Mitochondrial VDAC, the Na+/Ca2+ Exchanger, and the Ca2+ Uniporter in Ca2+ Dynamics and Signaling

Abstract

Mitochondrial Ca uptake and release play pivotal roles in cellular physiology by regulating intracellular Ca signaling, energy metabolism, and cell death. Ca transport across the inner and outer mitochondrial membranes (IMM, OMM, respectively), is mediated by several proteins, including the voltage-dependent anion channel 1 (VDAC1) in the OMM, and the mitochondrial Ca uniporter (MCU) and Na-dependent mitochondrial Ca efflux transporter, (the NCLX), both in the IMM. By transporting Ca across the OMM to the mitochondrial inner-membrane space (IMS), VDAC1 allows Ca access to the MCU, facilitating transport of Ca to the matrix, and also from the IMS to the cytosol. Intra-mitochondrial Ca controls energy production and metabolism by modulating critical enzymes in the tricarboxylic acid (TCA) cycle and fatty acid oxidation. Thus, by transporting Ca, VDAC1 plays a fundamental role in regulating mitochondrial Ca homeostasis, oxidative phosphorylation, and Ca crosstalk among mitochondria, cytoplasm, and the endoplasmic reticulum (ER). VDAC1 has also been recognized as a key protein in mitochondria-mediated apoptosis, and apoptosis stimuli induce overexpression of the protein in a Ca-dependent manner. The overexpressed VDAC1 undergoes oligomerization leading to the formation of a channel, through which apoptogenic agents can be released. Here, we review the roles of VDAC1 in mitochondrial Ca homeostasis, in apoptosis, and in diseases associated with mitochondria dysfunction.

Cardiac-specific Conditional Knockout of the 18-kDa Mitochondrial Translocator Protein Protects from Pressure Overload Induced Heart Failure

“…Together, these data are consistent with excess TSPO being a negative modulator of mitochondrial Ca 2+ entry, potentially by interacting with and modulating VDAC open probability 21 . VDAC operates at the OMM, and controls Ca 2+ entry into the intermembrane space in series with the mitochondrial Ca 2+ uniporter (MCU) on the IMM 46 , 47 . A recent study 13 demonstrated that reducing Ca 2+ flux via VDAC severely affected heart contractility in zebra fish, while interventions to increase Ca 2+ flux through the OMM restored normal contraction of the heart.…”

PGC1α and VDAC1 expression in endometrial cancer

“…The voltage-dependent anion channel type 1 (VDAC1) protein located in the outer mitochondrial membrane regulates mitochondrial import and export of ions and metabolites, including Ca 2+ , ATP and NADH, and thereby regulates oxidative phosphorylation (18). VDAC1 is also involved in regulating cell death through interactions with various proteins including hexokinase (HK), Bcl-2 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (19).…”

Internalization of the Aspergillus nidulans AstA Transporter into Mitochondria Depends on Growth Conditions, and Affects ATP Levels and Sulfite Oxidase Activity

“…Many proteins are translocated to the mitochondria or other organelles by the Hsp70 system under certain growth conditions [ 12 , 13 , 14 ]. Since the frequently used technique of culturing fungi on glass slides for microscopic studies may lead to false conclusions, results need to be interpreted with caution.…”

“…One of the mitochondrial import pathways leads through Porin, an oligomeric protein located in the mitochondrial outer membrane. Porin1, also known as the voltage-dependent anion channel (VDAC-1), participates in the mitochondrial import of multiple proteins and other low-molecular-weight compounds [ 12 , 13 ]. In humans, the Hsp90 chaperone was shown to primarily facilitate the import of proteins into the Porin1 channel with less Hsp70 involvement, whereas in fungi, Hsp70 is mostly responsible for this import [ 14 ].…”