Sequestration puts Drp1 on furlough

Strack et al. identify a splice variant of the mitochondrial fission protein Drp1 that can be sequestered away on microtubules.

Cells regulate their mitochondria by fusing them into an interconnected network or separating them into smaller, discrete structures. The dynamin-related GTPase Drp1 forms spiral-shaped oligomers on the surface of mitochondria that constrict and break the organelle apart. The Drp1 mRNA can be alternatively spliced with up to three additional exons, but the significance of this diversity is unclear.

Strack et al. found that Drp1 variants encoded by mRNAs containing the third alternative exon but excluding the second localized to microtubules. These variants—collectively known as Drp1-x01—appeared to directly bind microtubules via two arginine residues encoded by the third alternative exon, forming oligomeric spirals around the cytoskeletal filaments in vivo. Cells expressing Drp1-x01 had elongated mitochondria because this form of the GTPase showed a reduced association with the organelle. Mitochondrial fission is an important step in apoptosis, so these cells were more resistant to the apoptosis-inducing drug staurosporine.

Mitochondria also fragment during mitosis, a process promoted by the phosphorylation of a serine residue near the microtubule-binding domain of Drp1-x01. Strack et al. found that the cyclin-dependent kinase Cdk1 phosphorylated this serine during mitosis to promote Drp-x01’s release from microtubules. Cdk5 performed the same function during interphase.

Microtubule-bound Drp1-x01 therefore forms an inactive pool of the GTPase that can be mobilized to fragment mitochondria when needed. Lead author Stefan Strack now wants to investigate whether the expression of Drp1 splice variants is altered during disease.