Gone fission…: diverse consequences of cardiac Drp1 deficiency

Abstract

Mitochondrial fission and fusion proteins are highly expressed in myocardium. However, mitochondrial fission and fusion are rare, and mitochondrial networks are absent, in adult cardiomyocytes, obviating a need for morphometric mitochondrial remodeling. The critical role of mitochondrial dynamics factors in hearts therefore remains to be determined. In this issue of Circulation Research Ikeda et al describe a central function for the mitochondrial fission protein, Dynamin-related protein 1 (Drp-1), in macroautophagy and mitochondrial autophagy. Together with two other recent reports that cardiac-specific deletion of Drp1 perturbs mitophagy, these findings point to modulation of targeted mitochondrial elimination as a major quality control function for Drp1, and possible other mitochondrial dynamism factors, in the heart.

Keywords: Editorial; autophagy; mitochondria.

Figure 1. Mechanistic paradigm to explain different cardiac Drp1 KO findings

The normal role of Drp1-mediated asymmetric fission is shown in upper right (red background), as envisioned by Twig et al. Impaired/senescent mitochondria undergo asymmetric fission to produce a healthy, fusion competent daughter (green) that is retained, and a depolarized daughter (yellow) that is removed by mitophagy. As described by Ikeda et al, an early consequence of Drp1 deletion is interruption of asymmetric fission, retaining impaired mitochondria that fuse with similarly impaired partners (blue background). With more time after Drp1 deletion, absence of the normal asymmetric fission quality control pathway ultimately produces widespread activation of mitophagy (yellow background), which Song, et al indicate is intact in adult hearts and evokes mitochondrial loss. In neonatal hearts, Kageyama, et al suggest that prototypical Parkin-mediated mitophagy does not play a major role in mitochondrial removal after asymmetric fission. Drp1 deletion in this context stimulates mitophagy that is interrupted before lysosomal incorporation (green background).