A syntaxin 10-SNARE complex distinguishes two distinct transport routes from endosomes to the trans-Golgi in human cells

Mannose 6-phosphate receptors (MPRs) are transported from endosomes to the Golgi after delivering lysosomal enzymes to the endocytic pathway. This process requires Rab9 guanosine triphosphatase (GTPase) and the putative tether GCC185. We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport but not for the STX6-dependent transport of TGN46 or cholera toxin from early endosomes to the Golgi. Depletion of STX10 leads to MPR missorting and hypersecretion of hexosaminidase. Mouse and rat cells lack STX10 and, thus, must use a different target membrane SNARE for this process. GCC185 binds directly to STX16 and is competed by Rab6. These data support a model in which the GCC185 tether helps Rab9-bearing transport vesicles deliver their cargo to the trans-Golgi and suggest that Rab GTPases can regulate SNARE–tether interactions. Importantly, our data provide a clear molecular distinction between the transport of MPRs and TGN46 to the trans-Golgi

Outstanding questions in mitophagy:what we do and do not know

The elimination of mitochondria via autophagy, termed mitophagy, is an evolutionarily conserved mechanism for mitochondrial quality control and homeostasis. Mitophagy, therefore, has an important contribution to cell function and integrity, which extends to the whole organism for development and survival. Research in mitophagy has boomed in recent years, and it is becoming clear that mitophagy is a complex and multi-factorial cellular response that depends on tissue, energetic, stress and signaling contexts. However, we know very little of its physiological regulation and the direct contribution of mitophagy to pathologies like neurodegenerative diseases. In this review, we aim to discuss the outstanding questions (and questions outstanding) in the field and reflect on our current understanding of mitophagy, the current challenges and the future directions to take.</p

Life in lights:tracking mitochondrial delivery to lysosomes in vivo

The past decade has seen an intensive and concerted research effort into the molecular regulation of mitophagy, the selective autophagy of mitochondria. Cell-based studies have implicated mitophagy in the pathology of diverse conditions ranging from cancer to neurodegeneration. However, a definitive link between mitophagy and the etiology of human disease remains to be demonstrated. Moreover, we do not know how pervasive mammalian mitophagy is in vivo and fundamental questions remain unanswered. For example, is mitophagy common to all tissues under basal conditions or does it only occur in highly oxidative tissues under stress? This paucity of knowledge is largely due to a lack of experimentally tractable tools that can measure and monitor mitophagy in tissues. Our recent work describes the development of mito-QC, a mouse model to study mitophagy at single cell resolution in vivo