YME1L-dependent regulation of mitochondrial Ca2+ transport: a role for mitochondrial uptake protein 1 (MICU1) in nutrient sensing

Abstract

Mitochondrial calcium uptake via the mitochondrial calcium uniporter complex (MCUc) is tightly regulated by gatekeeper proteins such as MICU1 and MICU2. While long-term nutritional interventions have been shown to remodel the MCUc, its short-term regulation during postprandial transitions and acute nutrient stress remains unclear. Here, we demonstrate that non-gated MCUc increases in the postprandial liver due to a transient loss of mature MICU1 (m-MICU1), accompanied by changes in its precursor form (p-MICU1). These changes are more pronounced and occur earlier than the general increase in mitochondrial mass and respiratory protein content, indicating that they are independent of mitochondrial remodelling during refeeding. In vitro, serum deprivation, insulin signalling, modulation of mTOR activity, and glutamine starvation all affect mature or precursor MICU1 protein levels, indicating that multiple nutritional changes promote MICU1 processing alterations, leading to the formation of a non-gated, MICU-deficient MCUc. Under these conditions, mitochondrial, but not cytosolic, Ca{superscript 2} levels increase in intact cells. Moreover, mitochondrial Ca{superscript 2} uptake rates are enhanced, which correlates with higher mitochondrial oxygen consumption, increased reactive oxygen species (ROS) production, and enhanced sensitivity to mitochondrial permeability transition. We identify the mitochondrial protease YME1L as essential for MICU1 turnover in response to nutrient availability. YME1L silencing prevents MICU1 degradation and suppresses the enhanced Ca{superscript 2} uptake induced by glutamine deprivation. Together, these results reveal nutrient-sensitive, YME1L-dependent remodelling of the MCU complex and establish MICU1 degradation as a key mechanism linking metabolic signals to mitochondrial Ca{superscript 2} transport.