Pharmacological modulation of mitochondrial calcium homeostasis

Abstract

Mitochondria are pivotal organelles in calcium (Ca²⁺ ) handling and signalling, constituting intracellular checkpoints for numerous processes that are vital for cell life. Alterations in mitochondrial Ca²⁺ homeostasis have been linked to a variety of pathological conditions and are critical in the aetiology of several human diseases. Efforts have been taken to harness mitochondrial Ca²⁺ transport mechanisms for therapeutic intervention, but pharmacological compounds that direct and selectively modulate mitochondrial Ca²⁺ homeostasis are currently lacking. New avenues have, however, emerged with the breakthrough discoveries on the genetic identification of the main players involved in mitochondrial Ca²⁺ influx and efflux pathways and with recent hints towards a deep understanding of the function of these molecular systems. Here, we review the current advances in the understanding of the mechanisms and regulation of mitochondrial Ca²⁺ homeostasis and its contribution to physiology and human disease. We also introduce and comment on the recent progress towards a systems-level pharmacological targeting of mitochondrial Ca²⁺ homeostasis.

Keywords: calcium; calcium signaling; drug discovery; drug screening; mitochondria; mitochondrial calcium uniporter.

Figure 1. Workflow of the drug screen assay in reconstituted yeast mitochondria

The yeast S. cerevisiae constitutes a versatile system that can be reconstituted with different components of the MCUC machinery (e.g. MCU and EMRE and additionally MCUb, MICU1 and/or MICU2, as represented with dashed lines). When D‐Lactate (D‐Lac) is supplied to mitochondria as the energy source, it provides a bioenergetic shunt pathway that minimizes the detection of false‐positive hits. This drug screen platform allows the quantification of mitochondrial Ca²⁺ uptake kinetics based on mitochondria‐targeted‐aequorin luminescence emitted at 469 nm. MCUC modulators are accurately identified based on their effects on mitochondrial Ca²⁺ uptake kinetics. MAS, mannitol‐sucrose buffer; DLD, D‐lactate:cytochrome c oxidoreductase; TCA, tricarboxylic acid cycle; Q, coenzyme Q; Cytc, cytochrome c; II, succinate dehydrogenase; III, coenzyme Q:cytochrome c‐oxidoreductase; IV, cytochrome c oxidase.