Ca handling in the mitochondria
Mitochondria can act as biological calcium sensors.
Calcium uptake is dependent on mitochondrial membrane potential. Mitochondrial calcium uptake is mediated by channels on both the outer mitochondrial membrane (OMM) and inner mitochondria membrane (IMM). In the OMM, Ca permeability is attributed to voltage-dependent anion channels (VDACs). These appear to be the limiting factor in Ca equilibration, as demonstrated by increased agonist-dependent rises in Ca concentration with VDAC overexpression. In the IMM, it is the mitochondrial calcium uniporter (MCU), a highly selective, low conductance channel. Interactions with MICU1 and other regulatory elements allow rapid, agonist-mediated Ca uptake.
Mutations in MICU1 can cause systemic disease (Logan et al 2014), described by Logan and colleagues as childhood-onset, progressive muscle weakness, ataxia and microcephaly with extrapyramidal motor signs. Patient mitochondria showed increased Ca uptake.
Mitochondria are in close proximity to microdomains of raised Ca2+, near calcium channels such as Ins(1,4,5)P3 and ryanodine-sensitive channels (RYR) on the endoplasmic reticulum (ER). This is supported by the close physical contact between mitochondria and the ER, as shown by co-sedimentation and electron microscopy (Mannella et al 1998). This allows mitochondria to respond rapidly to the generation of a rapidly dissipating Ca2+ microdomain to prevent mitochondrial Ca overload.
Calcium uptake can be imaged in mitochondria using aequorin probes. Aequorin is a Ca-sensitive photo-protein. Other protein constructs containing GFP whose fluorescence properties change with Ca binding can also be used.
Calcium efflux
Ca efflux from mitochondria is mediated by the ion exchangers mNCX and mHCX.
Review: Rizzuto et al 2012 (https://pubmed.ncbi.nlm.nih.gov/22850819/)
Calcium buffering
Mitochondria contribute to cytosolic Ca buffering properties. Some of this is due to close mitochondria-ER contacts. After Ca release from the ER, the sigma 1 receptor is released from its chaperone protein at the ER and binds to Ins(1,4,5)P3Rs on the mitochondria-associated membranes
Ca channels in the plasma membrane are also subject to regulation by local cytosolic Ca concentration and therefore mitochondrial Ca uptake.
The buffering activity of mitochondria can create large increases in Ca in defined subcellular domains.
The impact of Ca
Calcium increases the activity of matrix dehydrogenases such as pyruvate dehydrogenase, a-ketoglutarate-dehydrogenase and isocitrate dehydrogenase. Overall, this results in increased NADH availability and ATP synthesis. This was shown by spikes in NADH autofluorescence in response to transient Ca currents. High frequency Ca oscillations could therefore serve as a signal for stimulation of aerobic metabolism.
Ca processing and cell death
Bcl-2 proteins, which are integral to apoptosis, are localised to Ca-processing organelles.