Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System

Abstract

Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn 2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating ''bad sectors'' in the mitochondrial network, serving as a mitochondrial quality surveillance system.

Mitochondrial Dynamics Imbalance: A Strategy for Promoting Viral Infection

“…Fusion complements the complete alleles of the two damaged mitochondria to maintain mitochondrial function and the demand for cell biological energy, which is also a key step in the fight against cell aging (Sato et al, 2006;Twig and Shirihai, 2011). Studies have found that before mitochondrion fission, Drp1 interacts with mitochondrial zinc transporter ZIP1 and mediates Zn 2+ to enter mitochondrial inter-membrane space through coupling mitochondrial calcium uniporter (MCU), thus regulating MMP (Min et al, 2019). However, most Parkindependent mitochondrial autophagy is related to MMP loss (Burman et al, 2017).…”

Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis

“…It should also be noted that Drp1 performs many functions in addition to mitochondrial fission. Drp1 can interact with many different proteins localized at different subcellular locations, thereby being involved in many biological processes such as peroxisomal fragmentation, vesicle endocytosis/recycling, MMP changes, and cytoskeletal remodeling 29,62 . Indeed, restoration of Drp1 activity to a normal physiological level in the long-term may be difficult to achieve, meaning that alternative robust and druggable targets for ALS therapy are highly desirable.…”

“…On the other hand, the morphological changes in the mitochondria in ALS pathology may hint at additional links between mitochondria and MN function. The morphological dynamics of mitochondria are homeostatically controlled by the balance between continuous fission and fusion, and this is necessary for the maintenance of mitochondrial quality 28,29 . Mitochondrial dynamics are controlled by large GTPase dynamin-related proteins, including Dynamin-related protein 1 (Drp1), Mitofusin1/2 (MFN1/2), and Optic atrophy 1 (Opa1) 30 .…”

The Application and Analytical Pathway of Dexmedetomidine in Ischemia/Reperfusion Injury

“…Zn 2+ enters the mitochondrial through the Zip1-MCU complex. Once the mitochondria fail to restore MMP, it will undergo division and mitophagy [43]. Bain believed that accumulation of mitochondrial Zn 2+ induced PINK/parkin-mediated mitophagy for dysfunctional mitochondria suffering hypoxia-reoxygenation conditions [44].…”