Yeast homologs of human MCUR1 regulate mitochondrial proline metabolism
Mohammad Zulkifli, John K. Neff, Shrishiv Timbalia, Natalie M. Garza, Yingqi Chen, Jeramie D. Watrous, Marta Murgia, Prachi P. Trivedi, Steven K. Anderson, Dhanendra Tomar, Roland Nilsson, Muniswamy Madesh, Mohit Jain, Vishal M. Gohil
Abstract
Mitochondria house evolutionarily conserved pathways of carbon and nitrogen metabolism that drive cellular energy production. Mitochondrial bioenergetics is regulated by calcium uptake through the mitochondrial calcium uniporter (MCU), a multi-protein complex whose assembly in the inner mitochondrial membrane is facilitated by the scaffold factor MCUR1. Intriguingly, many fungi that lack MCU contain MCUR1 homologs, suggesting alternate functions. Herein, we characterize Saccharomyces cerevisiae homologs Put6 and Put7 of MCUR1 as regulators of mitochondrial proline metabolism. Put6 and Put7 are tethered to the inner mitochondrial membrane in a large hetero-oligomeric complex, whose abundance is regulated by proline. Loss of this complex perturbs mitochondrial proline homeostasis and cellular redox balance. Yeast cells lacking either Put6 or Put7 exhibit a pronounced defect in proline utilization, which can be corrected by the heterologous expression of human MCUR1. Our work uncovers an unexpected role of MCUR1 homologs in mitochondrial proline metabolism.