Recent research has opened new avenues for the evaluation of mitochondrial function; for example, mitochondria are no longer perceived as thread-like static entities within the cytosol, but instead are viewed as highly dynamic organelles that can change in shape and size, and are transported to strategic locations within the cell. Mitochondrial morphology, size and position within cells are maintained through a balance of fission and fusion events. Perturbation of the steady state between these opposing processes has been directly implicated in several human disorders (Chan, 2006). Although the list of genes for mitochondrial morphogenesis is rapidly increasing, dynamin-related protein 1 (Drp1)—a cytosolic dynamin GTPase—was among the first fission proteins to be discovered; however, the mechanism by which Drp1 function is regulated is poorly understood. In this issue of EMBO reports, Cribbs & Strack identify a new mechanism by which second messengers—cAMP and calcium—modulate mitochondrial shape and function through the regulation of Drp1 phosphorylation. Cyclic-AMP-dependent protein kinase (PKA)-mediated phosphorylation of Drp1 at Ser 656 induces mitochondrial elongation and resistance to apoptotic stimuli, whereas dephosphorylation of Ser 656 by calcineurin promotes mitochondrial fragmentation and increases cell vulnerability to apoptosis. These studies provide a new mechanistic insight into the link between the mitochondrial fission machinery and cell death signalling.

Drp1 is recruited to the mitochondrial surface at potential fission sites (Ingerman et al, 2005; Okamoto & Shaw, 2005). The energy generated by GTP hydrolysis is believed to provide the mechanical force required to execute fission (Ingerman et al, 2005). Although gainand loss-of-function studies of Drp1 correlate mitochondrial fission with apoptosis (Frank et al, 2001; Germain et al, 2005), there is no evidence to show that Drp1 alone, or mitochondrial fission by itself, can induce apoptosis. In addition, although Drp1 GTPase can be regulated by ubiquitination and sumoylation (Nakamura et al, 2006; Wasiak et al, 2007), there is little insight as to how Drp1 activation might be regulated during apoptosis signalling. In this issue, Cribbs & Strack have addressed some of these important questions and provide a mechanistic link for second messenger regulation of Drp1 GTPase activity and apoptosis signalling.