Yeast homologs of human MCUR1 regulate mitochondrial proline metabolism

Mohammad Zulkifli, John K. Neff, Shrishiv A. 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 and Vishal M. Gohil ()
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Mohammad Zulkifli: Texas A&M University
John K. Neff: Texas A&M University
Shrishiv A. Timbalia: Texas A&M University
Natalie M. Garza: Texas A&M University
Yingqi Chen: University of California, San Diego
Jeramie D. Watrous: University of California, San Diego
Marta Murgia: University of Padova
Prachi P. Trivedi: Texas A&M University
Steven K. Anderson: Texas A&M University
Dhanendra Tomar: Lewis Katz School of Medicine at Temple University
Roland Nilsson: Karolinska Institutet
Muniswamy Madesh: University of Texas Health Science Center at San Antonio
Mohit Jain: University of California, San Diego
Vishal M. Gohil: Texas A&M University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18704-1

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