Mitochondrial desensitization to the second of two stimuli is partly lost if PKCβ is inhibited (bottom).

Calcium signals destined for mitochondria are first screened by protein kinase C (PKC) isoforms, according to Pinton et al., on page 223. Different PKCs then adjust the organelles' responses to their liking.

PKC is a Ca2+-activated kinase that comes in many flavors. Pinton et al. analyzed the contribution of several of these flavors to Ca2+ signaling by overexpressing or inhibiting individual isoforms in cells. Their effects were assessed by stimulating cells with an extracellular agonist to elicit Ca2+ stores from the ER into the cytoplasm.

One flavor, PKCα, limited all Ca2+ signaling by dampening this ER release. Others, however, worked specifically at the mitochondria. PKCζ increased mitochondrial Ca2+ uptake, whereas PKCβ and δ reduced it. Thus, activation of PKC upon initial stimulation may alter the effect of subsequent Ca2+ spikes. Mitochondria are known to respond less to the second of two consecutive stimuli. The authors now show that PKCβ is needed for this dampening. This function might make cells less sensitive to apoptotic signals, for example, which induce mitochondrial Ca2+ influx.

The PKC isoforms that decrease Ca2+ uptake also decrease mitochondrial membrane potential. There may be a causal link, but mitochondrial Ca2+ transporters have not been cloned, so identifying the relevant PKC substrates will require the purification of mitochondrial proteins that are phosphorylated in response to Ca2+. ▪