A brain-enriched Drp1 isoform associates with lysosomes, late endosomes, and the plasma membrane

Abstract

Dynamin-related protein 1 (Drp1) constricts mitochondria as a mechanochemical GTPase during mitochondrial division. The Drp1 gene contains several alternative exons and produces multiple isoforms through RNA splicing. Here we performed a systematic analysis of Drp1 transcripts in different mouse tissues and identified a previously uncharacterized isoform that is highly enriched in the brain. This Drp1 isoform is termed Drp1 because it contains four alterative exons: A, B, C, and D. Remarkably, Drp1 is located at lysosomes, late endosomes, and the plasma membrane in addition to mitochondria. Furthermore, Drp1 is concentrated at the interorganelle interface between mitochondria and lysosomes/late endosomes. The localizations of Drp1 at lysosomes, late endosomes, and the plasma membrane require two exons, A and B, that are present in the GTPase domain. Drp1 assembles onto these membranes in a manner that is regulated by its oligomerization and GTP hydrolysis. Experiments using lysosomal inhibitors show that the association of Drp1 with lysosomes/late endosomes depends on lysosomal pH but not their protease activities. Thus, Drp1 may connect mitochondria to endosomal-lysosomal pathways in addition to mitochondrial division.

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

“…Recently, mitochondrial-lysosomal contact sites have shown to regulate the rate of mitochondrial fission [84]. Indeed, most fission events are marked by lysosomal-associated membrane protein 1 (LAMP-1)-positive vesicles, but not early endosomes or peroxisomes [14].…”

“…Indeed, most fission events are marked by lysosomal-associated membrane protein 1 (LAMP-1)-positive vesicles, but not early endosomes or peroxisomes [14]. A novel murine isoform of DRP1 containing four alternative exons, Drp1 ABCD , has been identified [84]. DRP1 ABCD is located in late endosomes, the plasma membrane, and in association with LAMP-1-positive vesicles at the interface between mitochondria and lysosomes [84].…”

“…A novel murine isoform of DRP1 containing four alternative exons, Drp1 ABCD , has been identified [84]. DRP1 ABCD is located in late endosomes, the plasma membrane, and in association with LAMP-1-positive vesicles at the interface between mitochondria and lysosomes [84]. DRP1 ABCD localization relies upon acidification of late endosomes and lysosomes, which suggests additional roles for DRP1 isoforms at mitochondrial-lysosomal contact sites [84].…”

“…DRP1 ABCD is located in late endosomes, the plasma membrane, and in association with LAMP-1-positive vesicles at the interface between mitochondria and lysosomes [84]. DRP1 ABCD localization relies upon acidification of late endosomes and lysosomes, which suggests additional roles for DRP1 isoforms at mitochondrial-lysosomal contact sites [84]. In yeast, the equivalent of the mammalian mitochondrial-lysosomal contact site, termed vacuole and mitochondria patch (vCLAMP), contains several tethering proteins, including translocase of outer mitochondrial membrane 40 (TOM40), mitochondrial distribution and morphology 10 (MDM10) complementing protein 1 (MCP1), and vacuole sorting protein (VPS) 13 and 39 [85].…”

Mechanical forces on cellular organelles

“…While the tubular morphology of this organelle has been known for decades (Swanson et al, 1987), we still know little about the biomechanical implications of lysosomal tubulation. Interestingly, an alternatively spliced DRP1 isoform, named DRP1ABCD, has been found on lysosomes, late endosomes and the plasma membrane, in addition to mitochondria (Itoh et al, 2018), certainly opening up new interesting areas of research.…”