DRP1: At the Crossroads of Dysregulated Mitochondrial Dynamics and Altered Cell Signaling in Cancer Cells.

In the past decade, compelling evidence has accumulated that highlights the role of various subcellular structures in human disease conditions. Dysregulation of these structures greatly impacts cellular function and, thereby, disease conditions. One such organelle extensively studied for its role in several human diseases, especially cancer, is the mitochondrion. DRP1 is a GTPase that is considered the master regulator of mitochondrial fission and thereby also affects the proper functioning of the organelle. Altered signaling pathways are a distinguished characteristic of cancer cells. In this review, we aim to summarize our current understanding of the interesting crosstalk between the mitochondrial structure-function maintained by DRP1 and the signaling pathways that are affected in cancer cells. We highlight the structural aspects of DRP1, its regulation by various modifications, and the association of the protein with various cellular pathways altered in cancer. A better understanding of this association may help in identifying potential pharmacological targets for novel therapies in cancer.

Insights into the role of the conserved GTPase domain residues T62 and S277 in yeast Dnm1.

Mitochondrial division is a highly regulated process. The master regulator of this process is the multi-domain, conserved protein called Dnm1 in yeast. In this study, we systematically analyzed two residues, T62 and S277, reported to be putatively phosphorylated in the GTPase domain of the protein. These residues lie in the G2 and G5 motifs of the GTPase domain. Both residues are important for the function of the protein, as evident from in vivo and in vitro analysis of the non-phosphorylatable and phosphomimetic variants. Dnm1T62A/D and Dnm1S277A/D showed differences with respect to the protein localization and puncta dynamics in vivo, albeit both were non-functional as assessed by mitochondrial morphology and GTPase activity. Overall, the secondary structure of the protein variants was unaltered, but local conformational changes were observed. Interestingly, both Dnm1T62A/D and Dnm1S277A/D exhibited dominant-negative behavior when expressed in cells containing endogenous Dnm1. To our knowledge, we report for the first time a single residue (S277) change that does not alter the localization of Dnm1 but makes it non-functional in a dominant-negative manner. Intriguingly, the two residues analyzed in this study are present in the same domain but exhibit variable effects when mutated to alanine or aspartic acid.

Mitochondrial dynamics and its impact on human health and diseases: inside the DRP1 blackbox.

Mitochondria are essential organelles that play a significant role in various cellular processes apart from providing energy in eukaryotic cells. An intricate link between mitochondrial structure and function is now unequivocally accepted. Several molecular players have been identified, which are important in maintaining the structure of the organelle. Dynamin-related protein 1 (DRP1) is one such conserved protein that is a vital regulator of mitochondrial dynamics. Multidisciplinary studies have helped elucidate the structure of the protein and its mechanism of action in great detail. Mutations in various domains of the protein have been identified that are associated with debilitating conditions in patients. The involvement of the protein in disease conditions such as neurodegeneration, cancer, and cardiovascular disorders is also gaining attention. The purpose of this review is to highlight recent findings on the role of DRP1 in human disease conditions and address its importance as a therapeutic target.