Pharmacological modulation of mitochondrial calcium homeostasis

Abstract

Mitochondria are pivotal organelles in calcium (Ca ) handling and signalling, constituting intracellular checkpoints for numerous processes that are vital for cell life. Alterations in mitochondrial Ca 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 Ca transport mechanisms for therapeutic intervention, but pharmacological compounds that direct and selectively modulate mitochondrial Ca homeostasis are currently lacking. New avenues have, however, emerged with the breakthrough discoveries on the genetic identification of the main players involved in mitochondrial Ca 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 Ca 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 Ca homeostasis.

Activation of the Calcium-Sensing Receptor Corrects the Impaired Mitochondrial Energy Status Observed in Renal Polycystin-1 Knockdown Cells Modeling Autosomal Dominant Polycystic Kidney Disease

“…As known, mitochondrial calcium homeostasis and uptake has a pivotal role in the regulation of mitochondrial ATP generation as well as cytosolic NAD + /NADH metabolism, thus sustaining the energy requirements of the cell (Raffaello et al, 2016 ; Arduino and Perocchi, 2018 ).…”

Aza‐CGP37157‐lipoic hybrids designed as novel Nrf2‐inducers and antioxidants exert neuroprotection against oxidative stress and show neuroinflammation inhibitory properties

“…Mitochondrial dysfunction also induces a deregulation of [Ca 2+ ] c homeostasis that, in turn, contributes to the production of free radicals, thereby increasing OS damage (Chan et al, ; Hurley, Brandon, Gentleman, & Dexter, ). In this connection, the mitochondrial Na + /Ca 2+ exchanger (mNCX) has been proposed as a potential target to reduce both [Ca 2+ ] c and OS (Arduino & Perocchi, ), since mNCX blockade decreases [Ca 2+ ] c overload and improves neuronal survival. Furthermore, mNCX blockade avoids mitochondrial Ca 2+ depletion and augments ATP synthesis and neuronal viability.…”

Gordon Research Conference on Ca2+ Signalling 2017 Editorial

“…Intriguingly, cytosolic Ca 2+ can affect protein function at the ER plasma membrane site as well as the distribution of lipids in both membranes (Balla, 2018). Mitochondrial Ca 2+ homeostasis is tightly linked to energy metabolism, and hence understanding its regulation is of critical importance (Arduino & Perocchi, 2018). Ca 2+ enters mitochondria via the mitochondrial calcium uniporter (MCU) protein, which is the pore-forming subunit in a macromolecular complex with several other regulatory proteins, including MICU1.…”