Behavioral Neurobiology: Leech Lust in the Lab

lead to the activation of OMA1 protease activity towards OPA1? Given previous work from the Langer lab, one model to potentially explain the results of Ehses et al. [6] would invoke the involvement of inner membrane lipid microdomains [14]. Prohibitins are inner membrane proteins thought to possess chaperone-like activity. These proteins are found in very large, megadalton complexes thought to function in the initiation of lipid microdomains, favouring the local assembly of functional platforms [15]. These functional platforms, which are enriched with prohibitin-binding partners, such as the m-AAA proteases, may sequester OMA1 to ensure its rapid cleavage and control the access of OMA1 to its substrates. Indeed, the bacterial homologues of OMA1 are highly catalytically active [16], suggesting that OMA1 must be kept under tight, yet reversible, control. It is then conceivable that the loss of the m-AAA proteases may disrupt these platforms, thereby allowing OMA1 to become available to process OPA1 (Figure 1B). This would couple inner membrane disorganization with the inhibition of mitochondrial fusion, resulting in the elimination of the fragmented, disorganized organelle. Finally, the role of OMA1 in the regulated cleavage of OPA1 is an evolutionary twist on the simpler system in yeast for the cleavage of the OPA1 homologue Mgm1. In yeast, the rhomboid protease Rbd1/Pcp1 cleaves Mgm1 under conditions of high energy [17]. Under low ATP conditions, Mgm1 cannot be pulled across the import channel by the matrix chaperones and instead its translocation is arrested at the first hydrophobic domain, resulting in the accumulation of the long, uncleaved forms of Mgm1, thereby inactivating fusion. Rather than altering the topology of OPA1, it appears that the mammalian mitochondria survey their health through the altered topology and activity of the OMA1 protease. The integration of OMA1 into OPA1 cleavage appears to be missing in Drosophila melanogaster or Caenorhabditis elegans, suggesting that these organisms may regulate OPA1 processing in a manner homologous to yeast. Indeed, work in flies has shown a role for the rhomboid protease Rhomboid-7 in OPA1 cleavage [18]. It will be important in future work to uncover the functional implications for these different mechanistic pathways that regulate OPA1/Mgm1 cleavage.