The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state
Anna Weiser,
Aurélie Hermant,
Flavien Bermont,
Federico Sizzano,
Sonia Karaz,
Pilar Alvarez-Illera,
Jaime Santo-Domingo,
Vincenzo Sorrentino,
Jerome N. Feige,
Umberto De Marchi
Affiliations
Anna Weiser
Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, CH-1015 Lausanne, Switzerland; Molecular Nutritional Medicine, Else Kröner Fresenius Center for Nutritional Medicine, Technische Universität München, 85354 Freising, Germany
Aurélie Hermant
Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, CH-1015 Lausanne, Switzerland
Flavien Bermont
Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, CH-1015 Lausanne, Switzerland
Federico Sizzano
Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, CH-1015 Lausanne, Switzerland
Sonia Karaz
Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, CH-1015 Lausanne, Switzerland
Pilar Alvarez-Illera
Department of Biochemistry and Molecular Biology, University of Valladolid, Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), 47003 Valladolid, Spain
Jaime Santo-Domingo
Department of Biochemistry and Molecular Biology, University of Valladolid, Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), 47003 Valladolid, Spain
Vincenzo Sorrentino
Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, CH-1015 Lausanne, Switzerland; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596, Singapore
Jerome N. Feige
Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, CH-1015 Lausanne, Switzerland
Umberto De Marchi
Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, CH-1015 Lausanne, Switzerland; Corresponding author.
Regulation of mitochondrial redox balance is emerging as a key event for cell signaling in both physiological and pathological conditions. However, the link between the mitochondrial redox state and the modulation of these conditions remains poorly defined. Here, we discovered that activation of the evolutionary conserved mitochondrial calcium uniporter (MCU) modulates mitochondrial redox state. By using mitochondria-targeted redox and calcium sensors and genetic MCU-ablated models, we provide evidence of the causality between MCU activation and net reduction of mitochondrial (but not cytosolic) redox state. Redox modulation of redox-sensitive groups via MCU stimulation is required for maintaining respiratory capacity in primary human myotubes and C. elegans, and boosts mobility in worms. The same benefits are obtained bypassing MCU via direct pharmacological reduction of mitochondrial proteins. Collectively, our results demonstrate that MCU regulates mitochondria redox balance and that this process is required to promote the MCU-dependent effects on mitochondrial respiration and mobility.
