29/02/2020

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MICAMETAFLEX- Mitochondrial cation signaling in the control of metabolic flexibility

Channels for Ca2+ and K+ have been extensively described to be present in the inner membrane of mitochondria, where they control several key organelle functions, including metabolism, redox state and cell fate. Unfortunately, their genuine physiopathological role has been largely underestimated, mainly because of the lack of molecular information on the machinery controlling mitochondrial cation homeostasis.

Remarkably, we can now finally overcome this limitation. Indeed, five years ago we first identified the Mitochondrial Calcium Uniporter (MCU) and here we unravel the identity of the mitochondrial ATP-sensitive Potassium channel (mitoKATP). The MICAMETAFLEX proposal arises from these ground-breaking results and investigates how mitochondrial cation channels control global metabolic programs. Mitochondria have indeed the extraordinary capacity to rapidly adapt fuel oxidation to substrates availability and energy demand, a feature known as “metabolic flexibility”. While the biological relevance of metabolic flexibility is now fully appreciated, the upstream signals that control this trait are largely unknown. Here we will use state-of-the-art techniques to interrogate i) global metabolism, ii) mitochondrial activity, iii) signaling pathways and iv) gene expression in diverse cellular and animal models lacking either MCU or mitoKATP.

Overall, the MICAMETAFLEX project will uncover the contribution of mitochondrial cation channels to metabolic reprogramming at the level of skeletal muscle, immune and cancer cells. In addition, these studies will shed new light on the mitochondria-to-nucleus retrograde signaling axis, thus untangling the broad impact that mitochondria exert on cellular functions.