Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons

Abstract

A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.

The strange case of Drp1 in autophagy: Jekyll and Hyde?

“…Although, most of the cargoes are transferred to lysosome, there is accumulation of a specific category of mitophagosome intermediates containing likely ruptured mitochondria lacking matrix protein. [71] A similar conclusion was obtained using Fis1 depletion to induce mitophagy in HeLa cells. This Pink-Parkin-independent mitophagy relies on the accumulation of the SNARE protein Syntaxin-17 (STX17) at the outer mitochondrial membrane.…”

Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia

“…Our observations confirm that VPS13D seems intolerant to complete loss of function of both alleles, being likely incompatible with life. Several studies in Drosophila and yeast have shown a major role of Vps13 in two processes that are essential to mitochondrial health: mitochondrial fission and mitophagy [ 1 – 3 , 7 , 8 ]. Our functional studies in this patient’s fibroblasts confirm that mutation in VPS13D induces defects in mitochondrial network and function.…”

“…VPS13D is a large ubiquitin-binding protein (492 kDa) which belongs to a family of 4 ubiquitously expressed genes encoding highly conserved proteins in eukaryotic cells (VPS13A–D). Recent studies have suggested that Vps13D plays a crucial role in mitochondrial dynamics and is important for mitochondrial integrity [ 1 – 3 ]. Indeed, in Drosophila , Vps13D is required for mitochondrial clearance and is essential in the mitophagy process by regulating mitochondrial fission.…”

“…Indeed, in Drosophila , Vps13D is required for mitochondrial clearance and is essential in the mitophagy process by regulating mitochondrial fission. Moreover, Vps13D depleted neurons display an incomplete mitophagy with an accumulation of mitophagy intermediates [ 3 ]. Depletion of VPS13D in HeLa cells also leads to enlarged and rounded mitochondria [ 2 ].…”

Analysis of Mitochondrial Dynamics in AdultDrosophilaAxons

“…Mitochondria are highly dynamic organelles and undergo constant fission and fusion. The key factors Opa-1, Marf, fzo, and Drp1 were found to be tightly regulated by changes in mitophagy, induction of programmed cell death, reactive oxygen species, transport, and the cytoskeleton (Hales and Fuller 1997;Deng et al 2008;Yang et al 2008;Berman et al 2009;DuBoff et al 2012;Ding et al 2016;Zhang et al 2016;Liao et al 2017;Insolera et al 2021). Fly genetics has given us a new perspective on fundamental mechanisms of mitochondrial regulation in neurons and the dynamic changes they undergo.…”