Response by Arezu Jahani-Asl & Ruth S. Slack

A recent study by Cribbs & Strack (2007) identified a new mechanism for the integration of the second messengers Ca²⁺ and cAMP in the regulation of mitochondria form and function. This study was the first to provide a mechanistic link between phosphorylation of dynamin-related protein 1 (Drp1)—a component of mitochondrial fission machinery—and the regulation of apoptosis. Our report also referred extensively to two previous studies that investigated the role of DRP1 phosphorylation in mitochondrial fission: one study published by Chang & Blackstone (2007a) also identified a cAMP-dependent protein kinase (PKA) phosphorylation site on human DRP1, and a report by Taguchi et al (2007) showed that DRP1 is phosphorylated by Cdk1/cyclin B (Cdk1 for cyclin-dependent kinase 1) in a cell-cycle-dependent manner. Together, these three studies provide evidence that the post-translational modification of DRP1 has a crucial role in the regulation of mitochondrial dynamics and cellular function. Chang & Blackstone (2007b) have responded to our report to clarify two points. First, they have provided a sequence alignment between the rat and human DRP1 sequence and have indicated that the PKA phosphorylation of DRP1 at Ser 656 in rat (reported by Cribbs & Strack, 2007) and Ser 637 in human (reported by Chang & Blackstone, 2007a) represent the same serine residue. Second, we had referred to the loss of GTPase activity in the Cribbs & Strack (2007) study where we should have described it as a loss of Drp1 fission activity. Therefore, although Drp1 activity and GTPase activity were interchangeably used, it is important to emphasize that in the Cribbs & Strack study no reduction in GTPase activity was shown, whereas the Chang & Blackstone (2007a) study did show a reduction in both fission and GTPase activity. Although we appreciate this clarification, we would like to re-emphasize that the crucial point of our Literature Report (Jahani-Asl & Slack, 2007) was to highlight the physiological relevance of PKA-mediated Drp1 phosphorylation that had not been previously shown. The findings of the Cribb & Strack (2007) paper bring the regulation of Drp1 phosphorylation into a broader context by showing its physiological importance for cell death. Understanding the physiological outcomes of post-translational modifications such as phosphorylation in the context of cellular function—including apoptosis and cell cycle regulation—is the ultimate challenge for cell biologists.