Molecular identities of mitochondrial Ca2+ influx mechanism: Updated passwords for accessing mitochondrial Ca2+-linked health and disease

Introduction Mitochondrial Ca 2+ homeostasis is crucial for balancing cell survival and death (Giacomello et al., 2007; Duchen et al., 2008). Mitochondrial Ca 2+ uptake mechanisms across the inner mitochondrial membrane (IMM) are especially important for the regulation of ATP synthesis , the amplitude and spatiotemporal patterns of intra-cellular Ca 2+ transients, the mitochondrial fission–fusion, dynamics, the opening of mitochondrial permeability transition pores (mPTPs), and the generation of reac-2+ influx was dogmatically considered to result from a single transport mechanism mediated by the mitochondrial Ca 2+ uniporter (MCU), principally a result of nearly complete inhibition by Ruthenium red and lanthanides (Gunter and Pfeiffer, 1990). However, subsequent studies have also identified additional Ca 2+ uptake pathways, such as the rapid mode of uptake (RaM) (Sparagna et al. which exhibit different Ca 2+ affinity, uptake kinetics, and pharmacological characteristics from the original MCU theory. Although the basic functional and pharmacological properties of various mitochondrial Ca 2+ uptake mechanisms have been well studied, the molecular identities of the channels/transporters responsible for these mechanisms have not been well understood until recently. In this Perspective, we focus on the recent studies that attempted to uncover the molecular identities of mito-chondrial Ca 2+ influx mechanisms using genetic manipulations including small interfering RNA (siRNA)